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Myelodysplastic syndrome (MDS) is a heterogeneous myeloid malignancy characterized by blood cell morphological dysplasia, ineffective clonal hematopoiesis, and risk of transformation to secondary acute myeloid leukemia (sAML). A number of genetic abnormalities have been identified in MDS and sAML, but sensitive sequencing methods can detect these mutations in nearly all healthy individuals by 60 years of age. To discover novel cellular pathways that accelerate MDS and sAML, we performed a CRISPR/Cas9 screen in the human MDS-L cell line. We report here that loss of the F-Box protein FBXO11, a component of the SCF ubiquitin ligase complex, confers cytokine independent growth to MDS-L cells, suggesting a tumor suppressor role for FBXO11 in myeloid malignancies. Putative FBXO11 substrates are enriched for proteins with functions in RNA metabolism and, of note, spliceosome mutations that are commonly found in MDS/sAML are rare in patients with low FBXO11 expression. We also reveal that loss of FBXO11 leads to significant changes in transcriptional pathways influencing leukocyte proliferation, differentiation, and apoptosis. Last, we find that FBXO11 expression is reduced in patients with secondary AML. We conclude that loss of FBXO11 is a mechanism for disease transformation of MDS into AML, and may represent a future therapeutic target.

Pulmonary alveolar microlithiasis (PAM) is an autosomal recessive lung disease caused by a deficiency in the pulmonary epithelial Npt2b sodium-phosphate co-transporter that results in accumulation of phosphate and formation of hydroxyapatite microliths in the alveolar space. The single cell transcriptomic analysis of a PAM lung explant showing a robust osteoclast gene signature in alveolar monocytes and the finding that calcium phosphate microliths contain a rich protein and lipid matrix that includes bone resorbing osteoclast enzymes suggested a role for osteoclast-like cells in the defense against microliths. While investigating the mechanisms of microlith clearance, we found that Npt2b modulates pulmonary phosphate homeostasis through effects on alternative phosphate transporter activity and alveolar osteoprotegerin, and that microliths induce osteoclast formation and activity in a receptor activator of nuclear factor-κB ligand (RANKL) and dietary phosphate dependent manner. This work reveals that Npt2b and pulmonary osteoclast-like cells play key roles in pulmonary homeostasis and suggest potential new therapeutic targets for the treatment of lung disease.

Autism Spectrum Disorders (ASD) are a set of neurodevelopmental conditions characterised by difficulties in social interaction and communication as well as stereotyped and restricted patterns of interest. Autistic traits exist in a continuum across the general population, whilst the extreme end of this distribution is diagnosed as clinical ASD. While many studies have investigated brain structure in autism using a case-control design, few have used a dimensional approach. To add to this growing body of literature, we investigated the structural brain correlates of autistic traits in a mixed sample of adults (N=91) with and without a clinical diagnosis of autism. We examined regional brain volumes (using voxel-based morphometry and surface-based morphometry) and white matter microstructure properties (using Diffusion Tensor Imaging). Our findings show widespread grey matter differences, including in the social brain regions, and some evidence for white matter microstructure differences related to higher autistic traits. These grey matter and white matter microstructure findings from our study are consistent with previous reports and support the brain structural differences in ASD. These findings provide further support for shared aetiology for autistic traits across the diagnostic divide.

Chronic pain continues to present a large burden to the US healthcare system. Neuropathic pain, a common class of chronic pain, remains particularly difficult to treat despite extensive research efforts. Current pharmacologic regimens exert limited efficacy and wide, potentially dangerous side effect profiles. This review provides a comprehensive, preclinical evaluation of the literature regarding the role of flavonoids in the treatment of neuropathic pain. Flavonoids are naturally occurring compounds, found in plants and various dietary sources, which may have potential benefit in neuropathic pain. Numerous animal-model studies have demonstrated this benefit, including reversal of hyperalgesia and allodynia. Flavonoids have also exhibited an anti-inflammatory effect relevant to neuropathic pain, as evidenced by the reduction in multiple pro-inflammatory mediators, such as TNF-α, NF-κB, IL-1β, and IL-6. Flavonoids represent a potentially new treatment modality for neuropathic pain in preclinical models, though human clinical evidence is yet to be explored at this time.

The objective of this systematic review is to present the available evidence for the utilization of the atypical opioids tapentadol, buprenorphine, and levorphanol for the treatment of neuropathic pain. In total, 1619 articles were retrieved of which 10 studies were included. Of 5 included studies pertaining to tapentadol, 4 studies show tapentadol monotherapy to be effective for the treatment of diabetic peripheral neuropathy or chronic, radiating low back pain. Of the 3 studies included for buprenorphine, only one was a randomized controlled trial found not to have a statistically significant reduction in pain with TD buprenorphine likely due to very high withdrawal rates during the trial. Only 2 case reports were included from the available literature for levorphanol providing low-quality anecdotal evidence. The role of tapentadol, buprenorphine, and levorphanol for neuropathic pain conditions requires robust research including randomized controlled trials to evaluate their efficacy and safety.

Highlights • Autistic traits exist along a continuum across the population. • Autistic traits linked to brain structure differences, measured using MRI and DTI. • Gray matter differences noted in regions including OFC and Lingual Gyrus. • White matter differences noted in tracts including ILF, IFOF, SLF., Autism Spectrum Disorders (ASD) are a set of neurodevelopmental conditions characterised by difficulties in social interaction and communication as well as stereotyped and restricted patterns of interest. Autistic traits exist in a continuum across the general population, whilst the extreme end of this distribution is diagnosed as clinical ASD. While many studies have investigated brain structure in autism using a case-control design, few have used a dimensional approach. To add to this growing body of literature, we investigated the structural brain correlates of autistic traits in a mixed sample of adult participants (25 ASD and 66 neurotypicals; age: 18–60 years). We examined the relationship between regional brain volumes (using voxel-based morphometry and surface-based morphometry) and white matter microstructure properties (using Diffusion Tensor Imaging) and autistic traits (using Autism Spectrum Quotient). Our findings show grey matter differences in regions including the orbitofrontal cortex and lingual gyrus, and suggestive evidence for white matter microstructure differences in tracts including the superior longitudinal fasciculus being related to higher autistic traits. These grey matter and white matter microstructure findings from our study are consistent with previous reports and support the brain structural differences in ASD. These findings provide further support for shared aetiology for autistic traits across the diagnostic divide.

Objectives Low-intensity ultrasound (LIU)/low-intensity pulsed ultrasound (LIPUS) may influence nerve tissue regeneration and axonal changes in the context of carpal tunnel syndrome (CTS) and in the animal model. The purpose of this pragmatic review is to understand the current knowledge for the effects of low-intensity therapeutic ultrasound in the animal and human model and determine the future directions of this novel field. Design Pragmatic review. Methods We performed a literature search of available material using OVID, EmBase, and PubMed for LIU/LIPUS, all of which were preclinical trials, case reports, and case series using animal models. For CTS, a literature search was performed on PubMed (1954 to 2019), CENTRAL (the Cochrane Library, 1970 to 2018), Web of Science (1954 to 2019), and SCOPUS (1954 to 2019) to retrieve randomized controlled trials. Results Eight articles were discussed showing the potential effects of LIU on nerve regeneration in the animal model. Each of these trials demonstrated evidence of nerve regeneration in the animal model using LIPUS or LIU. Seven randomized controlled trials were reviewed for ultrasound effects for the treatment of carpal tunnel syndrome, each showing clinical efficacy comparable to other treatment modalities. Conclusions LIU/LIPUS is a promising and noninvasive means of facilitating nerve regeneration in the animal model and in the treatment of carpal tunnel syndrome. Although many of the trials included in this review are preclinical, each demonstrates promising outcomes that could eventually be extrapolated into human studies.

Objectives Cancer-related neuropathic pain (CNP) affects an increasing proportion of cancer patients, given improved survival, but it remains difficult to treat. There are no studies on an extended intravenous ketamine protocol and its synergies with common neuropathy treatments to treat CNP. This study aims to 1) evaluate the safety and effectiveness of an intravenous ketamine protocol to treat refractory CNP and 2) uncover synergies between ketamine and common neuropathy treatments. Methods This is a single-center, retrospective review of 57 patients and 192 infusions, with prospective follow-up on 14 enrolled patients during the coronavirus disease 2019 (COVID-19) pandemic. Results The etiologies of CNP were as follows: 13 from tumor compression, 25 with chemotherapy-induced peripheral neuropathy, 13 from surgery, and 6 from radiation therapy. Overall, 42 of 57 patients (73.7%) were responders, and 71.8% of responders received >3 weeks of pain relief on their last infusion. Analysis of adjuvant treatments revealed that the combination of serotonin-norepinephrine reuptake inhibitors and ketamine resulted in an increase in responders compared with nonresponders (P Conclusion Intravenous ketamine may be a safe and effective adjuvant treatment for CNP, especially with serotonin-norepinephrine reuptake inhibitors. Larger, prospective studies are warranted and should explore parameters to help prognosticate response to ketamine infusions.

The objective of the study is to describe the development and user acceptance testing of a mobile-based application to monitor daily cannabis use of individuals at clinical high-risk for psychosis. Through participatory co-design, app development was staggered in two phases. In Phase 1 (app development), two focus groups were run to gather information on a) app content, and b) graphic design Participants named the application LooseLeaf, which comprised five features: home screen, inventory, daily questions, calculators, and stats. The application monitored daily cannabis consumption, cannabis-related experiences, other substances, and the perception of their day. In Phase 2 (user acceptance testing), a prototype of the application was debugged and tested by developers. Participants used the app for 1 week. Usability was measured with quantitative and qualitative data about the app through the Mobile Application Rating Scale user-version (uMARS). LooseLeaf received a good overall score in the MARS with the highest rating in esthetics, information, and functionality. In conclusion, co-design through focus groups with youth provided effective feedback for developing LooseLeaf, demonstrating initial acceptability and usability.

Reduced social motivation is hypothesised to underlie social behavioural symptoms of Autism Spectrum Disorder (ASD). The extent to which rewarding social stimuli are granted privileged access to awareness in ASD is currently unknown. We use continuous flash suppression to investigate whether individuals with and without ASD show privileged access to awareness for social over nonsocial rewarding scenes that are closely matched for stimulus features. Strong evidence for a privileged access to awareness for rewarding social over nonsocial scenes was observed in neurotypical adults. No such privileged access was seen in ASD individuals, and moderate support for the null model was noted. These results suggest that the purported deficits in social motivation in ASD may extend to early processing mechanisms.

Regenerative modalities have been identified in numerous clinical studies as beneficial in various settings. The focus of this review is to summarize key studies and current concepts for the role of regenerative medicine in the treatment of neuraxial back pain. Recent studies have demonstrated the benefit of regenerative therapies for the treatment of neuraxial back pain. A literature review of clinical trials published between 2015 and 2017 was performed using OVID, PubMed, and Google Scholar to identify investigations attempting to determine the efficacy of various regenerative modalities on two primary sources of low back pain: facet arthropathy and degenerative disc disease. The seven articles analyzed in this systematic review present promising data regarding the use of these autologous biologic treatments, but many of these investigations have several limitations in common including small sample size. Regenerative medicine has been shown to demonstrate efficacy in the treatment of neuraxial back pain. As the field advances, new studies are needed comparing efficacy and safety profiles to better determine best practice techniques and standards in the future.

Background Youth at clinical high risk for psychosis (CHR) often use cannabis, which can have a negative impact on their attenuated psychotic symptoms (APS). Our overall goal is to develop an app that will monitor cannabis use and its impact on APS. Objectives: (1) To describe the development of a mobile-based application named LooseLeaf (LL) to monitor daily cannabis use of individuals at CHR through participatory design; and (2) To test initial usability, discover and fix technical issues, and ensure correct data transmission of LL. Methods Two two-hour focus groups were run with CHR participants, age 12–30. Opinions of participants on (i) application content, (ii) graphic design, and (iii) user experience of the different features (i.e., home screen, inventory, questions, feedback, and calculator) were gathered from the first focus group. Based on the comments from the first focus group, a usable prototype of the application was created and was shown to the second focus group. The second focus group provided further feedback on the user experience of each feature, and finalized the application’s name and logo. The focus groups were audio recorded and transcribed verbatim for analysis. Following Braun and Clarke’s guidelines, data obtained from the focus groups was qualitatively analyzed with thematic analysis to identify patterns in responses. The application was refined accordingly. Then, six healthy controls and two CHR participants used LL for one week to test its effectiveness in monitoring cannabis use. On days that participants used cannabis they answered LL’ questions about how much cannabis they used, how they used, their subjective emotional experience, and what their social and environmental context was during and after using cannabis. When they did not use cannabis, LL asked questions about their subjective emotional experience and how they felt about not using cannabis. LL included a bug-report feature that participants were encouraged to use when they encountered problems. Qualitative data about LL was gathered through the 23-item Mobile Application Rating Scale (MARS) covering questions about engagement, functionality, aesthetics, information provided, and subjective quality of LL. Descriptive statistics were calculated for the quantitative data from MARS. Results Participants favored a minimal and neutral design, buttons with icons, and color-coding of the emotions. Participants named the application “LooseLeaf” and helped to refine its features. The final design of the application consisted of 11 questions about cannabis consumption and feelings associated with it (i.e., euphoria, anxiety, and psychosis-like experiences). Over the one-week usability testing period, LL had an 85.7% response rate. The bug-report feature was used 13 times by seven participants to flag technical issues and provide suggestions to improve user experience of LL. The App received a good overall score on the MARS. LL’s functionality, aesthetics, information, and safety rated high. Few customization options, lack of willingness to pay for applications in general, and technical issues resulted in lower engagement and subjective quality scores. LL’s perceived impact score was good. Discussion The application’s development process was based on the feedback of CHR youth. This provided important information on the design and content needed to build a user-centric mobile application. LL demonstrated initial usability, an effective bug-report feature, and some technical issues and problems with data transmission. The MARS, interviews, and bug-reports provided effective feedback for refining LL for the next phase of development.

Introduction The purpose of our study was to describe a novel technique for reconstruction of orbital defects after maxillectomy using a non-anatomic titanium mesh suspension of orbital contents for both support and volume correction. This construct is then articulated with a layered fibula osteocutaneous free flap that restores orbital rim, zygoma, and maxillary alveolus. We herein present our application of this technique, including refinements over time and long-term outcomes. Methods A retrospective review was performed on 12 patients who underwent reconstruction of Brown class III orbitopalatomaxillary defects with extensive orbital involvement (at minimum complete orbital floor and rim absent) with titanium mesh sling and a layered fibula free flap. Results Primary reconstruction was accomplished in all 12 patients. The mean postoperative length of stay was 8 days (6-14 days). There were no free flap failures or perioperative re-explorations. Patients were routinely extubated on postoperative day #1 and began oral intake by postoperative day #3. At a mean follow-up length of 48 months, unrestricted eye function was accomplished in all patients. Midfacial symmetry was accomplished in 10 of 12 patients; 2 patients had moderate asymmetry due to extirpation of facial musculature and/or soft tissue. Minor revisions were necessary for lower lid ectropion and exposure of the titanium plate. Two patients required adipofascial free flap coverage of exposed intraoral bone after radiation therapy. Conclusions This technique provides excellent restoration of eye position and function and also allows for implant-based prosthetic rehabilitation. It has become our procedure of choice for orbitomaxillary reconstruction.

Humans generally prefer social over nonsocial stimuli from an early age. Reduced preference for social rewards has been observed in individuals with autism spectrum conditions (ASC). This preference has typically been noted in separate tasks that measure orienting toward and engaging with social stimuli. In this experiment, we used two eye-tracking tasks to index both of these aspects of social preference in in 77 typical adults. We used two measures, global effect and preferential looking time. The global effect task measures saccadic deviation toward a social stimulus (related to ‘orienting’), while the preferential looking task records gaze duration bias toward social stimuli (relating to ‘engaging’). Social rewards were found to elicit greater saccadic deviation and greater gaze duration bias, suggesting that they have both greater salience and higher value compared to nonsocial rewards. Trait empathy was positively correlated with the measure of relative value of social rewards, but not with their salience. This study thus elucidates the relationship of empathy with social reward processing.

The acid β-glucosidase (glucocerbrosidase (GCase)) binding sequence to LIMP-2 (lysosomal integral membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome, has been identified. Heterologous expression of deletion constructs, the available GCase crystal structures, and binding and co-localization of identified peptides or mutant GCases were used to identify and characterize a highly conserved 11-amino acid sequence, DSPIIVDITKD, within human GCase. The binding to LIMP-2 is not dependent upon a single amino acid, but the interactions of GCase with LIMP-2 are heavily influenced by Asp399 and the di-isoleucines, Ile402 and Ile403. A single alanine substitution at any of these decreases GCase binding to LIMP-2 and alters its pH-dependent binding as well as diminishing the trafficking of GCase to the lysosome and significantly increasing GCase secretion. Enterovirus 71 also binds to LIMP-2 (also known as SCARB2) on the external surface of the plasma membrane. However, the LIMP-2/SCARB2 binding sequences for enterovirus 71 and GCase are not similar, indicating that LIMP-2/SCARB2 may have multiple or overlapping binding sites with differing specificities. These findings have therapeutic implications for the production of GCase and the distribution of this enzyme that is delivered to various organs.

Objectives/Hypothesis To evaluate the endoscopic surgical management of adult subglottic stenosis and describe treatment outcomes. Study Design Retrospective review. Methods Ten-year review of adult patients with subglottic stenosis. Results Ninety-two adults (23 male, 69 female) with subglottic stenosis underwent 247 endoscopic dilations between 2001 and 2010. The mean age was 48 years at time of first surgery. Etiology was GPA (granulomatosis with polyangiitis, formerly Wegener's granulomatosis) (45%), intubation (25%), or idiopathic (33%). Forty-one patients (45%) underwent a single procedure; 51 patients (55%) required multiple surgeries. The average interval for patients requiring a subsequent procedure was 13.7 months. Variations in surgical technique did not show differences in time to next procedure, and the use of mitomycin-C did not result in longer intervals between procedures. No significant complications were encountered after dilation. Conclusions Subglottic stenosis remains a treatment challenge. Although patients are often symptomatically improved after endoscopic dilation, recurrence rates remain high. Level of Evidence 4. Laryngoscope, 124:736–741, 2014

This review describes a general approach and philosophy in the management of massive facial trauma with extensive tissue loss, with particular highlight on the role of free tissue transfer.

Background Lisdexamfetamine dimesylate (LDX), a prodrug consisting of d-amphetamine and l-lysine, is being studied in clinical trials of major depressive disorder. Additional drug-drug interaction studies were warranted. Objective This study aimed to describe the pharmacokinetics and safety of LDX and venlafaxine extended-release (VXR), alone or combined. Study Design The study was an open-label, two-arm, single-sequence crossover investigation with randomization to treatment sequence. Setting and Participants The study was conducted at two clinical study centres and included healthy adult males and females (18–45 years of age). Intervention The study included two single-sequence crossover designs: LDX alone followed by LDX + VXR (Treatment Arm A); and VXR alone followed by VXR + LDX (Treatment Arm B). Drug treatment was initiated on day 1 with once-daily LDX or VXR alone with 15 days’ titration to final dose (LDX 30, 50 and 70 mg for 5 days each; VXR 75, 150 and 225 mg for 5 days each). On days 16–30, VXR, titrated to a final dose of 225 mg, or LDX, titrated to a final dose of 70 mg, was coadministered for participants in Treatment Arm A or B, respectively. On days 31–38, VXR doses were tapered. Main Outcome Measures On days 1–2, 15–16 and 30–31, safety evaluations and blood samples were obtained pre-dose through 24 h post-dose for analysis of LDX, d-amphetamine, venlafaxine (VEN), and O-desmethylvenlafaxine (ODV). Combination treatment was considered bioequivalent to single treatment if 90 % confidence intervals (CIs) for geometric mean ratios (GMRs) of analytes fell within the interval 0.80–1.25 based on maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from time zero to time of last measurable concentration (AUCτ). Safety assessments included treatment-emergent adverse events (TEAEs), pulse rate and blood pressure (BP), clinical laboratory assessments, and 12-lead electrocardiograms (ECG). Results Among 80 enrolled subjects, 77 were included in pharmacokinetic and safety analyses. Combination LDX + VXR was bioequivalent to LDX alone, based on exposure to d-amphetamine (GMR [95 % CI], Cmax (ng/mL): 0.97 [0.82, 1.14], AUCτ: 0.95 [0.81, 1.12]). Exposure to VEN with LDX + VXR (vs. VXR alone) was increased (Cmax: 1.10 [0.88, 1.38], AUCτ: 1.13 [0.88, 1.45]) and ODV decreased (Cmax: 0.91 [0.77, 1.06], AUCτ: 0.83 [0.71, 0.96]), whereas composite VEN + ODV was bioequivalent to VXR alone (Cmax: 0.96 [0.84, 1.09], AUCτ: 0.98 [0.85, 1.13]). TEAEs with LDX or LDX + VXR were similar. Maximum mean increases from baseline were: pulse rate, +8.73 to 12.76 beats/min with either treatment alone and +17.67 to 20.85 beats/min with LDX + VXR; systolic BP, +4.32 to 6.56 mmHg with either treatment alone and +12.96 to 13.78 mmHg with LDX + VXR; diastolic BP, +5.39 to 5.74 mmHg with either treatment alone and +12.09 to 12.46 mmHg with LDX + VXR. One participant was withdrawn due to a serious TEAE (presyncope). No unexpected, clinically meaningful trends or changes from baseline in mean laboratory or ECG parameters were observed during the trial. Conclusion In healthy adults, combination LDX + VXR (vs. LDX alone) did not alter exposure to d-amphetamine. Although small changes in exposure to VEN (increased) and ODV (decreased) were seen with combination treatment, total VEN + ODV exposure showed no change (vs. VEN alone). LDX + VXR led to increases in BP and pulse rate, supporting existing recommendations for vital sign monitoring when using these medications.

Many medical professionals use smartphone applications (apps) on a daily basis to support clinical decision making. Opioid switching (conversion of one opioid to another at equianalgesic dose) is common in clinical practice and often challenging for doctors. Apps providing an opioid conversion tool can therefore be a useful resource. Despite rapid growth in the use of medical apps, the lack of robust regulation and peer review to ensure the accuracy and reliability of app content is currently an area of concern. We searched major online app stores for apps providing an opioid dose conversion tool. We assessed output variability between apps in the dose calculation of seven opioid switches, as well as assessing the level of professional medical involvement in the authorship, creation and design of the apps. Of 23 different apps identified, more than half (n = 12; 52 %) had no stated medical professional involvement and only 11 (48 %) apps provided direct references to primary sources for their opioid conversion ratios. Conversion of 1 mg of oral morphine to oral codeine demonstrated the largest conversion output range (median 6.67 mg, range 3.333–12 mg). Conversion of 1 mg of oral morphine to methadone ranged from 0.05–0.67 mg, with only 44 % of methadone-converting apps (n = 4) commenting that the conversion ratio changes with magnitude of methadone dose. Overall, 35 % of apps (n = 8) did not warn the user about the standard practice of dose reduction when opioid switching. There was a statistically significant difference in the mean conversion output for hydromorphone (oral) between apps with and without medical professional involvement (0.2256 vs 0.2536; p = 0.0377). There are significant concerns with regard to the reliability of information provided by apps offering opioid dose conversion, with lack of information regarding evidence-based content and peer review in many cases. It is crucial that better regulation of medical apps is instigated in order to ensure that patient safety is maintained.

Objectives/Hypothesis: The use of topical drug delivery through nasal irrigations can minimize systemic side effects and deliver higher concentrations of drugs directly to diseased sinus mucosa. Complications related to this popular method of treatment are not well described. We present our experience with paranasal sinus exostosis (PSE), a new diagnostic entity that appears to be a complication of cold nasal irrigations. Study Design: Retrospective chart review. Methods: Retrospective chart reviews were performed on patients within the Cleveland Clinic Foundation from 2005 to 2011. Six patients were identified with sinus exostoses. A literature review for “sinonasal exostoses” and “paranasal sinus exostoses” was performed using PubMed. Results: Six patients with PSE were identified at the Cleveland Clinic Foundation between 2005 and 2011. All patients had undergone sinus surgery, and none had documented evidence of PSE prior to surgery. There was no evidence of worsening PSE once the cold irrigations were stopped. No patients showed any resolution of PSE over time. None of our patients has progressed to have disease burden significant enough to require intervention. Conclusions: PSE is a rare condition that mirrors a well-described otologic process; exostoses of the external auditory canal. PSE appears to be a complication of cold nasal irrigations. It does not resolve with the halting of cold irrigations, but does not appear to progress further after intervention. PSE only affects postoperative patients. With the evolving trend to treat postoperative sinus disease topically, the clinician should be aware of the dangers of cold irrigations, and patients should be counseled accordingly.

Cardiolipin (CL) is a mitochondrial phospholipid essential for electron transport chain (ETC) integrity. CL-deficiency in humans is caused by mutations in the tafazzin (Taz) gene and results in a multisystem pediatric disorder, Barth syndrome (BTHS). It has been reported that tafazzin deficiency destabilizes mitochondrial respiratory chain complexes and affects supercomplex assembly. The aim of this study was to investigate the impact of Taz-knockdown on the mitochondrial proteomic landscape and metabolic processes, such as stability of respiratory chain supercomplexes and their interactions with fatty acid oxidation enzymes in cardiac muscle. Proteomic analysis demonstrated reduction of several polypeptides of the mitochondrial respiratory chain, including Rieske and cytochrome c1 subunits of complex III, NADH dehydrogenase alpha subunit 5 of complex I and the catalytic core-forming subunit of F0F1-ATP synthase. Taz gene knockdown resulted in upregulation of enzymes of folate and amino acid metabolic pathways in heart mitochondria, demonstrating that Taz-deficiency causes substantive metabolic remodeling in cardiac muscle. Mitochondrial respiratory chain supercomplexes are destabilized in CL-depleted mitochondria from Taz knockdown hearts resulting in disruption of the interactions between ETC and the fatty acid oxidation enzymes, very long-chain acyl-CoA dehydrogenase and long-chain 3-hydroxyacyl-CoA dehydrogenase, potentially affecting the metabolic channeling of reducing equivalents between these two metabolic pathways. Mitochondria-bound myoglobin was significantly reduced in Taz-knockdown hearts, potentially disrupting intracellular oxygen delivery to the oxidative phosphorylation system. Our results identify the critical pathways affected by the Taz-deficiency in mitochondria and establish a future framework for development of therapeutic options for BTHS.

Idiopathic nephrotic syndrome (NS) is the most common glomerular disorder of childhood. Response to initial treatment with corticosteroids is an indicator of prognosis, as resistant patients often present more progressive disease. In this cross-sectional pilot study, we set out to discover a panel of noninvasive biomarkers that could distinguish steroid-resistant nephrotic syndrome (SRNS) from steroid-sensitive nephrotic syndrome (SSNS). Information gleaned from such a panel could yield more individualized treatment plans and prevent unnecessary steroid exposure in patients unlikely to respond. Urine was collected from 50 pediatric patients diagnosed with idiopathic NS at Cincinnati Children’s Hospital Medical Center. Isobaric tags for relative and absolute quantitation (iTRAQ) was used to discover 13 proteins that were differentially expressed in SSNS vs SRNS in a small 5 × 5 discovery cohort. Suitable assays were found for 9 of the 13 markers identified by iTRAQ and were used in a 25 SRNS × 25 SSNS validation cohort. Vitamin D–binding protein (VDBP), alpha-1 acid glycoprotein 1 (AGP1), alpha-1 acid glycoprotein 2 (AGP2), alpha-1-B glycoprotein (A1BG), fetuin-A, prealbumin, thyroxine-binding globulin and hemopexin, and alpha-2 macroglobulin were measured and combined with urine neutrophil gelatinase–associated lipocalin (NGAL), which had been previously shown to distinguish patients with SRNS. Urinary VDBP, prealbumin, NGAL, fetuin-A, and AGP2 were found to be significantly elevated in SRNS using univariate analysis, with area under the receiver operating characteristic curves (AUCs) ranging from 0.65 to 0.81. Multivariate analysis revealed a panel of all 10 markers that yielded an AUC of 0.92 for identification of SRNS. A subset of 5 markers (including VDBP, NGAL, fetuin-A, prealbumin, and AGP2) showed significant associations with SRNS and yielded an AUC of 0.85.

Many patients who undergo general anesthesia and surgery experience cognitive dysfunction, particularly memory deficits that can persist for days to months. The mechanisms underlying this postoperative cognitive dysfunction in the adult brain remain poorly understood. Depression of brain function during anesthesia is attributed primarily to increased activity of γ-aminobutyric acid type A receptors (GABA(A)Rs), and it is assumed that once the anesthetic drug is eliminated, the activity of GABA(A)Rs rapidly returns to baseline and these receptors no longer impair memory. Here, using a murine model, we found that a single in vivo treatment with the injectable anesthetic etomidate increased a tonic inhibitory current generated by α5 subunit-containing GABA(A)Rs (α5GABA(A)Rs) and cell-surface expression of α5GABA(A)Rs for at least 1 week. The sustained increase in α5GABA(A)R activity impaired memory performance and synaptic plasticity in the hippocampus. Inhibition of α5GABA(A)Rs completely reversed the memory deficits after anesthesia. Similarly, the inhaled anesthetic isoflurane triggered a persistent increase in tonic current and cell-surface expression of α5GABA(A)Rs. Thus, α5GABA(A)R function does not return to baseline after the anesthetic is eliminated, suggesting a mechanism to account for persistent memory deficits after general anesthesia.

Objectives This study is a review of our series of pediatric patients with unilateral sensorineural hearing loss (USNHL) to report abnormalities on imaging studies, review genetic and ophthalmologic results, and survey audiometric findings. Methods This study is a retrospective chart review of all pediatric patients with USNHL seen between 1/1/03 and 12/31/08 at our institution. The study was approved by the institutional review board. Results Eighty-nine cases were identified with audiometric findings confirming unilateral hearing thresholds greater than 20 dBHL with no conductive component. There were 48 males and 41 females. Average age of diagnosis was 7 years. One audiogram showed low-frequency loss, 17 mid-frequency, 29 high-frequency, and 32 flat. Ten patients were diagnosed by auditory brainstem response testing at another institution, with thresholds not available for review. Eleven percent of patients progressed to bilateral loss. Sixty-one patients underwent computed tomography of temporal bones (CTTB). Twenty of 61 scans identified 34 anomalies including 15 enlarged vestibular aqueducts (EVAs), 8 Mondini, and 3 superior semicircular canal dehiscences (SSCDs). Thirty-one of 89 patients underwent magnetic resonance imaging (MRI). Three of these 31 patients had positive findings including 1 EVA, 1 Mondini, and 1 asymmetric internal auditory canal. When CTTB was positive, no additional lesions were detected on MRI. When CTTB was negative and MRI was done in 20 patients, 2 additional lesions were detected by MRI. Fourteen patients had genetics evaluation of which 6 had positive findings, including CHARGE, VACTERL, Goldenhar, and 3 were heterozygous for a Connexin mutation. Conclusions CTTB is an effective diagnostic tool for USNHL. MRI should be considered in patients with negative CTTB. Genetics and ophthalmologic evaluations are recommended for patients with risk factors or an abnormal clinical examination. Close follow-up is essential due to high rate of hearing loss progression.

Patients with symptomatic cerebrovascular disease suffer a high mortality from myocardial ischemia, which may occur during rest or following the conclusion of exercise. In a pilot study, we screened 11 patients with transient cerebral ischemic attack or stroke for silent myocardial ischemia using bicycle ergometer stress testing with electrocardiographic (EKG) monitoring and ambulatory left ventricular function monitoring (VEST). Three of 11 patients had nondiagnostic exercise EKGs due to failure to achieve their target heart rates during exercise but had positive VEST tests during and after exercise. One patient was falsely positive. VEST may be useful in combination with stress EKG for the detection of silent myocardial ischemia in cerebrovascular patients, but further assessment of the sensitivity and specificity in this patient population needs to be accomplished.

We come together as an educator (L.M.R.) and undergraduate university student (S.J.H.) to emphasize the importance of first person accounts of mental illness in education and research. Undergraduate and graduate students often lack knowledge about severe mental illness partly because education concerning severe mental illnesses is not a compulsory component of primary or secondary school health education curriculums, and media portrayal of severe mental illness is often inaccurate and biased to serve a dramatic purpose. Many students acquire advanced degrees in fields directly related to brain-behavior disorders with little firsthand experience of those afflicted. Coursework in psychology and neuroscience frequently presents theories and models of mental illness without the personal dimension. A major challenge is to provide the student with insight into how severe mental illness is experienced by the person. An appreciation of the effects of illness on a person may humanize the condition, foster empathy and compassion, reduce stigma, and provide hope. Direct discussions with people who experience severe mental illness are ideal but often not feasible for the classroom and lecture hall environments. First person accounts are a shortcut to the direct experience and an important tool that helps address this challenge. First person accounts help take severe mental illness out of the theoretical domain and place it in the context of those affected. First person accounts are useful beyond the description of symptoms listed in textbooks and vividly illustrate how someone’s life has been changed. This requires some degree of imagination, but first person accounts can diminish the burden by providing a direct, factual example of what someone with severe mental illness experiences. One striking example for me (S.J.H.) came from a 31-year-old graduate student with onset of delusions that rapidly progressed to full blown psychosis. She describes her condition as “a disease of information.”1 She recalled how, “without warning my life became suffused with meaning like light.” She would interpret many random patterns or situations as secret messages directed at her; a movie poster or the way a leaf fell acted as a “courier of meaning.”1 The author recalls being disoriented and frightened during this confusing time, which is clearly presented by her detailed, intense descriptions. I (S.J.H.) gained a better appreciation for what it is like to experience delusional thought from this first person account. This story struck me (S.J.H.) as poignant and meaningful. First person accounts are especially important so that one can empathize with and gain a better understanding of the experiences of those with severe mental illness. Another remarkable account illustrated to me (S.J.H.) how schizophrenia impacted a promising life. A young man was in the midst of his graduate work when he experienced his first psychotic episode. His relationships slowly deteriorated. He lost his girlfriend, his immediate family, and friends and he became homeless for 10 years.2 This first person account provides an important example of a person with severe mental illness who became marginal in society, a concept often underappreciated by students with limited mental health education. But, this first person account also touches on improvement (eg, “my life has been improving a little each year”) and fosters hope, which is also important discussion point for students. Other lessons that I (S.J.H.) have gleaned from first person accounts relate to the uninformed impressions that I had developed about someone with schizophrenia. The heterogeneity of severe mental illness is dramatic and eye opening, characterized by accounts that differ substantially in symptomatology and personal narrative. Similarly, the functional outcomes associated with different lives also differed greatly. Some achieve an effective and successful lifestyle, while others struggle daily for years after their first psychotic episodes. The first person accounts reveal stories ranging from constant struggle to hope and recovery. Another striking contrast between different accounts is how the authors view their illness. Some despise it and others are comforted by it. First person accounts have important limitations. Some argue that they reduce people to “curiosities” and others argue that they only represent a minority of persons with severe mental illness. It is important to note that the individuals with severe disorganization and/or very low motivation are not likely to prepare first person account for publication. Educators need to enforce the appreciation that these accounts are individual, unique, and subjective; they do not generalize precisely to others with severe mental illness. The diversity in accounts represents the heterogeneity of severe mental illness, which is a key point in mental health education. Schizophrenia Bulletin’s first person accounts are an accessible (free online at http://schizophreniabulletin.oxfordjournals.org/ after 1 year in press) and widely available educational resource to students, clinical and nonclinical researchers, family members trying to better understand a relative with severe mental illness, and the general public. First person accounts continue to be vital in our own ongoing education as student (S.J.H.) and educator/researcher (L.M.R.).

Dopexamine hydrochloride is a new synthetic catechol that offers a unique profile of adrenergic and dopaminergic activity. In this multicenter, parallel design, placebo-controlled study, 45 patients with functional class III or IV chronic congestive heart failure were randomized to receive a placebo infusion or one of three different doses of dopexamine. After a 2-h dose titration sequence, patients received a 6-h constant dose infusion. During this 6-h period, dopexamine was infused at rates of 1, 2 and 4 micrograms/kg body weight per min in the low, intermediate and high dose groups, respectively. In patients receiving high dose infusion, dopexamine produced a 78% increase in cardiac index associated with a 43% decrease in systemic vascular resistance and 24% increase in heart rate (p less than 0.05 vs. placebo for all three variables). There was a trend (p = NS) toward a moderate increase in cardiac index at low and intermediate doses. In patients randomized to receive dopexamine, right atrial, systemic arterial, pulmonary artery and pulmonary capillary wedge pressures showed minimal change from baseline and did not differ statistically from the placebo response. Very few patients developed adverse reactions related to dopexamine, although five patients randomized to receive high dose and three patients randomized to receive intermediate dose dopexamine required dose reduction because hemodynamic variables exceeded arbitrary safety limits or the patients developed symptoms related to the study medication. dopexamine in higher doses effectively increases cardiac index in association with a reduction in systemic vascular resistance. Additional clinical studies are indicated to evaluate the merits of dopexamine in comparison with other inotropic and vasodilator medications.

OBJECTIVE: To report an unusual reaction associated with weekly administration of paclitaxel. CASE SUMMARIES: Onycholysis was seen in four women with recurrent ovarian cancer being treated with low-dose, weekly paclitaxel. Two of the patients had previously received higher doses of paclitaxel on an every-three-week schedule without similar reactions. Onycholysis developed between weeks 10–13 of treatment in three of the patients. In the fourth patient, it developed shortly after initiation of weekly paclitaxel. None of the reactions required dose adjustments or discontinuation of therapy. Direct toxicity to the nail bed or inhibition of angiogenesis are possible mechanisms for this reaction. DISCUSSION: Onycholysis, separation of the nail from the nail bed, is an infrequent adverse effect of drug therapy. Antineoplastic drugs have previously been reported to cause onycholysis, pigmentation, bands, thickening or thinning of the nail bed, and nail shedding. Nail changes with the taxanes, primarily docetaxel, are reported in up to 30–40% of patients. Paclitaxel is not commonly associated with dermatologic reactions, although localized skin reactions and tissue necrosis have been reported. Nail changes, pigmentation or discoloration of the nail bed, occur in 2% of patients receiving paclitaxel. CONCLUSIONS: Onycholysis is an uncommon reaction that may occur in some patients receiving weekly, low-dose paclitaxel therapy. The reaction is not life-threatening and does not warrant discontinuation of therapy. However, clinicians should be aware of the possibility of this effect and be prepared to advise patients who develop signs of nail changes.

AIMS To compare the efficacy and safety of lanoteplase, a single-bolus thrombolytic drug derived from alteplase tissue plasminogen activator, with the established accelerated alteplase regimen in patients presenting within 6 h of onset of ST elevation acute myocardial infarction. METHODS AND RESULTS 15,078 patients were recruited from 855 hospitals worldwide and randomized in a 2:1 ratio to receive either lanoteplase 120 KU. kg(-1)as a single intravenous bolus, or up to 100 mg accelerated alteplase given over 90 min. The primary end-point was all-cause mortality at 30 days and the hypothesis was that the two treatments would be equivalent. By 30 days, 6.61% of alteplase-treated patients and 6.75% lanoteplase-treated patients had died (relative risk 1.02). Total stroke occurred in 1.53% alteplase- and 1.87% lanoteplase-treated patients (ns); haemorrhagic stroke rates were 0.64% alteplase and 1.12% lanoteplase (P=0.004). The net clinical deficit of 30-day death or non-fatal disabling stroke was 7.0% and 7.2%, respectively. By 6 months, 8.8% of alteplase-treated patients and 8.7% of lanoteplase-treated patients had died. CONCLUSION Single-bolus weight-adjusted lanoteplase is an effective thrombolytic agent, equivalent to alteplase in terms of its impact on survival and with a comparable risk-benefit profile. The single-bolus regimen should shorten symptoms to treatment times and be especially convenient for emergency department or out-of-hospital administration.

A 57-year-old male presented to the endocrinology service with a 2 month history of weight loss of 10 kg, sweatiness, confusion and disturbed sleep. He was hypertensive and tachycardic. Investigations for phaeochromocytoma were initiated. He developed pneumonia and respiratory failure requiring admission to an intensive treatment unit. A neurology opinion was sought following agitation and confusion. Marked muscle wasting with apparent fasciculation was obvious. ALS was considered. EEG suggested moderate to severe encephalopathy. Brain MRI had high signal in the basal ganglia. Electromyography showed doublets, triplets and multiplets. Serum had voltage-gated potassium (VGK)-channel antibodies. CT chest, abdomen and pelvis revealed no malignancy. Marked clinical improvement and a parallel fall in VGK-channel antibody titre followed treatment with steroids and plasmaphaeresis. Six months later, recovery was maintained. First described in 1890, the classical presentation of Morvan9s syndrome—hyperhidrosis, neuromyotonia and encephalopathy is extremely rare. It is of historical importance in prompting the recognition of potentially reversible VGK-channel antibody-related encephalopathies, and has been associated with thymoma, small cell lung cancer and prostate cancer. This case illustrates the potential to mimic motor neurone disease and the importance of the neurophysiologist in the electrophysiological characterisation of apparent fasciculations.

Everyday in the United States persons who are functioning effectively in activities that meet their daily living needs and role responsibilities are rendered incapable by events such as traumatic brain injury (TBI), stroke, and other neurological disorders. As medical technology and emergency medical systems have become increasingly effective at reducing the mortality associated with neurological disease and trauma, there has been a concomitant rise in morbidity. Physiologic existence is perpetuated, yet many survivors are left permanently disabled. The quality of their lives is a function of the degree to which they can resume everyday life and role-related activities.

Survivors of traumatic brain injury (TBI) often exhibit aggressive behaviors that can frighten, alienate, intimidate, or place stress upon their caregivers, treatment personnel, and family members. Such aggression presents a formidable barrier to the TBI survivor’s resumption of preinjury activities, roles, and status. The challenge to rehabilitation professionals and families is to discover ways of interacting with these TBI survivors that will promote learning of the prosocial behaviors necessary to support community resettlement.

The short-term effects of omega-3 fatty acids on exercise test parameters in patients with known coronary artery disease are poorly defined. Therefore, we administered a preparation containing 5.4 g of eicosapentaenoic acid and 3.6 g docosahexaenoic acid to 8 patients in a random order, double-blind, crossover design. The patients were given either fish oil or a vegetable oil control for 6 wk and then crossed over to the other treatment for a second 6-wk period, after a 2-wk wash-out interval. Exercise test parameters, angina frequency, and lipoprotein composition were measured at baseline and at the end of each trial phase. No significant changes were found in resting or peak exercise heart rate or double product, exercise duration or ischemic electrocardiographic changes at peak exercise. Angina frequency and sublingual nitroglycerin usage did not change during either the fish oil or the control oil phase. Plasma triglyceride levels decreased significantly with fish oil treatment and HDL cholesterol levels rose slightly. Total and LDL cholesterol levels were unchanged. We conclude that relatively high dose, short-term administration of omega-3 fatty acids does not alter exercise test parameters.

It has become axiomatic that cognitive and psychosocial deficits severely retard recovery from traumatic brain injury. Jennett’s (1975) review of the management of traumatically head-injured patients reported persistent cognitive losses as the main contribution to social disability. He also cited the apparent failure to recognize the extent of family disruption resulting from a trauma to one of its members. Lundholm, Jepsen, and Thornvak (1975) reported that in 80% of patients followed 8 to 14 years posttrauma, social rehabilitation was impeded by reductions in mental capacity. Oddy, Humphrey, and Uttley (1978) found that the two most common stresses experienced by families 6 and 12 months posttrauma concerned the trauma patient’s current and future deficits. Their findings suggested that families desired “more details regarding the extent and nature of the brain damage” (p. 511). They also stated that the families complained about the lack of continued psychological counseling “other than through the usual psychiatric channels which they regarded as inappropriate” (p. 511). Our clinical experience is consistent with these findings.