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Background: Anterior cruciate ligament (ACL) injury is a well-known risk factor for the development of posttraumatic osteoarthritis (PTOA). However, whether using continuous passive motion (CPM) with or without additional treadmill exercise (TRE) in early ACL injury might provide chondroprotective effects and further decrease the risk of PTOA has yet to be determined., Hypothesis: CPM may offer an enhanced chondroprotective effect, but TRE may attenuate that effect due to the mechanical stress on the joint and inflammatory cytokines in the joint., Study Design: Controlled laboratory study., Methods: Thirty adult New Zealand White male rabbits were randomly allocated to sedentary (SED), CPM, TRE, or CPM+TRE groups. Each rabbit underwent an ACL transection (ACLT) on the right knee, with the contralateral knee used as an internal control (sham). The 4 joint surfaces (ie, medial and lateral femoral condyles and tibial plateaus) were evaluated 4 weeks after surgery for gross appearance, histological characteristics, and quantitative osteoarthritis (OA) scores., Results: Overall, at the end of testing, the CPM group experienced the best protective therapeutic effects in all compartments. In gross appearance, CPM resulted in normal articular surfaces, while the TRE and SED groups exhibited surface abrasion. Histological analysis showed significant differences in articular cartilage status. The CPM group had significantly better histological OA scores ( P < .01), corresponding to the smoothest cartilage surface and sound chondrocyte and collagen arrangement. This group also showed abundant glycosaminoglycan (GAG) content and a sound growth microenvironment, with significantly lower expression levels of the inflammatory cytokine tumor necrosis factor α and the apoptotic marker caspase 3. In contrast, the TRE and SED groups showed several features of damage: distinct graded cartilage abrasion; damaged collagen fibers, corresponding to noticeable collagen type X (osteoarthritic cartilage); reduced cartilage thickness; fewer cartilaginous cells; and the appearance of chondrocyte clusters. These groups also showed loss of GAG, corresponding to higher levels of inflammatory cytokines and apoptosis of articular chondrocytes. Furthermore, the CPM+TRE group displayed visible pathological changes in the superficial cartilage, indicating that early loading exercise may contribute to osteoarthritis. The sham treatment showed no difference in the changes in all compartments between groups., Conclusion: Immediate CPM therapy produces a superior in situ microenvironment for reducing the occurrence of PTOA after ACL injury without reconstruction in rabbits., Clinical Relevance: These data suggest that immediate application of CPM therapy may be necessary to create a sound microenvironment in joints and possibly to decrease the risk of PTOA without or while awaiting ACL reconstruction. In contrast, both early active loading exercise and inactivity lead to the development of PTOA.

Background: The purpose of this study was to characterize seizures among preterm neonates enrolled in the Neonatal Seizure Registry, a prospective cohort of consecutive neonates with seizures at seven pediatric centers that follow the American Clinical Neurophysiology Society's neonatal electroencephalography monitoring guideline., Study Design: Of 611 enrolled neonates with seizures, 92 (15%) were born preterm. Seizure characteristics were evaluated by gestational age at birth for extremely preterm (<28 weeks, N = 18), very preterm (28 to <32 weeks, N = 18), and moderate to late preterm (32 to <37 weeks, N = 56) and compared with term neonates., Results: Hypoxic-ischemic encephalopathy (33%) and intracranial hemorrhage (27%) accounted for the etiology in more than half of preterm neonates. Hypothermia therapy was utilized in 15 moderate to late preterm subjects with encephalopathy. The presence of subclinical seizures, monotherapy treatment failure, and distribution of seizure burden (including status epilepticus) was similar in preterm and term neonates. However, exclusively subclinical seizures occurred more often in preterm than term neonates (24% vs 14%). Phenobarbital was the most common initial medication for all gestational age groups, and failure to respond to an initial loading dose was 63% in both preterm and term neonates. Mortality was similar among the three preterm gestational age groups; however, preterm mortality was more than twice that of term infants (35% vs 15%)., Conclusions: Subclinical seizures were more common and mortality was higher for preterm than term neonates. These data underscore the importance of electroencephalographic monitoring and the potential for improved management in preterm neonates., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Clinicians have qualitatively described rhythmic delta activity as a prominent EEG abnormality in individuals with Angelman syndrome, but this phenotype has yet to be rigorously quantified in the clinical population or validated in a preclinical model. Here, we sought to quantitatively measure delta rhythmicity and evaluate its fidelity as a biomarker., Methods: We quantified delta oscillations in mouse and human using parallel spectral analysis methods and measured regional, state-specific, and developmental changes in delta rhythms in a patient population., Results: Delta power was broadly increased and more dynamic in both the Angelman syndrome mouse model, relative to wild-type littermates, and in children with Angelman syndrome, relative to age-matched neurotypical controls. Enhanced delta oscillations in children with Angelman syndrome were present during wakefulness and sleep, were generalized across the neocortex, and were more pronounced at earlier ages., Conclusions: Delta rhythmicity phenotypes can serve as reliable biomarkers for Angelman syndrome in both preclinical and clinical settings.

We report on a technique that can extend the use of nanowire sensors to the detection of interactions involving nonpolar and neutral molecules in an ionic solution environment. This technique makes use of the fact that molecular interactions result in a change in the permittivity of the molecules involved. For the interactions taking place at the surface of nanowires, this permittivity change can be determined from the analysis of the measured complex impedance of the nanowire. To demonstrate this technique, histidine was detected using different charge polarities controlled by the pH value of the solution. This included the detection of electrically neutral histidine at a sensitivity of 1 pM. Furthermore, it is shown that nonpolar molecules, such as hexane, can also be detected. The technique is applicable to the use of nanowires with and without a surface-insulating oxide. We show that information about the changes in amplitude and the phase of the complex impedance reveals the fundamental characteristics of the molecular interactions, including the molecular field and the permittivity.

Knee instability resulting from anterior cruciate ligament (ACL) rupture is a high-risk factor for posttraumatic osteoarthritis (PTOA) in the patellofemoral joint (PFJ). However, whether non-weight-bearing and weight-bearing treatments have chondroprotective effects remains unclear. Twenty-four adult New Zealand White male rabbits were employed in this study. All animals received ACL transection in the right knee and sham surgery in the left knee. The rabbits were randomly assigned to the following groups: (I) In the sedentary (SED) group, the rabbits ( n = 6) were simply kept in their cage; (II) In the continuous passive motion (CPM) group, the rabbits ( n = 6) performed CPM exercise for 7 days, starting from the first postoperative day; (III) In the active treadmill exercise (TRE) group, the rabbits ( n = 6) performed TRE for 2 weeks; (IV) In the CPM + TRE group, the rabbits ( n = 6) executed CPM exercise, followed by TRE. Two joint surfaces (the retropatella and femoral trochlear groove) were assessed at 4 weeks after operation. Although the gross appearance in each group was comparable, histological examination revealed significant differences in the articular cartilage status. The CPM group exhibited a greater thickness of articular cartilage, maintenance of tidemark continuity, abundant glycosaminoglycan (GAG), and significantly lower inflammatory cytokine 9, e.g., tumor necrosis factor-alpha (TNF-α) 0 levels, with modest cell apoptosis (i.e., caspase-3). By contrast, the TRE group displayed the worst pathological features: an irregular cartilage surface and chondrocyte disorganization, reduced cartilage thickness, breakdown of the tidemark, depletion of collagen fibers, loss of GAG, and the highest levels of TNF-α and caspase-3 expression. Furthermore, the CPM + TRE group had more favorable outcomes than the SED group, indicating that suitable exercise is needed. The sham treatment displayed no variance in the changes in the two joint surfaces among groups. These data indicate that the application of early CPM rehabilitation is suggested for subjects in order to decrease the risk of PTOA without ACL reconstruction in the PFJ compartment in rabbits. The early TRE program, however, had harmful outcomes. Additionally, inactivity was discovered to initiate the development of PTOA.

Background: Platelet count (PC) and fatty liver are both associated with metabolic syndrome (MS), obesity, and type 2 diabetes. While PC increases in obesity and type 2 diabetes, the severity of hepatic fibrosis caused by fatty liver reduces PC. We aimed to investigate the correlation of PC and MS in patients with and without fatty liver., Methods: We enrolled consecutive patients who received health check-ups at Taipei Veterans General Hospital from 2002 to 2009. Ultrasonography was used to diagnose fatty liver, and MS was diagnosed according to the criteria defined by the International Diabetes Federation Task Force on Epidemiology and Prevention., Results: Among the 29,797 patients, MS was present in 28.74%. Higher PC was correlated with MS using multivariate analysis, while fatty liver had the strongest association with MS. After dividing the patients by the presence or absence of fatty liver, higher PC was still associated with MS in both groups. The patients were further stratified by age and gender, and MS was correlated with PC among all age groups in women and in men under 60 years of age; however, the association between PC and MS did not reach statistical difference in men older than 60 years., Conclusion: There is a significant correlation between PC and MS, and the correlation exists independent of gender, age, and fatty liver. PC may act as a surrogate marker for MS, and physicians should be concerned with the presence of MS among patients with high PC., (Copyright © 2016. Published by Elsevier Taiwan LLC.)

We aimed to define determinants of duration of treatment for acute symptomatic neonatal seizures in a contemporary multicenter observational cohort study. After adjustment for potential confounders, only study site and seizure etiology remained significantly associated with the chance of continuing antiseizure medication after discharge to home., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: High frequency oscillations are emerging as a clinically important indicator of epileptic networks. However, manual detection of these high frequency oscillations is difficult, time consuming, and subjective, especially in the scalp EEG, thus hindering further clinical exploration and application. Semi-automated detection methods augment manual detection by reducing inspection to a subset of time intervals. We propose a new method to detect high frequency oscillations that co-occur with interictal epileptiform discharges., New Method: The new method proceeds in two steps. The first step identifies candidate time intervals during which high frequency activity is increased. The second step computes a set of seven features for each candidate interval. These features require that the candidate event contain a high frequency oscillation approximately sinusoidal in shape, with at least three cycles, that co-occurs with a large amplitude discharge. Candidate events that satisfy these features are stored for validation through visual analysis., Results: We evaluate the detector performance in simulation and on ten examples of scalp EEG data, and show that the proposed method successfully detects spike-ripple events, with high positive predictive value, low false positive rate, and high intra-rater reliability., Comparison With Existing Method: The proposed method is less sensitive than the existing method of visual inspection, but much faster and much more reliable., Conclusions: Accurate and rapid detection of high frequency activity increases the clinical viability of this rhythmic biomarker of epilepsy. The proposed spike-ripple detector rapidly identifies candidate spike-ripple events, thus making clinical analysis of prolonged, multielectrode scalp EEG recordings tractable., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background & Aims: Hepatic encephalopathy (HE) is a serious complication of cirrhosis and is associated with gut dysbiosis. Proton pump inhibitors (PPIs), frequently prescribed to patients with cirrhosis, can contribute to small-bowel bacterial overgrowth. We investigated whether PPI predisposes patients with cirrhosis to HE using a large database of patients., Methods: We performed a case-control study nested within a sample of Taiwan National Health Insurance beneficiaries (n = 1,000,000), followed up longitudinally from 1998 through 2011. Patients with cirrhosis and an occurrence of HE (n = 1166) were selected as the case cohort and matched to patients without HE (1:1, controls) for sex, enrollment time, end point time, follow-up period, and advanced cirrhosis. Information on prescribed drugs, drug dosage, supply days, and numbers of dispensed pills was extracted from the Taiwan National Health Insurance database. PPI use was defined as more than 30 cumulative defined daily doses (cDDDs); PPI nonuse was defined as 30 cDDDs or fewer. We performed logistic regression analyses to estimate the association between PPI use and the occurrence of HE., Results: Among patients with cirrhosis and an occurrence of HE, 38% (n = 445) had a history of PPI use before HE occurrence. We observed a relationship between dose of PPI taken and HE risk. The confounder-adjusted odd ratios were 1.41 (95% confidence interval [CI], 1.09-1.84), 1.51 (95% CI, 1.11-2.06), and 3.01 (95% CI, 1.78-5.10) for patients with 30-120 cDDDs, 120-365 cDDDs, and more than 365 cDDDs, respectively, compared with PPI nonusers. All categories of PPIs, except rabeprazole, were associated with an increased risk of HE., Conclusions: Based on an analysis of data from Taiwan National Health Insurance beneficiaries, we found that use of PPIs in patients with cirrhosis increases the risk for HE; risk increases with dose. It therefore is important for health care providers to carefully consider prolonged PPI use by patients with cirrhosis., (Copyright © 2017. Published by Elsevier Inc.)

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations over time in the blood-oxygenation level dependent signal. rs-fcMRI has been applied extensively to identify abnormalities in brain connectivity in different neurologic and psychiatric diseases. However, the relationship among rs-fcMRI connectivity abnormalities, brain electrophysiology and disease state is unknown, in part because the causal significance of alterations in functional connectivity in disease pathophysiology has not been established. Transcranial Magnetic Stimulation (TMS) is a technique that uses electromagnetic induction to noninvasively produce focal changes in cortical activity. When combined with electroencephalography (EEG), TMS can be used to assess the brain's response to external perturbations. Here we provide a protocol for combining rs-fcMRI, TMS and EEG to assess the physiologic significance of alterations in functional connectivity in patients with neuropsychiatric disease. We provide representative results from a previously published study in which rs-fcMRI was used to identify regions with abnormal connectivity in patients with epilepsy due to a malformation of cortical development, periventricular nodular heterotopia (PNH). Stimulation in patients with epilepsy resulted in abnormal TMS-evoked EEG activity relative to stimulation of the same sites in matched healthy control patients, with an abnormal increase in the late component of the TMS-evoked potential, consistent with cortical hyperexcitability. This abnormality was specific to regions with abnormal resting-state functional connectivity. Electrical source analysis in a subject with previously recorded seizures demonstrated that the origin of the abnormal TMS-evoked activity co-localized with the seizure-onset zone, suggesting the presence of an epileptogenic circuit. These results demonstrate how rs-fcMRI, TMS and EEG can be utilized together to identify and understand the physiological significance of abnormal brain connectivity in human diseases.

Background: Sleep-wake disturbances are common in patients with cirrhosis and have a considerable effect on health-related quality of life; however, the underlying mechanism behind the phenomenon is unclear. Cytokines are involved in the mediation of signalling pathways regulating fibrogenesis, leading to cirrhosis. In addition, increased cytokines could contribute to sleep disturbances., Aim: To determine the relationship between pro-inflammatory cytokines and sleep disturbance in cirrhotic patients., Methods: Ninety-eight nonalcoholic cirrhotic patients without overt hepatic encephalopathy were enrolled in this cross-sectional study. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. The Psychometric Hepatic Encephalopathy Score (PHES) was used to examine cognitive performance and define minimal hepatic encephalopathy (MHE). The Hospital Anxiety and Depression Scale (HADS) was used to evaluate the mood status of the patients. Pro-inflammatory cytokines that include interleukin 6 (IL-6) and tumour necrosis factor-α, as well as HBV-DNA or HCV-RNA levels were determined in patients., Results: A total of 56 (57%) cirrhotic patients were identified as 'poor' sleepers (PSQI > 5). After multivariate analysis, IL-6 (P = 0.001) and HADS scores (P = 0.002) were found to be independent predictive factors of poor sleep quality. No significant relationships were observed between the sleep indices and the presence of MHE. HCV-RNA, but not HBV-DNA, viraemia was associated with sleep disturbance in cirrhotic patients., Conclusions: Sleep disturbance is found commonly in cirrhotic patients and a high serum IL-6 level is predictive of poor sleep quality. Minimal hepatic encephalopathy by itself may not contribute to sleep dysfunction in cirrhotic patients., (© 2016 John Wiley & Sons Ltd.)

Background & Aims: In Taiwan, patients with chronic hepatitis C virus (HCV) infection are currently treated with pegylated interferon-alpha plus ribavirin, but interferon-based regimens can be poorly tolerated, especially by those with advanced liver disease and the elderly. Sofosbuvir, an oral nucleotide analogue inhibitor of HCV NS5B polymerase, is approved in Europe, the USA and Japan for treating chronic HCV infection. This phase 3b study examined the efficacy and safety of sofosbuvir plus ribavirin in Taiwanese patients with chronic genotype 2 HCV infection ± compensated cirrhosis., Methods: In this multicentre, open-label, phase 3b (NCT02021643) study, 87 patients (n = 43, treatment-naive; n = 44, treatment-experienced) received 12 weeks of treatment with sofosbuvir plus weight-based ribavirin. The primary efficacy endpoint was the proportion of patients with sustained virological response 12 weeks after treatment discontinuation (SVR12). Safety and pharmacokinetic data were also collected., Results: All 87 patients (100%; 95% confidence interval, 92-100%) achieved SVR12, including the 13 patients with compensated cirrhosis. The most common treatment-emergent adverse events (AEs) were insomnia (16%, 14/87) and upper respiratory tract infection (16%, 14/87). No grade 3 or grade 4 AE was reported. There was one serious AE (biliary colic), which was deemed unrelated to study treatment. Laboratory abnormalities other than ribavirin-related reductions in haemoglobin were uncommon., Conclusions: The results from this phase 3b study demonstrate that 12 weeks of treatment with the interferon-free regimen sofosbuvir plus ribavirin is effective and well tolerated in both treatment-naive and treatment-experienced Taiwanese patients with chronic genotype 2 HCV infection., (© 2016 The Authors. Liver International Published by John Wiley & Sons Ltd.)

Background and Aim: Pegylated-interferon-alpha plus ribavirin is the current standard-of-care regimen for treating chronic hepatitis C virus (HCV) infection in Taiwan; however, interferon-based regimens can be poorly tolerated. The interferon-free, two-drug, fixed-dose combination tablet ledipasvir/sofosbuvir is approved in Europe, the USA, and Japan for treating chronic genotype 1 HCV infection. Little is known about its efficacy/safety in Taiwanese patients., Methods: In this multicenter, open-label, phase 3b (NCT02021656) study, 85 Taiwanese patients (n = 42, treatment-naïve; n = 43, treatment-experienced) with chronic genotype 1 HCV infection (±compensated cirrhosis) received 12 weeks of ledipasvir/sofosbuvir fixed-dose combination tablet. The primary efficacy end point was the proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12). Safety and pharmacokinetic data were collected., Results: The overall SVR12 rate was 98% (83/85), with 100% (42/42) and 95% (41/43) of treatment-naïve and treatment-experienced patients, respectively, achieving SVR12. There were no on-treatment virologic failures. One patient relapsed after treatment discontinuation; one patient withdrew consent on day 2. The most common treatment-emergent adverse event (AE) was headache (14%, 12/85). There was one grade 3 AE (small cell lung cancer unrelated to ledipasvir/sofosbuvir), no grade 4 AEs, and four grade 3-4 laboratory abnormalities. Only the patient with small cell lung cancer prematurely discontinued treatment. Two patients reported three serious AEs; none was considered related to ledipasvir/sofosbuvir., Conclusions: Data from this phase 3b study suggest that 12 weeks of once-daily treatment with the interferon-free, ribavirin-free regimen ledipasvir/sofosbuvir is effective and well-tolerated in Taiwanese patients with chronic genotype 1 HCV infection, irrespective of treatment history., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Reactivation of hepatitis B virus (HBV) infection is common (~20-50%) during cancer chemotherapy. Baseline HBV replication status is an important risk factor for HBV reactivation. To date, data on the baseline HBV DNA level for chronic hepatitis B (CHB) patients prior to chemotherapy, particularly for non-hematological malignancies, are limited. A total of 105 consecutive CHB patients with solid tumors who received prophylactic antiviral therapy prior to chemotherapy from November, 2011 to December, 2014, were enrolled in this study. The patients' tumors included: Breast cancer (37.1%), lung cancer (18.1%), colon cancer (17.1%), head and neck cancer (10.5%), other gastrointestinal tract malignancies (8.6%), gynecological cancer (4.8%) and others (3.8%). The mean age of the enrolled patients was 55.2±1.1 years, 48 of the patients were male, 3 were hepatitis B e antigen-positive, and 26.7% had abnormal alanine aminotransferase (ALT) levels at baseline. The median HBV DNA level measured by quantitative polymerase chain reaction assay prior to chemotherapy was 3.30 log 10 IU/ml and 49.5% of the enrolled patients had a baseline HBV DNA level >2,000 IU/ml. A wide range of HBV distribution was found: <20 IU/ml (15.2%), 20≤DNA<2,000 IU/ml (35.3%), 2,000≤DNA<20,000 IU/ml (26.6%), 20,000≤DNA<10 6 IU/ml (17.2%) and <10 6 IU/ml (5.7%). Age and baseline ALT level were not strongly associated with virological activity. The mean HBV DNA and the percentage of patients with HBV DNA >2,000 IU/ml were comparable between different cancer groups. Quantitative HBsAg level was a major determinant of baseline HBV DNA, and a significant correlation was noted between log 10 hepatitis B surface antigen and log 10 HBV DNA levels (γ=0.641, P<0.001). Our study demonstrated a wide distribution of baseline HBV DNA level among CHB patients diagnosed with non-hematological malignancies. Of note, approximately half of the patients (i.e., those with HBV DNA >2,000 IU/ml) had a higher risk of HBV reactivation if no appropriate antiviral prophylaxis was undertaken.

Objective: To determine the contemporary etiology, burden, and short-term outcomes of seizures in neonates monitored with continuous video-electroencephalogram (cEEG)., Study Design: We prospectively collected data from 426 consecutive neonates (56% male, 88% term) ≤44 weeks' postmenstrual age with clinically suspected seizures and/or electrographic seizures. Subjects were assessed between January 2013 and April 2015 at 7 US tertiary care pediatric centers following the guidelines of the American Clinical Neurophysiology Society for cEEG for at-risk neonates. Seizure etiology, burden, management, and outcome were determined by chart review by the use of a case report form designed at study onset., Results: The most common seizure etiologies were hypoxic-ischemic encephalopathy (38%), ischemic stroke (18%), and intracranial hemorrhage (11%). Seizure burden was high, with 59% having ≥7 electrographic seizures and 16% having status epilepticus; 52% received ≥2 antiseizure medications. During the neonatal admission, 17% died; 49% of survivors had abnormal neurologic examination at hospital discharge. In an adjusted analysis, high seizure burden was a significant risk factor for mortality, length of hospital stay, and abnormal neurological examination at discharge., Conclusions: In this large contemporary profile of consecutively enrolled newborns with seizures treated at centers that use cEEG per the guidelines of the American Clinical Neurophysiology Society, about one-half had high seizure burden, received ≥2 antiseizure medications, and/or died or had abnormal examination at discharge. Greater seizure burden was associated with increased morbidity and mortality. These findings underscore the importance of accurate determination of neonatal seizure frequency and etiology and a potential for improved outcome if seizure burden is reduced., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Endotoxin-induced uveitis (EIU) in rodents is a model of acute Toll-like receptor 4 (TLR4)-mediated organ inflammation, and has been used to model human anterior uveitis, examine leukocyte trafficking and test novel anti-inflammatory therapeutics. Wider adoption has been limited by the requirement for manual, non-specific, cell-count scoring of histological sections from each eye as a measure of disease severity. Here, we describe a comprehensive and efficient technique that uses ocular dissection and multimodal tissue analysis. This allows matched disease scoring by multicolour flow cytometric analysis of the inflammatory infiltrate, protein analysis on ocular supernatants and qPCR on remnant tissues of the same eye. Dynamic changes in cell populations could be identified and mapped to chemokine and cytokine changes over the course of the model. To validate the technique, dose-responsive suppression of leukocyte infiltration by recombinant interleukin-10 was demonstrated, as well as selective suppression of the monocyte (CD11b+Ly6C+) infiltrate, in mice deficient for eitherCcl2orCcr2 Optical coherence tomography (OCT) was used for the first time in this model to allowin vivoimaging of infiltrating vitreous cells, and correlated with CD11b+Ly6G+ counts to provide another unique measure of cell populations in the ocular tissue. Multimodal tissue analysis of EIU is proposed as a new standard to improve and broaden the application of this model., (© 2016. Published by The Company of Biologists Ltd.)

Purpose: To define the incidence of pseudophakic macular edema (PME) after cataract surgery and to identify contributory risk factors., Design: Retrospective database study of electronic medical records (EMRs)., Participants: A total of 81984 eyes undergoing cataract surgery between December 2010 and December 2014 from 8 independent United Kingdom clinical sites., Methods: Structured clinical data mandated by the EMR were anonymized and extracted for each eye undergoing cataract surgery including: perioperative visual acuity, copathologic features, simultaneous surgical procedures, and the presence or absence of a specified list of intraoperative complications. Diabetic status with matched Early Treatment Diabetic Retinopathy Study (ETDRS) grading also was mandated by the EMR. Eyes receiving prophylactic nonsteroidal anti-inflammatory drugs were excluded., Main Outcome Measure: Diagnosis of cystoid macular edema or new-onset macular edema in patients with diabetes, recorded by a healthcare professional within 90 days of surgery., Results: Baseline incidence of PME in eyes without operative complications, diabetes, or risk factors was 1.17%. Eyes in which PME developed were more likely to be male, older, and to demonstrate risk factors. The relative risk (RR) was increased in eyes with capsule rupture with or without vitreous loss (RR, 2.61; 95% confidence interval [CI], 1.57-4.34), a previous diagnosis of epiretinal membrane (RR, 5.60; 95% CI, 3.45-9.07), uveitis (RR, 2.88; 95% CI, 1.50-5.51), retinal vein occlusion (RR, 4.47; 95% CI, 2.56-5.92), or retinal detachment repair (RR, 3.93; 95% CI, 2.60-5.92). High myopia, age-related macular degeneration, or prostaglandin analog use were not shown to increase risk. Eyes with PME on average had poorer postoperative visual acuity, which persisted to the latest time point assessed, up to 24 weeks. Eyes from patients with diabetes, even in the absence of retinopathy, had an increased RR (RR, 1.80; 95% CI, 1.36-2.36) of new macular edema after surgery. The risk was higher in the presence of any diabetic retinopathy (DR; RR, 6.23; 95% CI, 5.12-7.58) and rose proportionately with increasing severity of DR., Conclusions: Pseudophakic macular edema occurs commonly after phacoemulsification cataract surgery, even in the absence of complications and risk factors. This large retrospective study using structured EMR data quantified the RRs of PME and the risk with increasing ETDRS severity of DR. It highlights the need for prophylactic therapy, especially in those groups of eyes with the highest RRs., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The regeneration of hyaline cartilage remains clinically challenging. Here, we evaluated the therapeutic effects of using cell-free porous poly(lactic-co-glycolic acid) (PLGA) graft implants (PGIs) along with early loading exercise to repair a full-thickness osteochondral defect. Rabbits were randomly allocated to a treadmill exercise (TRE) group or a sedentary (SED) group and were prepared as either a PGI model or an empty defect (ED) model. TRE was performed as a short-term loading exercise; SED was physical inactivity in a free cage. The knees were evaluated at 6 and 12 weeks after surgery. At the end of testing, none of the knees developed synovitis, formed osteophytes, or became infected. Macroscopically, the PGI-TRE group regenerated a smooth articular surface, with transparent new hyaline-like tissue soundly integrated with the neighboring cartilage, but the other groups remained distinct at the margins with fibrous or opaque tissues. In a micro-CT analysis, the synthesized bone volume/tissue volume (BV/TV) was significantly higher in the PGI-TRE group, which also had integrating architecture in the regeneration site. The thickness of the trabecular (subchondral) bone was improved in all groups from 6 to 12 weeks. Histologically, remarkable differences in the cartilage regeneration were visible. At week 6, compared with SED groups, the TRE groups manifested modest inflammatory cells with pro-inflammatory cytokines (i.e., TNF-α and IL-6), improved collagen alignment and higher glycosaminoglycan (GAG) content, particularly in the PGI-TRE group. At week 12, the PGI-TRE group had the best regeneration outcomes, showing the formation of hyaline-like cartilage, the development of columnar rounded chondrocytes that expressed enriched levels of collagen type II and GAG, and functionalized trabecular bone with osteocytes. In summary, the combination of implanting cell-free PLGA and performing an early loading exercise can significantly promote the full-thickness osteochondral regeneration in rabbit knee joint models., Statement of Significance: Promoting effective hyaline cartilage regeneration rather than fibrocartilage scar tissue remains clinically challenging. To address the obstacle, we fabricated a spongy cell-free PLGA scaffold, and designed a reasonable exercise program to generate combined therapeutic effects. First, the implanting scaffold generates an affordable mechanical structure to bear the loading forces and bridge with the host to offer a space in the full-thickness osteochondral regeneration in rabbit knee joint. After implantation, rabbits were performed by an early treadmill exercise 15 min/day, 5 days/week for 2 weeks that directly exerts in situ endogenous growth factor and anti-inflammatory effects in the reparative site. The advanced therapeutic strategy showed that neo-hyaline cartilage formation with enriched collagen type II, higher glycosaminoglycan, integrating subchondral bone formation and modest inflammation., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

We have developed a method to label and image myeloid cells infiltrating the mouse retina and choroid in vivo, using a single depot injection of indocyanine green dye (ICG). This was demonstrated using the following ocular models of inflammation and angiogenesis: endotoxin-induced uveitis, experimental autoimmune uveoretinitis and laser-induced choroidal neovascularization model. A near-infrared scanning ophthalmoscope was used for in vivo imaging of the eye, and flow cytometry was used on blood and spleen to assess the number and phenotype of labelled cells. ICG was administered 72 h before the induction of inflammation to ensure clearance from the systemic circulation. We found that in vivo intravenous administration failed to label any leukocytes, whereas depot injection, either intraperitoneal or subcutaneous, was successful in labelling leukocytes infiltrating into the retina. Progression of inflammation in the retina could be traced over a period of 14 days following a single depot injection of ICG. Additionally, bright-field microscopy, spectrophotometry and flow cytometric analysis suggest that the predominant population of cells stained by ICG are circulating myeloid cells. The translation of this approach into clinical practice would enable visualization of immune cells in situ. This will not only provide a greater understanding of pathogenesis, monitoring and assessment of therapy in many human ocular diseases but might also open the ability to image immunity live for neurodegenerative disorders, cardiovascular disease and systemic immune-mediated disorders., (© 2015. Published by The Company of Biologists Ltd.)

The present study was designed to evaluate the protective effects of ethanol extracts of Rabdosia japonica var. glaucocalyx (Maxim.) Hara (RJ) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and the possible underlying mechanisms of action. The mice were orally administrated with RJ extract (16, 32 or 64 mg(kg(-1)) daily for consecutive7 days before LPS challenge. The ung specimens and the bronchoalveolar lavage fluid (BALF) were collected for histopathological examinations and biochemical analyses. Pretreatment with RJ significantly enhanced superoxide dismutase (SOD) activity and reduced the wet-to-dry weight (W/D) ratio, the levels of nitric oxide (NO) and protein leakage, and myeloperoxidase (MPO) activity in mice with ALI, in a dose-dependent manner. RJ reduced complement deposition and significantly attenuated LPS-induced ALI by reducing productions of inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β). The results demonstrated that RJ may attenuate LPS-induced ALI via reducing the production of pro-inflammatory mediators, and reducing complement deposition and radicals., (Copyright © 2015 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Background: Autism spectrum disorders (ASD) are increasingly prevalent and have a significant impact on the lives of patients and their families. Currently, the diagnosis is determined by clinical judgment and no definitive physiological biomarker for ASD exists. Quantitative biomarkers obtainable from clinical neuroimaging data - such as the scalp electroencephalogram (EEG) - would provide an important aid to clinicians in the diagnosis of ASD. The interpretation of prior studies in this area has been limited by mixed results and the lack of validation procedures. Here we use retrospective clinical data from a well-characterized population of children with ASD to evaluate the rhythms and coupling patterns present in the EEG to develop and validate an electrophysiological biomarker of ASD., Methods: EEG data were acquired from a population of ASD (n = 27) and control (n = 55) children 4-8 years old. Data were divided into training (n = 13 ASD, n = 24 control) and validation (n = 14 ASD, n = 31 control) groups. Evaluation of spectral and functional network properties in the first group of patients motivated three biomarkers that were computed in the second group of age-matched patients for validation., Results: Three biomarkers of ASD were identified in the first patient group: (1) reduced posterior/anterior power ratio in the alpha frequency range (8-14 Hz), which we label the "peak alpha ratio", (2) reduced global density in functional networks, and (3) a reduction in the mean connectivity strength of a subset of functional network edges. Of these three biomarkers, the first and third were validated in a second group of patients. Using the two validated biomarkers, we were able to classify ASD subjects with 83 % sensitivity and 68 % specificity in a post-hoc analysis., Conclusions: This study demonstrates that clinical EEG can provide quantitative biomarkers to assist diagnosis of autism. These results corroborate the general finding that ASD subjects have decreased alpha power gradients and network connectivities compared to control subjects. In addition, this study demonstrates the necessity of using statistical techniques to validate EEG biomarkers identified using exploratory methods.

Background & Aims: It remains unknown what the prevalence of minimal hepatic encephalopathy is in Taiwan, a highly endemic country for chronic viral hepatitis infection. It is also unclear whether abnormal serum cytokine levels can be indicative of the presence of minimal hepatic encephalopathy. We aimed to standardize the tests of psychometric hepatic encephalopathy score and predictive value of proinflammatory cytokines in minimal hepatic encephalopathy in Taiwan., Methods: 180 healthy subjects and 94 cirrhotic patients without a history of overt hepatic encephalopathy from a tertiary center were invited to participate in this cross-sectional study. Blood sampling for determination of serum levels of interleukin 6 and 18 and tumor necrosis factor-α was performed. Based on the normogram of psychometric hepatic encephalopathy score from healthy volunteers, patients with minimal hepatic encephalopathy were identified from the cirrhotic patients using the criterion of a psychometric hepatic encephalopathy score less than -4., Results: In the healthy subjects, age and education were predictors of subtests of psychometric hepatic encephalopathy score. Minimal hepatic encephalopathy was identified in 27 (29%) cirrhotic patients. Serum interleukin 6 level (OR = 6.50, 95% CI = 1.64-25.76, P = 0.008) was predictive of the presence of minimal hepatic encephalopathy after multivariate analysis., Conclusions: The psychometric hepatic encephalopathy score can be a useful tool for detecting patients with minimal hepatic encephalopathy in Taiwan and around one third of cirrhotic outpatients fulfill this diagnosis. A high serum interleukin 6 level is predictive of the presence of minimal hepatic encephalopathy.

Elevated tumor necrosis factor (TNF) α levels are associated with chronic autoimmune diseases in which effects of TNFα on immune cells are multiple and complex. Analysis of uveitis in mice exhibiting severe autoimmune inflammation, resulting in a destructive subtotal loss of photoreceptors, revealed the presence of high plasma levels of TNFα and a significant population of CD4(+)TNFα(+) cells in the periphery and the eye at peak disease (TNFα(hi)). We have shown previously by pharmacological activation that the deacetylase Sirtuin 1 (SIRT1) has an anti-inflammatory role in a less severe, TNFα(lo) model of uveitis. We now show that SIRT1 activation fails to clinically suppress severe TNFα(hi) disease, whereas glucocorticoid treatment is successful. TNFα has been reported to mediate cleavage and inactivation of SIRT1 during inflammation, and at peak disease we observed both full-length and cleaved SIRT1 in draining lymph node cells. In vivo systemic TNFα blockade suppressed severe ocular disease and restricted SIRT1 cleavage in the periphery, maintaining full-length active SIRT1 protein. When combining a suboptimal TNFα blockade with SIRT1 activation, a synergistic suppression of severe disease compared with TNFα blockade alone occurred. Our data suggest a new role for TNFα in exacerbating the severity of autoimmune disease by regulating SIRT1 cleavage in draining lymph node effector cells. SIRT1 activation may be effective as an adjunctive treatment for inflammatory conditions not fully controlled by TNFα inhibitors., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Annexin-A1 (Anx-A1) is an endogenous anti-inflammatory molecule and while described as a repressor of innate immune responses, the role of Anx-A1 in adaptive immunity, and in particular in T helper (Th) cell responses, remains controversial. We have used a T-cell mediated mouse model of retinal autoimmune disease to unravel the role of Anx-A1 in the development of autoreactive Th cell responses and pathology. RBP1-20-immunized C57BL/6 Anx-A1(-/-) mice exhibit significantly enhanced retinal inflammation and pathology as a result of an uncontrolled proliferation and activation of Th17 cells. This is associated with a limited capacity to induce SOCS3, resulting in un-restricted phosphorylation of STAT3. RBP1-20-specific CD4(+) cells from immunized Anx-A1(-/-) animals generated high levels of Th17 cells-associated cytokines. Following disease induction, daily systemic administration of human recombinant Anx-A1 (hrAnx-A1), during the afferent phase of disease, restrained autoreactive CD4(+) cell proliferation, reduced expression of pro-inflammatory cytokines IL-17, IFN-γ and IL-6 and attenuated autoimmune retinal inflammatory disease. Furthermore, in man, Anx-A1 serum levels when measured in active uveitis patient sera were low and associated with the detection of IgM and IgG anti-Anx-A1 antibodies when compared to healthy individuals. This data supports Anx-A1 as an early and critical regulator of Th17 cell driven autoimmune diseases such as uveitis., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: To characterize the risk for seizures over time in relation to EEG findings in hospitalized adults undergoing continuous EEG monitoring (cEEG)., Methods: Retrospective analysis of cEEG data and medical records from 625 consecutive adult inpatients monitored at a tertiary medical center. Using survival analysis methods, we estimated the time-dependent probability that a seizure will occur within the next 72-h, if no seizure has occurred yet, as a function of EEG abnormalities detected so far., Results: Seizures occurred in 27% (168/625). The first seizure occurred early (<30min of monitoring) in 58% (98/168). In 527 patients without early seizures, 159 (30%) had early epileptiform abnormalities, versus 368 (70%) without. Seizures were eventually detected in 25% of patients with early epileptiform discharges, versus 8% without early discharges. The 72-h risk of seizures declined below 5% if no epileptiform abnormalities were present in the first two hours, whereas 16h of monitoring were required when epileptiform discharges were present. 20% (74/388) of patients without early epileptiform abnormalities later developed them; 23% (17/74) of these ultimately had seizures. Only 4% (12/294) experienced a seizure without preceding epileptiform abnormalities., Conclusions: Seizure risk in acute neurological illness decays rapidly, at a rate dependent on abnormalities detected early during monitoring. This study demonstrates that substantial risk stratification is possible based on early EEG abnormalities., Significance: These findings have implications for patient-specific determination of the required duration of cEEG monitoring in hospitalized patients., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Over the past decade, networks have become a leading model to illustrate both the anatomical relationships (structural networks) and the coupling of dynamic physiology (functional networks) linking separate brain regions. The relationship between these two levels of description remains incompletely understood and an area of intense research interest. In particular, it is unclear how cortical currents relate to underlying brain structural architecture. In addition, although theory suggests that brain communication is highly frequency dependent, how structural connections influence overlying functional connectivity in different frequency bands has not been previously explored. Here we relate functional networks inferred from statistical associations between source imaging of EEG activity and underlying cortico-cortical structural brain connectivity determined by probabilistic white matter tractography. We evaluate spontaneous fluctuating cortical brain activity over a long time scale (minutes) and relate inferred functional networks to underlying structural connectivity for broadband signals, as well as in seven distinct frequency bands. We find that cortical networks derived from source EEG estimates partially reflect both direct and indirect underlying white matter connectivity in all frequency bands evaluated. In addition, we find that when structural support is absent, functional connectivity is significantly reduced for high frequency bands compared to low frequency bands. The association between cortical currents and underlying white matter connectivity highlights the obligatory interdependence of functional and structural networks in the human brain. The increased dependence on structural support for the coupling of higher frequency brain rhythms provides new evidence for how underlying anatomy directly shapes emergent brain dynamics at fast time scales., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Many forms of epilepsy are associated with aberrant neuronal connections, but the relationship between such pathological connectivity and the underlying physiological predisposition to seizures is unclear. We sought to characterize the cortical excitability profile of a developmental form of epilepsy known to have structural and functional connectivity abnormalities., Methods: We employed transcranial magnetic stimulation (TMS) with simultaneous electroencephalographic (EEG) recording in 8 patients with epilepsy from periventricular nodular heterotopia and matched healthy controls. We used connectivity imaging findings to guide TMS targeting and compared the evoked responses to single-pulse stimulation from different cortical regions., Results: Heterotopia patients with active epilepsy demonstrated a relatively augmented late cortical response that was greater than that of matched controls. This abnormality was specific to cortical regions with connectivity to subcortical heterotopic gray matter. Topographic mapping of the late response differences showed distributed cortical networks that were not limited to the stimulation site, and source analysis in 1 subject revealed that the generator of abnormal TMS-evoked activity overlapped with the spike and seizure onset zone., Interpretation: Our findings indicate that patients with epilepsy from gray matter heterotopia have altered cortical physiology consistent with hyperexcitability, and that this abnormality is specifically linked to the presence of aberrant connectivity. These results support the idea that TMS-EEG could be a useful biomarker in epilepsy in gray matter heterotopia, expand our understanding of circuit mechanisms of epileptogenesis, and have potential implications for therapeutic neuromodulation in similar epileptic conditions associated with deep lesions., (© 2015 American Neurological Association.)

Epilepsy is a network phenomenon characterized by atypical activity during seizure both at the level of single neurons and neural populations. The etiology of epilepsy is not completely understood but a common theme among proposed mechanisms is abnormal synchronization between neuronal populations. Recent advances in novel imaging and recording technologies have enabled the inference of comprehensive maps of both the anatomical and physiological inter-relationships between brain regions. Clinical protocols established for diagnosis and treatment of epilepsy utilize both advanced neuroimaging techniques and neurophysiological data. These growing clinical datasets can be further exploited to better understand the complex connectivity patterns in the epileptic brain. In this article, we review results and insights gained from the growing body of research focused on epilepsy from a network perspective. In particular, we put an emphasis on two different notions of network connectivity: functional and effective; and studies investigating these notions in epilepsy are highlighted. We also discuss limitations and opportunities in data collection and analyses that will further our understanding of epileptic networks and the mechanisms of seizures., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Understanding phenotype-genotype correlations in retinal degeneration is a major challenge. Mutations in CRB1 lead to a spectrum of autosomal recessive retinal dystrophies with variable phenotypes suggesting the influence of modifying factors. To establish the contribution of the genetic background to phenotypic variability associated with the Crb1(rd8/rd8) mutation, we compared the retinal pathology of Crb1(rd8/rd8)/J inbred mice with that of two Crb1(rd8/rd8) lines backcrossed with C57BL/6JOlaHsd mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1(rd8/rd8) lines showed a significant increase in the number of inferior retinal lesions that was strikingly variable between the lines. Optical coherence tomography, semithin, ultrastructural morphology and assessment of inflammatory and vascular marker by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction revealed that the lesions were associated with photoreceptor death, Müller and microglia activation and telangiectasia-like vascular remodelling-features that were stable in the inbred, variable in the second, but virtually absent in the third Crb1(rd8/rd8) line, even at 12 months of age. This suggests that the Crb1(rd8/rd8) mutation is necessary, but not sufficient for the development of these degenerative features. By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified. This may carry one or more genetic modifiers for the manifestation of the retinal pathology associated with mutations in Crb1. This study also provides insight into the nature of the retinal vascular lesions that likely represent a clinical correlate for the formation of retinal telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers., (© The Author 2014. Published by Oxford University Press.)

Purpose: Persistent uncertainty over the clinical significance of various pathological continuous electroencephalography (cEEG) findings in the intensive care unit (ICU) has prompted efforts to standardize ICU cEEG terminology and an ensuing debate. We set out to understand the reasons for, and a satisfactory resolution to, this debate., Method: We review the positions for and against standardization, and examine their deeper philosophical basis., Results: We find that the positions for and against standardization are not fundamentally irreconcilable. Rather, both positions stem from conflating the three cardinal steps in the classic approach to EEG, which we term "description", "interpretation", and "prescription". Using real-world examples we show how this conflation yields muddled clinical reasoning and unproductive debate among electroencephalographers that is translated into confusion among treating clinicians. We propose a middle way that judiciously uses both standardized terminology and clinical reasoning to disentangle these critical steps and apply them in proper sequence., Conclusion: The systematic approach to ICU cEEG findings presented herein not only resolves the standardization debate but also clarifies clinical reasoning by helping electroencephalographers assign appropriate weights to cEEG findings in the face of uncertainty., (Copyright © 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both., Methods: We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203., Findings: This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85-94) patients in the treatment-naive cohort, 168 (82%, 77-87) in the non-responder cohort, and 192 (82%, 77-87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (≤2% each)., Interpretation: Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferon-free and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis., Funding: Bristol-Myers Squibb., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The electroencephalogram (EEG) remains the primary tool for diagnosis of abnormal brain activity in clinical neurology and for in vivo recordings of human neurophysiology in neuroscience research. In EEG data acquisition, voltage is measured at positions on the scalp with respect to a reference electrode. When this reference electrode responds to electrical activity or artifact all electrodes are affected. Successful analysis of EEG data often involves re-referencing procedures that modify the recorded traces and seek to minimize the impact of reference electrode activity upon functions of the original EEG recordings., New Method: We provide a novel, statistically robust procedure that adapts a robust maximum-likelihood type estimator to the problem of reference estimation, reduces the influence of neural activity from the re-referencing operation, and maintains good performance in a wide variety of empirical scenarios., Results: The performance of the proposed and existing re-referencing procedures are validated in simulation and with examples of EEG recordings. To facilitate this comparison, channel-to-channel correlations are investigated theoretically and in simulation., Comparison With Existing Methods: The proposed procedure avoids using data contaminated by neural signal and remains unbiased in recording scenarios where physical references, the common average reference (CAR) and the reference estimation standardization technique (REST) are not optimal., Conclusion: The proposed procedure is simple, fast, and avoids the potential for substantial bias when analyzing low-density EEG data., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Block copolymers have been extensively studied over the last few decades because they can self-assemble into well-ordered nanoscale structures. The morphologies of block copolymers in confined geometries, however, are still not fully understood. In this work, the fabrication and morphologies of three-dimensional polystyrene-block-polydimethylsiloxane (PS-b-PDMS) nanostructures confined in the nanopores of anodic aluminum oxide (AAO) templates are studied. It is discovered that the block copolymers can wet the nanopores using a novel solvent-annealing-induced nanowetting in templates (SAINT) method. The unique advantage of this method is that the problem of thermal degradation can be avoided. In addition, the morphologies of PS-b-PDMS nanostructures can be controlled by changing the wetting conditions. Different solvents are used as the annealing solvent, including toluene, hexane, and a co-solvent of toluene and hexane. When the block copolymer wets the nanopores in toluene vapors, a perpendicular morphology is observed. When the block copolymer wets the nanopores in co-solvent vapors (toluene/hexane = 3:2), unusual circular and helical morphologies are obtained. These three-dimensional nanostructures can serve as naontemplates for refilling with other functional materials, such as Au, Ag, ZnO, and TiO2 ., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background and Objectives: In cirrhosis, hypersensitivity to benzodiazepines (BZD) and precipitating hepatic encephalopathy (HE) have been reported. The aim of this study was to evaluate the safety, economic impact and modifiable factors that are associated with the excess risk of BZD-associated HE in cirrhotic patients., Methods: Between July 2005 and March 2012, 1,612 Chinese cirrhotic patients with and without using long-t 1/2-BZD or short-t 1/2-BZD were enrolled and followed up for 6 months., Results: Among BZD users, the per-person HE-related healthcare utilization and medical costs were found to have progressively increased from 2005 to 2012. Cirrhotic BZD users had a higher percentage of smoking, alcohol drinking, simultaneous consumption of non-BZD drugs, and had a higher incidence of non-cirrhotic chronic illness than non-BZD users. Multivariate analysis indicated that hypoalbuminemia (<3 g/dL), long-acting (t 1/2 > 12-h), high-dosage (>1.5 defined daily dose equivalents) and long-duration (>2-months) BZD use, carrier of variant genotypes (AG + GG) of GABRA 1 (rs2290732) and having the wild genotype (TT) of GABRG 2 (rs211037) were significant predictors of the development of BZD-associated HE in cirrhotic patients. Additionally, synergistic effects of the above significant predictors on BZD-associated HE risk could be identified., Conclusions: Our study confirms the clinical and economic impact of BZD-associated HE in cirrhotic BZD-users. Accordingly, extra caution is needed when treating cirrhotic BZD users with the above risk factors in order to avoid the BZD-associated HE in cirrhotic patients.

Objective: Although neuronal activity drives all aspects of cortical development, how human brain rhythms spontaneously mature remains an active area of research. We sought to systematically evaluate the emergence of human brain rhythms and functional cortical networks over early development., Methods: We examined cortical rhythms and coupling patterns from birth through adolescence in a large cohort of healthy children (n=384) using scalp electroencephalogram (EEG) in the sleep state., Results: We found that the emergence of brain rhythms follows a stereotyped sequence over early development. In general, higher frequencies increase in prominence with striking regional specificity throughout development. The coordination of these rhythmic activities across brain regions follows a general pattern of maturation in which broadly distributed networks of low-frequency oscillations increase in density while networks of high frequency oscillations become sparser and more highly clustered., Conclusion: Our results indicate that a predictable program directs the development of key rhythmic components and physiological brain networks over early development., Significance: This work expands our knowledge of normal cortical development. The stereotyped neurophysiological processes observed at the level of rhythms and networks may provide a scaffolding to support critical periods of cognitive growth. Furthermore, these conserved patterns could provide a sensitive biomarker for cortical health across development., (Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Experimental autoimmune uveoretinitis is a model for noninfectious posterior segment intraocular inflammation in humans. Although this disease is CD4(+) T cell dependent, in the persistent phase of disease CD8(+) T cells accumulate. We show that these are effector memory CD8(+) T cells that differ from their splenic counterparts with respect to surface expression of CD69, CD103, and Ly6C. These retinal effector memory CD8(+) T cells have limited cytotoxic effector function, are impaired in their ability to proliferate in response to Ag-specific stimulation, and upregulate programmed death 1 receptor. Treatment with fingolimod (FTY720) during the late phase of disease revealed that retinal CD8(+) T cells were tissue resident. Despite signs of exhaustion, these cells were functional, as their depletion resulted in an expansion of retinal CD4(+) T cells and CD11b(+) macrophages. These results demonstrate that, during chronic autoimmune inflammation, exhausted CD8(+) T cells become established in the local tissue. They are phenotypically distinct from peripheral CD8(+) T cells and provide local signals within the tissue by expression of inhibitory receptors such as programmed death 1 that limit persistent inflammation.

Rabdosia japonica var. glaucocalyx (Maxim.) Hara, belonging to the Labiatae family, is widely used as an anti-inflammatory and antitumor drug for the treatment of different inflammations and cancers. Aim of the Study. To investigate therapeutic effects and possible mechanism of the flavonoids fraction of Rabdosia japonica var. glaucocalyx (Maxim.) Hara (RJFs) in acute lung injury (ALI) mice induced by lipopolysaccharide (LPS). Materials and Methods. Mice were orally administrated with RJFs (6.4, 12.8, and 25.6 mg/kg) per day for 7 days, consecutively, before LPS challenge. Lung specimens and the bronchoalveolar lavage fluid (BALF) were isolated for histopathological examinations and biochemical analysis. The level of complement 3 (C3) in serum was quantified by a sandwich ELISA kit. Results. RJFs significantly attenuated LPS-induced ALI via reducing productions of the level of inflammatory mediators (TNF- α , IL-6, and IL-1 β ), and significantly reduced complement deposition with decreasing the level of C3 in serum, which was exhibited together with the lowered myeloperoxidase (MPO) activity and nitric oxide (NO) and protein concentration in BALF. Conclusions. RJFs significantly attenuate LPS-induced ALI via reducing productions of proinflammatory mediators, decreasing the level of complement, and reducing radicals.

Eight years after emigrating from Brazil, an otherwise healthy man developed rabies. An exposure prior to immigration was reported. Genetic analysis revealed a canine rabies virus variant found only in the patient's home country, and the patient had not traveled internationally since immigrating to the United States. We describe how epidemiological, phylogenetic, and viral sequencing data provided confirmation that rabies encephalomyelitis may present after a long, multiyear incubation period, a consideration that previously has been hypothesized without the ability to exclude a more recent exposure. Accordingly, rabies should be considered in the diagnosis of any acute encephalitis, myelitis, or encephalomyelitis., (© 2013 American Neurological Association.)

Irreversible blindness caused by loss of photoreceptors may be amenable to cell therapy. We previously demonstrated retinal repair and restoration of vision through transplantation of photoreceptor precursors obtained from postnatal retinas into visually impaired adult mice. Considerable progress has been made in differentiating embryonic stem cells (ESCs) in vitro toward photoreceptor lineages. However, the capability of ESC-derived photoreceptors to integrate after transplantation has not been demonstrated unequivocally. Here, to isolate photoreceptor precursors fit for transplantation, we adapted a recently reported three-dimensional (3D) differentiation protocol that generates neuroretina from mouse ESCs. We show that rod precursors derived by this protocol and selected via a GFP reporter under the control of a Rhodopsin promoter integrate within degenerate retinas of adult mice and mature into outer segment-bearing photoreceptors. Notably, ESC-derived precursors at a developmental stage similar to postnatal days 4-8 integrate more efficiently compared with cells at other stages. This study shows conclusively that ESCs can provide a source of photoreceptors for retinal cell transplantation.

We argue that the structure ordering of self-assembled probing molecular monolayers is essential for the reliability and sensitivity of nanowire-based field-effect sensors because it can promote the efficiency for molecular interactions as well as strengthen the molecular dipole field experienced by the nanowires. In the case of monolayers, we showed that structure ordering could be improved by means of electrical field alignment. This technique was then employed to align multilayer complexes for nanowire sensing applications. The sensitivity we achieved for detection of hybridization between 15-base single-strand DNA molecules is 0.1 fM and for alcohol sensors is 0.5 ppm. The reliability was confirmed by repeated tests on chips that contain multiple nanowire sensors.

Purpose: Diffuse infiltrative hepatocellular carcinoma (D-HCC) is an incurable disease with short survival time. Transarterial chemoembolization (TACE) was often used to alleviate patient's symptoms and reduce tumor burden. However, it remains unknown if the TACE benefits the survival of D-HCC patients., Methods: A hospital-based retrospective study was conducted at a large referral hospital in Taiwan for a 9-year period (2000-2008)., Results: Of the 150 D-HCC patients, 106 patients were related to hepatitis B virus (HBV), 17 to hepatitis C virus (HCV), 3 to both HBV and HCV, and 24 not to HBV or HCV. Multivariate Cox regression analysis showed treatment strategy, serum alpha-fetoprotein level, model for end-stage liver disease (MELD) score, serum gamma glutamyl transferase, and serum lactic acid dehydrogenase were associated with survival time. Compared to supportive treatment, the adjusted hazard ratios of transarterial chemoembolization (TACE) and chemotherapy including oral or systemic chemotherapy were 0.383 (p < 0.001) and 0.711 (p = 0.289), respectively., Conclusion: TACE is a preferred therapy for D-HCC patients.

Despite advances in clinical imaging and grading our understanding of retinal immune responses and their morphological correlates in experimental autoimmune uveoretinitis (EAU), has been hindered by the requirement for post-mortem histology. To date, monitoring changes occurring during EAU disease progression and evaluating the effect of therapeutic intervention in real time has not been possible. We wanted to establish whether optical coherence tomography (OCT) could detect intraretinal changes during inflammation and to determine its utility as a tool for accurate scoring of EAU. EAU was induced in C57BL/6J mice and animals evaluated after 15, 26, 36 and 60 days. At each time-point, contemporaneous Spectralis-OCT scanning, topical endoscopic fundal imaging (TEFI), fundus fluorescein angiography (FFA) and CD45-immunolabelled histology were performed. OCT features were further characterised on retinal flat-mounts using immunohistochemistry and 3D reconstruction. Optic disc swelling and vitreous opacities detected by OCT corresponded to CD45+ cell infiltration on histology. Vasculitis identified by FFA and OCT matched perivascular myeloid and T-cell infiltrates and could be differentiated from unaffected vessels. Evolution of these changes could be followed over time in the same eye. Retinal folds were visible and found to encapsulate mixed populations of activated myeloid cells, T-cells and microglia. Using these features, an OCT-based EAU scoring system was developed, with significant correlation to validated histological (Pearson r(2) = 0.6392, P<0.0001, n = 31 eyes) and TEFI based scoring systems (r(2) = 0.6784, P<0.0001). OCT distinguishes the fundamental features of murine EAU in vivo, permits dynamic assessment of intraretinal changes and can be used to score disease severity. As a result, it allows tissue synchronisation with subsequent cellular and functional assessment and greater efficiency of animal usage. By relating OCT signals with immunohistochemistry in EAU, our findings offer the opportunity to inform the interpretation of OCT changes in human uveitis.

Background & Aims: Hepatic encephalopathy (HE) is a reversible neuropsychiatric disorder in cirrhotic patients. The cognitive dysfunction and increased accidental falls in HE and osteodystrophy in cirrhotic patients may contribute to orthopedic fractures. This study investigated the fracture incidence and risk factors in cirrhotic patients with HE., Methods: In total, 3764 cirrhotic patients with HE were identified from the Taiwan National Health Insurance database between 2000 and 2009. The fracture incidence of the HE patients was compared with that of 3764 age-, sex-, and comorbidity-matched cirrhotic patients without HE and non-cirrhotic controls. Cox proportional hazard models were used to estimate the risk of fracture in the HE patients., Results: Cirrhotic patients with and without HE had comparable increased risks of fracture (p <0.05) and cumulative incidences of fracture than controls (log-rank p <0.001). The estimated fracture rates were 7.09% for the HE group, 7.72% for the cirrhosis without HE group, and 4.05% for the controls, during the 18-month follow-up. The HE group had a higher incidence rate of skull fractures (IRR=2.61, 95% CI 1.04-6.57), but a lower rate of upper limb fractures (IRR=0.45, 95% CI 0.29-0.70) than the cirrhosis without HE group. Alcoholism, heart failure, and cerebrovascular disease were associated with increased risk of fracture in HE patients., Conclusions: Cirrhotic patients, with or without HE, are at an increased risk of orthopedic fractures. Skull fractures, rather than fractures in weight-bearing bones, are more frequently observed in HE patients, particularly those with comorbidities., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)