Optimization of Quantitative Dynamic Postgadolinium MRI Technique Using Normalized Ratios for the Evaluation of Temporomandibular Joint Synovitis in Patients with Juvenile Idiopathic Arthritis [HEAD & NECK]

BACKGROUND AND PURPOSE:

MR imaging has been shown to be useful in the diagnosis of juvenile idiopathic arthritis of the temporomandibular joint. Prior MR imaging approaches have relied mainly on the subjective interpretation of synovial enhancement as a marker for synovial inflammation. Although, more recently, several attempts have been made to quantify synovial enhancement, these methods have not taken into account the dynamic enhancement characteristics of the temporomandibular joint and the effect of sampling time. Our aim was to develop a clinically feasible, reproducible, dynamic, contrast-enhanced MR imaging technique for the quantitative assessment of temporomandibular joint synovitis in patients with juvenile idiopathic arthritis and to study the effect of sampling time on the evaluation of synovitis.

MATERIALS AND METHODS:

This was a retrospective study of all patients who had dynamic, contrast-enhanced coronal T1 3T MR imaging through the temporomandibular joint at our institution between January 1, 2015, and July 8, 2016. Patients in this cohort included those with a history of juvenile idiopathic arthritis and control patients who underwent MR imaging for other routine, clinical purposes. Synovial enhancement was calculated for each temporomandibular joint using 3 different types of equations termed normalization ratios. The enhancement profiles generated by each equation were studied to determine which provided the best discrimination between affected and unaffected joints, was the least susceptible to sampling errors, and was the most clinically feasible.

RESULTS:

A ratio of synovial enhancement (defined as the difference between the postgadolinium and the pregadolinium T1 signal of the synovium) to the postgadolinium signal of the longus capitis provided the best discrimination between affected and unaffected joints, the least susceptibility to sampling error, and was thought to be the most clinically feasible method of quantification of synovial inflammation. Additional synovial enhancement ratios studied did not provide the same level rates of discrimination between the affected and unaffected joints and were thought to be too temporally variable to provide reliable clinical use.

CONCLUSIONS:

We provide a robust, reproducible, dynamic gadolinium-enhanced MR imaging technique for the quantitative assessment of temporomandibular joint synovitis in patients with juvenile idiopathic arthritis.

Leukoaraiosis Attenuates Diagnostic Accuracy of Large-Vessel Occlusion Scales [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Prehospital stroke scales may help identify patients likely to have large-vessel occlusion to facilitate rapid triage to thrombectomy-capable stroke centers. Scale misclassification may result in inaccurate decisions and possible harm. Pre-existing leukoaraiosis has been shown to attenuate the association between deficit type and stroke severity. We sought to determine whether leukoaraiosis affects the predictive ability of 5 commonly used large-vessel occlusion scales.

MATERIALS AND METHODS:

We retrospectively analyzed 274 consecutive patients with stroke with available brain MR imaging and vessel imaging. We used the following large-vessel occlusion scales: the 3-Item Stroke Scale; Field Assessment Stroke Triage for Emergency Destination; Rapid Arterial Occlusion Evaluation; Vision, Aphasia, Neglect score; and Cincinnati Prehospital Stroke Severity Scale. For diagnostic scale accuracy, we assessed sensitivity, specificity, positive predictive value, negative predictive value, and . Multivariable logistic regression was used to determine the predictive ability of the scales after adjustment for leukoaraiosis and potential confounders.

RESULTS:

In unadjusted analyses, all scales predicted the presence of large-vessel occlusion (n = 46, P < .01 each), though diagnostic accuracy was attenuated among patients with moderate-to-severe leukoaraiosis. After adjustment, the Field Assessment Stroke Triage for Emergency Destination (OR = 3.2; 95% CI, 1.1–9.5; P = .033) and Rapid Arterial Occlusion Evaluation (OR = 3.7; 95% CI, 1.3–10.8; P = .015), but not the 3-Item Stroke Scale (OR = 5.4; 95% CI, 0.86–33.9; P = .073), Vision, Aphasia, Neglect score (OR = 2.5; 95% CI, 0.8–7.2), and Cincinnati Prehospital Stroke Severity Scale (OR = 2.8; 95% CI, 1.0–8.0), predicted large-vessel occlusion.

CONCLUSIONS:

The diagnostic accuracy of the tested large-vessel occlusion scales was attenuated in the presence of moderate-to-severe leukoaraiosis. This information that may aid the design of future studies that require large-vessel occlusion scale screening of patients who are likely to have concomitant leukoaraiosis.

Posttreatment Infarct Volumes when Compared with 24-Hour and 90-Day Clinical Outcomes: Insights from the REVASCAT Randomized Controlled Trial [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Endovascular therapy has become the standard of care for patients with disabling anterior circulation ischemic stroke due to proximal intracranial thrombi. Our aim was to determine whether the beneficial effect of endovascular treatment on functional outcome could be explained by a reduction in posttreatment infarct volume in the Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours (REVASCAT) trial.

MATERIALS AND METHODS:

The REVASCAT trial was a multicenter randomized open-label trial with blinded outcome evaluation. Among 206 enrolled subjects (endovascular treatment, n = 103; control, n = 103), posttreatment infarct volume was measured in 204 subjects. Posttreatment infarct volumes were compared with treatment assignment and recanalization status. Appropriate statistical models were used to assess the relationship among baseline clinical and imaging variables, posttreatment infarct volume, the 24-hour NIHSS score, and functional status with the 90-day modified Rankin Scale score.

RESULTS:

The median posttreatment infarct volume in all subjects was 23.7 mL (interquartile range = 68.9 mL) and 16.3 mL (interquartile range = 50.2 mL) in the endovascular treatment arm and 38.6 mL (interquartile range = 74.9 mL) in the control arm (P = .02 for endovascular treatment versus control subjects). Baseline NIHSS (P < .01), site of occlusion (P < .03), baseline NCCT ASPECTS (P < .01), and recanalization status (P = .02) were independently associated with posttreatment infarct volume. Baseline NIHSS (P < .01), time from symptom onset to randomization (P = .02), treatment type (P = .04), and recanalization status (P < .01) were independently associated with the 24-hour NIHSS scores. The 24-hour NIHSS score strongly mediated the relationship between treatment type and 90-day mRS (P < .01 for indirect effect when adjusted for age), while posttreatment infarct volume did not (P = .26).

CONCLUSIONS:

Endovascular treatment saves brain and improves 90-day clinical outcomes primarily through a beneficial effect on the 24-hour stroke severity.

Perivascular Spaces in Old Age: Assessment, Distribution, and Correlation with White Matter Hyperintensities [ADULT BRAIN]

BACKGROUND AND PURPOSE:

The visual rating scales for perivascular spaces vary considerably. We sought to develop a new scale for visual assessment of perivascular spaces and to further describe their distribution and association with white matter hyperintensities in old age.

MATERIALS AND METHODS:

This population-based study included 530 individuals who did not have dementia and were not institutionalized (age, ≥60 years or older; mean age, 70.7 years; 58.9% women) who were living in central Stockholm, Sweden. A semiquantitative visual rating scale was developed to score the number and size of visible perivascular spaces in 7 brain regions in each hemisphere. A modified Scheltens visual rating scale was used to assess white matter hyperintensities.

RESULTS:

The global scores for perivascular spaces ranged from 4–32 for number, 3–22 for size, and 7–54 for the combination of number and size. The weighted statistics for the intra- and interrater reliability both were 0.77. The global score for the number of perivascular spaces increased with advancing age (P < .001). The scores for the number of perivascular spaces in the basal ganglia and subinsular regions were significantly correlated with the load of white matter hyperintensities, especially in lobar and deep white matter regions (partial correlation coefficients, >0.223; P < .01).

CONCLUSIONS:

The new visual rating scale for perivascular spaces shows excellent intra- and interrater reliability. The number of perivascular spaces globally and, especially, in the basal ganglia, is correlated with the load of lobar and deep white matter hyperintensities, supporting the view that perivascular spaces are a marker for cerebral small-vessel disease.

An exploratory open-label, investigator-initiated study to evaluate the efficacy and safety of combination sonidegib and buparlisib for advanced basal cell carcinomas

Climate mitigation, low-carbon society, and dynamism of educational institutes in a low-income country

Abstract

This paper aims to investigate carbon footprints of faculty members of University of Agriculture Faisalabad (UAF) associated with income and education in pursuance of a low-carbon society. For the study, 140 UAF faculty members (professors, associate professors, assistant professors, and lecturers) were selected using stratified random sampling technique, and a representative questionnaire was used to record primary data. Moreover, the ordinary least square (OLS) method was used to explain the statistical relationship between income, education, and carbon footprints. It was found that carbon footprints of UAF faculty members were 10.06 metric tons (mt) per year per person on an average. Our results further indicated that carbon footprints of assistant professors, associate professors, and professors were 10.83, 11.95, and 10.96 mt per person per annum, respectively. OLS estimates showed that an increase in one Doctor of Philosophy (Ph.D.) faculty member increases the carbon footprint by 1.15 mt per annum. Male faculty members emit more carbon footprints than females. Faculty members of Tenure Track System (TTS) had a higher income than those of Basic Pay Scale (BPS). Therefore, emissions of TTS faculty members were higher. Hence, in order to reduce carbon footprints and corroborate UAF campus environment-friendly, the attitude towards this aspect should be changed and awareness should be created. Furthermore, reduced car usage can be another bottom-up policy suggestion. As witnessed in green campuses of international universities, UAF should also be a motor-free campus (cycling and pedestrian only).

Facts and Values in Pragmatism and Logical Empiricism: Addressing the Eclipse Narrative

Abstract

The story of the rise and fall of pragmatism is sometimes called the eclipse narrative. This paper addresses a specific version of this narrative that the logical empiricists arrived in North America in the 1930s and within 30 years had supplanted the pragmatists as the dominant philosophy there. Philosophers such as Alan Richardson and Cheryl Misak have challenged this view by emphasizing the similarities between these two movements. While both seem to admit that there is a distinction between the two when it comes to values, I point out that the issue of values feeds into all aspects of pragmatist thinking, and so despite what seems on the surface to be agreements between the two movements, they were still quite different in all areas of their thinking. I challenge the degree of similarities by arguing that there were some sharp distinctions between the two movements, with the most important being the fact-value distinction and its impact on how each conceived of the term "practical." I close by addressing how these distinctions should affect how we conceive of the eclipse narrative.

Chemometric and high-resolution mass spectrometry tools for the characterization and comparison of raw and treated wastewater samples of a pilot plant on the SIPIBEL site

Abstract

Due to its key role in the contamination of natural resources, the assessment of raw and treated wastewater effluents is a current major concern and urges comprehensive analytical methods capable of selectively capturing the chemodiversity of these samples. In this context, the overall objective of this work can be summarized as (i) the assessment of the performance of secondary and tertiary (advanced oxidation) wastewater treatments through multivariate analysis followed by (ii) the comprehensive characterization of wastewater samples based on their spectral fingerprints and a combination of suspect and non-target screening approaches. Several compounds, belonging to different sources of contamination were annotated and/or partially identified: pharmaceuticals, metabolites and transformation compounds, human activity markers, surfactants, and polyethoxy compounds. These results highlight the contribution of filtering and screening tools such as monoisotopic exact mass, mass defect, MS/MS data-dependent acquisitions, isotopic pattern and retention time to the selection, and the identification of environmental contaminants and their metabolites/degradation products. This paper completes the target study conducted in the SIPIBEL site and offers an alternative for the assessment of treatment processes by broadening the spectrum to a larger number of compounds and the correlations between them.

Recycling of wastes from fish beneficiation by composting: chemical characteristics of the compost and efficiency of their humic acids in stimulating the growth of lettuce

Abstract

Waste from the beneficiation of fish was composted with crushed grass aiming to characterize their chemical composition and investigate the possibility of the use of the final compost as source of humic acids (HA) able to stimulate the growth of lettuce. Compost presented pH value, C/N ratio, and electrical conductivity that allow its use as an organic fertilizer. The element content was present in the following order of abundance in the compost: P > Ca > N > Mg > K > Fe > Zn > Mn > Mo > Cu, and the humus composition was similar to that observed in others kind of organic residues composted. The high content of oxygen pointed out a high level of oxidation of HA, in line with the predominance of phenolic acidity in the functional groups. The ¹³C-NMR spectra showed marked resonances due to the presence of lipids and other materials resistant to degradation as methoxy substituent and N-alkyl groups. A concentration of 20 mg L⁻¹ HA increased significantly both dry and wet root matter in lettuce but the CO₂ assimilation, stomatal conductance, and number of lateral roots of the plants were not affected. However, increases of 64% in the water-use efficiency was observed due to the HA addition, probably related to the root morphology alteration which resulted in 1.6-fold increase of lateral root average length and due to the higher H⁺ extrusion activity. Reuse of residues from the fish beneficiation activity by composting may represent a safe tool to increase the value of recycled organic residues and generate HA with potential use as plant growth stimulants.

Unequal Exposure or Unequal Vulnerability? Contributions of Neighborhood Conditions and Cardiovascular Risk Factors to Socioeconomic Inequality in Incident Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis

Abstract

Risk factors can drive socioeconomic inequalities in cardiovascular disease (CVD) through differential exposure and differential vulnerability. We show how econometric decomposition directly enables simultaneous, policy-oriented assessment of these two mechanisms. We specifically estimated contributions via these mechanisms of neighborhood environment and proximal risk factors to socioeconomic inequality in CVD incidence. We followed 5,608 participants in the Multi-Ethnic Study of Atherosclerosis (2000–2012) until the first CVD event (median follow-up 12.2 years). We used a summary measure of baseline socioeconomic position (SEP). Covariates included baseline demographics, neighborhood, psychosocial, behavioral, and biomedical risk factors. Using Poisson models, we decomposed the difference (inequality) in incidence rates between low- and high-SEP groups into contributions of 1) differences in covariate means (differential exposure), and 2) differences in CVD risk associated with covariates (differential vulnerability). Notwithstanding large uncertainty in neighborhood estimates, our analysis suggests that differential exposure to poorer neighborhood socioeconomic conditions, adverse social environment, diabetes, and hypertension accounts for most of inequality. Psychosocial and behavioral contributions were negligible. Further, neighborhood SEP, female gender, and White race were more strongly associated with CVD among low-SEP (vs. high-SEP) participants. These differentials in vulnerability also accounted for nontrivial portions of the inequality, and could have important implications for intervention.

Maternal and Neonatal Vitamin D Status are not Associated With Risk of Childhood Type 1 Diabetes: A Scandinavian Case-Cohort Study

Abstract

Studies on vitamin D status during pregnancy and risk of type 1 diabetes (T1D) lack consistency, and are limited by small sample sizes or single measures of 25-hydroxyvitamin D (25(OH)D). We investigated whether average maternal 25(OH)D plasma concentrations during pregnancy are associated with risk of childhood T1D. In a case-cohort design, we identified 459 children with T1D and a random sample (n = 1,561) from the Danish National Birth Cohort (n = 97,127) and Norwegian Mother and Child Cohort Study (n = 113,053). Participants were born between 1996 and 2009. The primary exposure was the estimated average 25(OH)D concentration based on serial samples from the first trimester until delivery, and umbilical cord plasma. We estimated hazard ratios using weighted Cox regression adjusting for multiple confounders. The adjusted hazard ratio for T1D per 10 nmol/L increase in the estimated average 25(OH)D concentration was 1.00 (95% confidence interval: 0.90, 1.10). Results were consistent in both cohorts, in multiple sensitivity analyses, and when we analyzed mid-pregnancy or cord blood separately. In conclusion, our large study demonstrated that normal variation in maternal or neonatal 25(OH)D is unlikely to have a clinically important effect on risk of childhood T1D.

Bacillus amyloliquefaciens ssp. plantarum F11 isolated from Algerian salty lake as a source of biosurfactants and bioactive lipopeptides

Abstract

In this study, we identified a new Bacillus strain isolated from an Algerian salty lake that produces metabolites that are active against Gram-positive and Gram-negative bacteria, as well as fungal pathogens. The draft genome sequence of the strain is presented herein. Genome sequence analysis identified the strain to be B. amyloliquefaciens subspecies plantarum F11, and showed that the strain carries the gene clusters for the production of a number of bioactive and surface-active compounds. These include the lipopeptides surfactin and fengycin, antibacterial polyketides macrolactin and bacillaene, and a putative novel lanthipeptide, among others. Through an activity-guided purification method using hydrophobic interaction chromatographic techniques, we confirmed the ability of the strain to produce fengycin lipopeptides. The identities of the isolated fengycin homologues were ascertained through tandem mass spectrometry.

OV21/PETROC: A randomized Gynecologic Cancer Intergroup phase II study of intraperitoneal versus intravenous chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer

Abstract

Background

The purpose of this multistage, adaptively, designed randomized phase II study was to evaluate the role of intraperitoneal (IP) chemotherapy following neoadjuvant chemotherapy (NACT) and optimal debulking surgery in women with epithelial ovarian cancer (EOC).

Patients and Methods

We performed a multicentre, 2 stage, phase II trial. Eligible patients with stage IIB-IVA EOC treated with platinum-based intravenous (IV) NACT followed by optimal (<1cm) debulking surgery were randomized to one of 3 treatment arms: 1) IV carboplatin/paclitaxel; 2) IP cisplatin plus IV/IP paclitaxel, or 3) IP carboplatin plus IV/IP paclitaxel. The primary endpoint was 9 month progressive disease rate (PD9). Secondary endpoints included progression free survival (PFS), overall survival (OS), toxicity and quality of life (QOL).

Results

Between 2009 and 2015, 275 patients were randomized. IP cisplatin containing arm did not progress beyond the first stage of the study after failing to meet the pre-set superiority rule. The final analysis compared IV carboplatin/paclitaxel (n = 101) to IP carboplatin, IV/IP paclitaxel (n = 102). The intention to treat PD9 was lower in the IP carboplatin arm compared to the IV carboplatin arm: 24.5% (95% CI 16.2%-32.9%) vs. 38.6% (95% CI 29.1%- 48.1%) p = 0.065. The study was underpowered to detect differences in PFS: HR PFS 0.82 (95% CI 0.57 - 1.17); p = 0.27 and OS HR 0.80 (95% CI 0.47-1.35) p = 0.40. The IP carboplatin based regimen was well tolerated with no reduction in QOL or increase in toxicity compared to IV administration alone.

Conclusion

In women with stage IIIC or IVA EOC treated with NACT and optimal debulking surgery, IP carboplatin based chemotherapy is well tolerated and associated with an improved PD9 compared to IV carboplatin based chemotherapy.clinicaltrials.gov, NCT01622543

Prevalence and clinical association of gene mutations through Multiplex Mutation Testing in patients with NSCLC: Results from the ETOP Lungscape Project

Abstract

Background

Reported prevalence of driver gene mutations in non-small cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the ETOP Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathological features and patient outcome (relapse-free survival, time-to-relapse, overall survival).

Methods

Clinically-annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is > 1% for most of the ∼150 (13 genes) mutations covered in the multiplex test.

Results

Multiplex testing has been performed in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years).FFPE samples mostly date from 2005-8, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63µg; 38 cases (1.4%) failed QC and were excluded from study. 95.1% of included cases allowed the complete panel of mutations to be tested.Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9% respectively.KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups.EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers.For all the above mutations, there was no difference in outcome between mutated and non-mutated cases.

Conclusion

Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically-annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance.

New antiemetics: facing the current challenge

Sampling of Wide Local Excision Specimens in Cutaneous Malignant Melanoma

Background

Wide local excisions (WLE) are frequently undertaken in the management of cutaneous melanoma; however there is considerable variability in their macroscopic sampling. The aim of our study was to establish evidence-based guidelines for the macroscopic handling of these specimens with a subsequent review of the impact on our service.

Methods

The study group of 128 cases with initial biopsy and subsequent WLE in our institution in 2010 were identified by a computer-generated search. From analysis of this group, guidelines for macroscopic sampling were derived with a repeat search performed in 2012.

Results

Residual melanoma was detected only in those cases in which the original specimen had clear margins of ≤1mm or with a pigmented lesion. A 32% increase in case numbers was noted over this period with a reduction of 6.2% in block numbers. Average block numbers per case were reduced by 2.3 (30.7%).

Conclusions

We have shown that for WLE specimens with no evidence of a macroscopic lesion and clear margins on original biopsy, little is to be gained from extensive sampling. In these cases we recommend a maximum of 3 blocks per case. Reduction in sampling based on this evidence would result in saving valuable laboratory resources.

Severe Respiratory Illness Associated with Rhinovirus during the EV-D68 Outbreak in the United States, August – November, 2014

Abstract

BACKGROUND

In 2014, a nationwide outbreak of severe respiratory illness occurred in the United States, primarily associated with enterovirus D-68 (EV-D68). A proportion of illness was associated with rhinoviruses and other enteroviruses, which we aimed to characterize further.

METHODS

Respiratory specimens from pediatric and adult patients with respiratory illness were submitted to CDC during August – November 2014. While initial laboratory testing focused on identification of EV-D68, the negative specimens were typed by molecular sequencing to identify additional enterovirus (EV) and rhinovirus (RV) types. Testing for other pathogens was not conducted. We compared available clinical and epidemiologic characteristics among patients with EV-D68 and RV species A-C identified.

RESULTS

Among 2629 typed specimens, 1012 were EV-D68 (39%) and 81 (3.1%) represented 24 other EV types; 968 were RVs (37%) covering 114 types and grouped into three human RV species (RV-A=446, RV-B=133, RV-C=389); and 568 (22%) had no RV or EV detected. EV-D68 was more frequently identified in patients presenting earlier in the investigation period. Among patients with EV-D68, RV-A, RV-B, or RV-C identified, the age distributions markedly differed. Clinical syndromes and ICU admissions by age were largely similar among those with EV-D68 and RV species.

CONCLUSIONS

RVs were commonly associated with severe respiratory illness, alongside EV-D68, during the nationwide outbreak. Clinical characteristics were largely similar among those with EV-D68, RV-A, RV-B, or RV-C. A better understanding of the epidemiology of RVs and EVs is needed to help inform development and use of diagnostic tests, therapeutics, and preventive measures.

Efficacy and Safety of Oseltamivir in Children: Systematic Review and Individual Patient Data Meta-analysis of Randomized Controlled Trials

Abstract

Background

Oseltamivir has been used to treat children with influenza for nearly two decades, with treatment currently approved for infants 2 weeks of age or older, but efficacy and safety remain controversial. Newer randomized placebo controlled trials (RCT), not included in previous meta-analyses, can add to the evidence base.

Methods

We conducted a systematic review to identify RCTs of oseltamivir therapy in children. We obtained individual patient data and examined protocol-defined outcomes. We then conducted a two-stage, random effects meta-analysis to determine the efficacy of treatment in reducing the duration of illness, estimated using differences in restricted mean survival time (RSMT) by treatment group. We also examined complications and safety.

Results

We identified 5 trials including 2561 patients in the intent to treat (ITT) and 1598 in the intent to treat infected (ITTI) population. Overall, oseltamivir treatment significantly reduced the duration of illness in the ITTI population (RMST difference -17.6 hours 95% CI: -34.7 to -0.62 hours). In trials that enrolled patients without asthma, the difference was larger (-29.9 hours 95% CI -53.9 to -5.8 hours). Risk of otitis media was 34% lower in the ITTI population. Vomiting was the only adverse event with a significantly higher risk in the treatment group.

Conclusion

Despite substantial heterogeneity in pediatric trials, we found that treatment with oseltamivir significantly reduced the duration of illness in those with influenza and lowered the risk of developing otitis media. Alternative endpoints may be required to evaluate the efficacy of oseltamivir in pediatric patients with asthma.

Cognitive function among antiretroviral treatment-naïve individuals infected with HIV-1 Subtype G versus CRF02_AG in Nigeria

Abstract

Background

HIV-1 subtype has been shown to be associated with disease progression. We compared cognitive function between individuals infected with HIV-1 subtype G and CRF02_AG in Nigeria.

Methods

For this cross-sectional study, samples were analyzed from 146 antiretroviral naïve participants. Genotypic analysis of plasma HIV RNA was performed by nested PCR of protease and reverse transcriptase genes, and sequences aligned with curated HIV-1 subtype references. Cognitive status was determined using demographically adjusted T scores and global deficit scores (GDS) obtained from a comprehensive neuropsychological test battery.

Results

A total of 76 (52.1%) participants were infected with CRF02_AG, 48 (32.8%) with subtype G, and 22 (15.1%) with other HIV-1 strains. In a multivariable linear regression adjusting for plasma HIV RNA, CD4 count and depression score, mean global T score was lower among subtype G as compared to CRF02_AG infected participants (Mean difference: -3.0 [95% CI: -5.2,-0.7]; P = .011). Also, T scores were significantly lower among subtype G than CRF02_AG infected participants for the speed of information processing, executive function, and verbal fluency ability domains. Adjusting for similar variables in a logistic regression, the odds of global cognitive impairment (GDS ≥ 0.5) were 2.2 times higher among subtype G as compared to CRF02_AG infected participants (OR: 2.2 [95% CI: 0.9, 5.4]; P = .078).

Conclusion

Cognitive performance was significantly worse among antiretroviral naïve individuals with HIV-1 subtype G versus CRF02_AG infection. Further studies are required to characterize the mechanistic basis for these differences.

A Roadmap to Implementing Antimicrobial Stewardship Principles in Long-Term Care Facilities (LTCFs): Collaboration Between an Acute-Care Hospital and LTCFs

Abstract

The Centers for Medicare and Medicaid Services (CMS) finalized a rule in October 2016 mandating long-term care facilities (LTCFs) to have antimicrobial stewardship programs (ASPs) in place by 2017. Although guidance exists for establishing ASPs in LTCFs, limited data exists on the "how". As comprehensive ASPs already exist in many acute-care hospitals (ACHs) and, with the known "sharing of patients" between both settings, extending ACH ASP expertise to LTCFs will not only aid LTCFs in complying with the CMS mandate, but will likely also facilitate in decreasing multi-drug resistant organisms and Clostridumdifficile infection rates in patients of both organizations. In this report, we provide a roadmap on how to implement ASPs in LTCFs, using examples from our own ACH's collaboration with local LTCFs to develop and sustain LTCF ASPs. We discuss critical elements to achieving successful LTCF ASPs, including the potential barriers and how to overcome them.

Limited evidence for need for region-specific, genotypic drug-susceptibility assays for Mycobacterium tuberculosis

Mycobacterium tuberculosisgenotypic drug-susceptibility assaysIndia

Imaging mass spectrometry for novel insights into contact allergy – a proof-of-concept study on nickel

Summary

Background

In spite of extensive regulation to limit exposure, nickel remains the main cause of contact allergy in the general population. More detailed knowledge on the skin uptake of haptens is required. So far, no method exists for the visualization of clinically relevant haptens and their distribution in the skin.

Objectives

To show, in terms of a proof of concept, that imaging mass spectrometry [time of flight secondary ion mass spectrometry (ToF-SIMS)] can be applied for investigation of the penetration and distribution of nickel in human skin.

Method

Full-thickness human skin obtained from breast reduction surgery was exposed to nickel sulfate (5% in deionized water) for 24 h in Franz-type diffusion cells. Biopsies were obtained from nickel-treated samples and control (deionized water). The tissue was sliced, and analysed with ToF-SIMS, generating high-resolution images of ion distribution in the epidermis and upper dermis.

Results

The skin layers could be discerned from the ToF-SIMS data, particularly on the basis of the collagen signal. Nickel ions were localized to the stratum corneum and upper epidermis.

Conclusions

This is the first time that ToF-SIMS has been applied to trace the distribution of a hapten in human skin. Proof of principle was shown for nickel, and the technique can, in the future, be expanded for investigation of the skin distribution of clinically relevant sensitizers in general.

Percutaneous bone anchored hearing system implant survival after 550 primary implant surgeries

Abstract

The Bone Anchored Hearing System (BAHS) has become an established option for rehabilitation of several type of hearing impairment such as conductive hearing loss, mixed hearing loss and single sided deafness ¹. Overall good outcomes have been reported. Nevertheless, complications such as inflammation of the skin around the percutaneous abutment, pain and implant loss are related to BAHS ².

This article is protected by copyright. All rights reserved.

Postoperative efficacy analysis of patients with facial nerve palsy associated with cholesteatoma otitis media: Our experience with 32 patients

Abstract

Patients who underwent surgery within 4 weeks after facial palsy had better outcomes than those who had surgery later.

The results of partial and near-complete decompression were good, with no difference between the two methods.

Even if the symptom duration of facial paralysis was > 4 weeks, surgery still had an impact.

Unlike in surgery for facial paralysis due to other causes, the integrity of the sheath membrane should be preserved.

There is a lag in the electroneurography test results.

This article is protected by copyright. All rights reserved.

Non-corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis

Abstract

Topical corticosteroid phobia is an important problem in the treatment of atopic dermatitis as it can affect the ability to control disease severity and itch by reducing treatment adherence. Topical corticosteroid phobia often ends up even non-corticosteroid adherence. As such, non-corticosteroid adherence, disease severity and itch are likely to be associated with each other, but their relationship has yet to be thoroughly investigated. Thus, the purpose of this study is to investigate it in atopic dermatitis. Using data from 1190 participants in an Internet survey, we identified 255 non-corticosteroid users and 225 with moderate to severe itch who were defined as non-corticosteroid adherents. Corticosteroid users with the same itch categories (n = 878) served as controls. We also examined how itch severity affects the perception of itch in atopic dermatitis. Unexpectedly, non-corticosteroid adherents were less sensitive to the conditions to elicit itch such as perspiring, commuting homeward, drinking alcohol and wearing woolen clothes compared with the control. We also found that patients with severer itch were more sensitive to itch during/after bathing, when lying in bed, commuting homeward, studying/working, drinking alcohol, undressing, getting up in the morning, after a meal, ingesting piquant foods and when they were unoccupied, angry, busy, nervous, sad or enjoying themselves. In conclusion, we found that non-corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis and discuss possible mechanisms underlying these results. The information obtained in this study may be useful for communication with and education of atopic dermatitis patients and their treatment in outpatient clinics.

Three cases of Nagashima-type palmoplantar keratosis associated with atopic dermatitis: A diagnostic pitfall

Waardenburg syndrome type IIE in a Japanese patient caused by a novel non-frame-shift duplication mutation in the SOX10 gene

Abrupt generalized pustules in patients with rheumatoid arthritis and interstitial lung disease

Abstract

We report a case of a 30-year-old Chinese woman with rheumatoid arthritis and interstitial lung disease who abruptly developed generalized pustules and a high fever for 10 days. She had been taking oral prednisone, iguratimod and total glucosides of peony regularly for 5 months prior. In addition, she had taken metronidazole for 3 days 20 days prior which she had used before with no adverse reaction. She had no history of similar lesions and psoriasis. A biopsy of a pustule on the back showed spongiform pustule of Kogoj. She was suspected of having generalized pustular psoriasis or acute generalized exanthematous pustulosis. Finally, she was diagnosed with generalized pustular psoriasis (von Zumbusch type) considering the characteristics and clinical course of the rash. In addition to the above three drugs, systemic cyclosporin (5 mg/kg per day) was applied, and the lesions and fever resolved within the proceeding 2 months.

Economic assessment of actual prescription of drugs for treatment of atopic dermatitis: Differences between dermatology and pediatrics in large-scale receipt data

Abstract

Using large-scale receipt data, we analyzed the differences in the prescription of drugs and their costs between dermatology and pediatrics in the treatment of atopic dermatitis (AD) in children. Between August 2010 and July 2011, 50 706 patients were diagnosed as having AD, and the data of 21 075 (15 257 dermatology, 5818 pediatric) patients aged 0–14 years were included in this study. The use of classes I (strongest), II (very strong), and III (strong) topical corticosteroids and tacrolimus was significantly higher in dermatology than in pediatrics (class I, 2.88% vs 0.76%; class II, 27.68% vs 8.32%; class III, 52.53% vs 39.88%; tacrolimus, 5.05% vs 2.82%; all P < 0.05). Although total drug costs were higher in dermatology than in pediatrics, mean drug costs per person were significantly higher in pediatrics. Moisturizers and protective agents had the highest cost (~ ¥690 million). The introduction rate of generic drugs was low at 8.3% among classes I–V. The introduction rate of moisturizers and protective agents, for which costs were the highest, was approximately 9%. The prescription of generic classes II–V topical corticosteroids and moisturizers and protective agents was also significantly higher in dermatology than in pediatrics (P < 0.05). Among patients younger than 2 years, 4405 received drugs for AD; classes I and II topical corticosteroids and tacrolimus (against the guidelines) were administrated in 35 (0.8%), 474 (10.8%) and 29 patients (0.7%), respectively. The introduction of generic drugs is still low, and the use of generic moisturizers and protective agents should be addressed further.

Unusual subcutaneous invasion of myxoid liposarcoma

Transverse nasal crease with milia and comedones: Dermoscopic observation

Successful treatment of hidradenitis suppurativa with rituximab for a patient with idiopathic carpotarsal osteolysis and chronic active antibody-mediated rejection

Agranulocytosis associated with voriconazole-induced hypersensitivity syndrome

Effectiveness of Gastrostomy for Improving Nutritional Status and Quality of Life in Patients with Epidermolysis Bullosa: A Systematic Review

Abstract

Inherited epidermolysis bullosa (EB) is a group of rare genetic disorders clinically characterized by a wide range of skin and mucosal blistering after minor trauma¹. This condition is caused by mutations on genes coding for structural proteins of the skin and affects both genders from all ethnic groups, and its estimated prevalence is about 500,000 cases worldwide².

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Acknowledgements to Reviewers

Author Guidelines

Synergistic inhibition of cell proliferation by combined targeting with kinase inhibitors and dietary xanthone is a promising strategy for melanoma treatment

Summary

α-Mangostin is a dietary xanthone that displays various biological activities, and numerous reports have shown its efficacy in cancer prevention and inhibition. As most agents have been shown to be ineffective as single-agent therapy for malignant melanoma (MM), the principle of targeted chemotherapy for MM is to use effective inhibitors and combination methods. In this study, we tested the cytotoxicity of several kinase inhibitors, including the glycogen synthase kinase (GSK)-3 inhibitor CHIR99021, and rapamycin, in combination with a dietary xanthone, α-mangostin, by screening from a kinase inhibitor library for melanogenesis in SK-MEL-2 MM cells, and verified these by clone formation efficiency, terminal dUTP nick end labelling, and expression of apoptosis-related proteins. We also explored the molecular mechanisms for the apoptosis-inducing effects reported. We found a marked synergistic effect of CHIR99021 or rapamycin in combination with α-mangostin, which we verified through apoptosis-related methods. These data provide a strong rationale for the use of α-mangostin as an adjunct to GSK-3 inhibitor or mammalian target of rapamycin inhibitor treatment. The intrinsic mechanism behind α-mangostin might be inhibition of phosphatidylinositol 3-kinase/AKT signalling and autophagy, and induction of reactive oxygen species generation.

Environmental levels of avian antigen are relevant to the progression of chronic hypersensitivity pneumonitis during antigen avoidance

Abstract

Background

In chronic hypersensitivity pneumonitis (chronic HP), antigen avoidance is critical for disease management; however, complete avoidance is difficult because of unrecognized exposure to antigens. Recently, we revealed that the amount of avian antigen (AAA) in household dust at the time of diagnosis predicted the progression of chronic bird-related HP. The purpose of this study is to evaluate the relationship between the prognosis of chronic bird-related HP and the AAA that remained in the environment during antigen avoidance.

Methods

First, we measured the AAA in household dust of 28 consecutive patients (22 with chronic bird-related HP and 6 with acute bird-related HP) and 12 healthy volunteers. Second, we measured the AAA and collected questionnaires on the environmental conditions of the homes of 53 patients with various lung diseases, including bird-related HP, to investigate the environmental parameters related to a higher AAA. Finally, we prospectively recruited 14 consecutive patients with chronic bird-related HP, measured the AAA periodically, and collected clinical data.

Results

The AAA was higher in patients with chronic bird-related HP at the time of diagnosis compared to healthy volunteers and was highest in patients with acute bird-related HP. Logistic regression analysis showed that birds frequenting a residence was the only significant factor for a higher AAA (odds ratio, 5.686; 95%CI, 1.263–25.59; P = 0.024). There was a correlation between the mean AAA and decline of vital capacity for 1 year (r = −0.55; 95%CI −0.84 to −0.01; P = 0.043).

Conclusion

Measurements of the AAA after diagnosis predict the progression of chronic bird-related HP. Avian antigen can exist in the indoor environment regardless of antigen avoidance. The presence of avian antigen in the indoor environment can be attributed to wild birds found outdoors.

There was a correlation between the mean amount of avian antigen (AAA) and the decline of vital capacity for 1 year (r = −0.55; 95%CI −0.84 to −0.01; P = 0.043). The annual decline in VC from baseline in the high-level exposure group was higher than in the low-level exposure group (≥0.74 µg/g of dust) (332 ± 89 ml vs. 53 ± 116 ml, P = 0.004). Measurements of AAA after diagnosis predict the progression of chronic bird-related HP.

Applicability of energy-positive net-zero water management in Alaska: technology status and case study

Abstract

Challenges of water and wastewater management in Alaska include the potential need for above-grade and freeze-protected piping, high unit energy costs and, in many rural areas, low population density and median annual income. However, recently developed net-zero water (NZW), i.e., nearly closed-loop, direct potable water reuse systems, can retain the thermal energy in municipal wastewater, producing warm treated potable water without the need for substantial water re-heating, heat pumping or transfer, or additional energy conversion. Consequently, these systems are projected to be capable of saving more energy than they use in water treatment and conveyance, in the temperate USA. In this paper, NZW technology is reviewed in terms of potential applicability in Alaska by performing a hypothetical case study for the city of Fairbanks, Alaska. Results of this paper study indicate that in municipalities of Alaska with local engineering and road access, the use of NZW systems may provide an energy-efficient water service option. In particular, case study modeling suggests hot water energy savings are equivalent to five times the energy used for treatment, much greater savings than in mid-latitudes, due largely to the substantially higher energy needed for heating water from a conventional treatment system and lack of need for freeze-protected piping. Further study of the applicability of NZW technology in cold regions, with expanded evaluation in terms of system-wide lifecycle cost, is recommended.

The operations of the free maternal care policy and out of pocket payments during childbirth in rural Northern Ghana

To promote skilled attendance at births and reduce maternal deaths, the government of Ghana introduced the free maternal care policy under the National Health Insurance Scheme (NHIS) in 2008. The objective is ...

Characterization of a Pseudoxanthoma elasticum-like patient with coagulation deficiency, cutaneous calcinosis and GGCX compound heterozygosity

Pseudoxanthoma elasticum (PXE, MIM 264800) is a rare recessive genodermatosis associated with variable ocular and cardiovascular manifestations, which are the result of mineralization and fragmentation of elastic fibers caused by ABCC6 mutations. Emerging evidences suggest the presence of a disease spectrum and several related phenotypes were described comprising PXE-like with coagulation deficiency (CD) (MIM 610842) [1,2]. Similarities between PXE-like with CD and PXE are striking since they share skin manifestations, i.e., yellowish papules that coalesce and form plaques on the neck and in flexural areas, sometimes referred to as cutaneous peau d'orange (Pd'O), calcification of elastic fibers in the dermis, ocular involvement with angioid streaks (AS), and/or ocular Pd'O.

The expression of mCTLA-4 in skin lesion inversely correlates with the severity of psoriasis

Psoriasis is an immune-mediated chronic inflammatory disease characterized by abnormal epidermal differentiation, hyperproliferation, angiogenesis, and increased T-cell infiltrates. As a chronic relapsing and remitting inflammatory skin disease, it affects approximately 1-3% of the population [1].

Pesticide residues in muscles of some marine fish species and seaweeds of Iskenderun Bay (Northeastern Mediterranean), Turkey

Abstract

Pesticide residues in muscles of nine marine fish and four seaweed species of Iskenderun Bay (Northeastern Mediterranean) have been investigated. In sampled fish species, two herbicides, three insecticides, two fungicides, and one synergist were identified and quantified. Metribuzin DADK, propamocarb HCl, and piperonyl butoxide (PBO) were detected in all the muscles of sampled fish species. Metribuzin DADK was the most abundant pesticide residue in fish muscles and the highest metribuzin DADK concentration was found in sardine (311.20 μg/kg). Propamocarb HCl concentrations varied greatly among species; from 0.530 ± 0.020 μg/kg in striped sea bream to 34.170 μg/kg in sea bass. The level of PBO ranged from 0.001 μg/kg for fourlined terapon to 0.013 μg/kg for sardine. No measurable oxamyl residue was found in any of the muscles of sampled fish species (except sardine). In seaweeds, two herbicides and two insecticides were identified and quantified. Metribuzin DADK was the most abundant and found in Cystoseira corniculata (5.01 mg/kg), Corallina elongata (0.703 mg/kg), and Jania rubens (3.85 mg/kg). Molinate was a minor contaminant and only found in Corallina elongata (0.002 mg/kg). Pyrethrin I was determined only in Padina pavonia to be 0.567 mg/kg. Pyrethrine II was found in Padina pavonia and Corallina elongate to be 1.214 and 0.229 mg/kg, respectively. The most hazardous pesticide residues of organochlorines and organophosphorus were not detected in both sampled fish muscles and seaweeds. There are no clear maximum residue limits for the detected eight pesticide residues declared for fish muscle by European Union MRL (2017). In conclusion, it can be considered that observed concentrations of pesticides in sampled nine marine fish species do not have a potential health risk for consumers. Some of the detected pesticide residues can be toxic for algae and aquatic life and regular monitoring studies are therefore essential to control the pesticide concentrations of aquatic biota in the region.

Metabolomic analysis of the toxic effect of chronic exposure of cadmium on rat urine

Abstract

This study aimed to assess the toxic effect of chronic exposure to cadmium through a metabolomic approach based on ultra-performance liquid chromatography/mass spectrometry (UPLC–MS). Forty male Sprague–Dawley rats were randomly assigned to the following groups: control, low-dose cadmium chloride (CdCl₂) (0.13 mg/kg body weight (bw)), middle-dose CdCl₂ (0.8/kg bw), and high-dose CdCl₂ (4.9 mg/kg bw). The rats continuously received CdCl₂ via drinking water for 24 weeks. Rat urine samples were then collected at different time points to establish the metabolomic profiles. Multiple statistical analyses with principal component analysis and partial least squares–discriminant analysis were used to investigate the metabolomic profile changes in the urine samples and screen for potential biomarkers. Thirteen metabolites were identified from the metabolomic profiles of rat urine after treatment. Compared with the control group, the treated groups showed significantly increased intensities of phenylacetylglycine, guanidinosuccinic acid, 4-pyridoxic acid, 4-aminohippuric acid, 4-guanidinobutanoic acid, allantoic acid, dopamine, LysoPC(18:2(9Z,12Z)), and L-urobilinogen. By contrast, the intensities of creatinine, L-carnitine, taurine, and pantothenic acid in the treated groups were significantly decreased. These results indicated that Cd disrupts energy and lipid metabolism. Meanwhile, Cd causes liver and kidney damage via induction of oxidative stress; serum biochemical indices (e.g., creatinine and urea nitrogen) also support the aforementioned results.

Survival in patients with primary Dermatofibrosarcoma Protuberans: National Cancer Data Base analysis

Large tumor size of dermatofibrosarcoma protuberans (DFSP) was found to predict mortality when relevant institution-based and treatment-specific factors were not considered, Older age, comorbidities. anaplastic histology, and positive margins predicted mortality while female gender, private insurance, and academic facility or Integrated Network Cancer Program (INCP) predicted survival, Thorough analysis of risk factors in DFSP patients is needed to improve management and increase survival.

Does the proposed removal of mitotic count as a prognostic indicator in melanoma, accurately reflect the risk profile for metastasis in UK patients?

We of the Newcastle upon Tyne Hospitals NHS Foundation Trust Specialist Skin Cancer MDT, write with concern regarding the most recently published AJCC 8th edition staging system for malignant melanoma 1 (proposed to be implemented in the UK in January 2018) and its possible implications for accurate risk stratification and prognostic forecasting.

Effects of soil properties and aging process on the acute toxicity of cadmium to earthworm Eisenia fetida

Abstract

This study was undertaken to investigate the effects of soil properties and aging process on the acute toxicity of cadmium (Cd) to Eisenia fetida (E. fetida) in 18 Cd-spiked soils. Results showed that the Cd toxicity to E. fetida differed in the 18 soils with different characteristics, and median lethal concentration (LC50) values varied from 440.7 to 1520.4 mg/kg in freshly spiked soils. Soil pH and organic matter (OM) content were the two major factors associated with Cd toxicity. The increase in LC50 values and decreases in both exchangeable Cd in soils and tissue Cd concentrations in earthworm whole body indicated that aging (180 and 360 days) could reduce the acute toxicity and bioavailability of Cd to E. fetida. Cadmium concentrations in E. fetida were positively correlated with exchangeable Cd content in soils, and soil pH and OM were the key factors controlling the distribution and transformation of the exchangeable Cd. The results will provide useful reference information for the risk assessment of Cd in the terrestrial environment.

Assessment of oral and lung bioaccessibility of Cd and Pb from smelter-impacted dust

Abstract

Soil and dust contamination by metals engenders significant environmental and health problems in northern France where a lead smelter was in activity for more than a century. This study aims to examine the long-term effects of the smelter, 10 years after its closedown, on the presence of metal in sidewalk dust for a better assessment of the local population's exposure to Cd and Pb. The investigation included: (i) the metal distribution in different dust particle sizes and (ii) the assessment of metal bioaccessibility via ingestion and inhalation of dust. Seventy-two sidewalk dust samples were collected using a dust-sampling vacuum. The samples were sieved to collect different particle sizes from 0.3 to 1000 μm. The unified bioaccessibility method (UBM) was employed to evaluate the oral bioaccessibility of metals in the different particle sizes. The pulmonary bioaccessible fraction of Cd and Pb via the finest particles was extracted with lung-simulating solution (artificial lysosomal fluid). Ten years after the smelter closedown, (i) a strong relationship was observed between the concentrations of metals in dust and the distance to the former smelter, whatever the particle size; (ii) both total and oral bioaccessible concentrations of metals were high in the finest fraction (0.3–5 μm) and decreased when the particle size increased; (iii) a higher oral bioaccessibility of Cd and Pb was measured in the gastric phase (on average 43% for both metals for all particle sizes) and compared to the gastrointestinal phase (on average 16% for both metals for all particle sizes); and (iv) metal bioaccessibility via inhalation of dust was relatively high (on average 74 and 69%, for Cd and Pb, respectively). The results of the present study suggest that this environmental compartment may be a sensitive and effective indicator of anthropogenic metal contamination and the human exposure in urban areas.

Adsorption of cadmium ions using the bioadsorbent of Pichia kudriavzevii YB5 immobilized by polyurethane foam and alginate gels

Abstract

Pichia kudriavzevii YB5, mutated from Pichia kudriavzevii A16 with a strong ability to remove cadmium ions, was immobilized by polyurethane foam and alginate gels in this work. The immobilization conditions were optimized as follows: sodium alginate concentration of 2% (w/v), calcium chloride concentration of 2% (w/v), biomass dose of 1 × 10⁹ cell/mL, and cross-linking time for 4 h. Then, the results of batch adsorption experiments showed that the removal capacity of prepared bioadsorbent was significantly affected by the pH of media, contact time, and the initial Cd(II) concentration, and a suitable adsorption conditions of Cd(II) could be achieved with a pH value of 6.0 at 20 °C for 90 min. Kinetic and isothermal results indicated the behavior of Cd(II) adsorption onto immobilized P. kudriavzevii YB5 fitted to the pseudo-second-order kinetic equation and the Langmuir adsorption model. Thermodynamic results showed that the Cd(II) adsorption process was endothermic and spontaneous in nature. Besides, the Cd(II) removing capacity of the prepared bioadsorbent was also tested in the oyster hydrolysates, showing an average removal rate of 54.35%. Thus, the immobilized P. kudriavzevii YB5 adsorbent had great potential for application in aquatic products to ensure the food safety.

Visible light-induced photocatalytic degradation of Reactive Blue-19 over highly efficient polyaniline-TiO 2 nanocomposite: a comparative study with solar and UV photocatalysis

Abstract

Polyaniline-TiO₂ (PANI-TiO₂) nanocomposite was prepared by in situ polymerisation method. X-ray diffractogram (XRD) showed the formation of PANI-TiO₂ nanocomposite with the average crystallite size of 46 nm containing anatase TiO₂. The PANI-TiO₂ nanocomposite consisted of short-chained fibrous structure of PANI with spherical TiO₂ nanoparticles dispersed at the tips and edge of the fibres. The average hydrodynamic diameter of the nanocomposite was 99.5 nm. The band gap energy was 2.1 eV which showed its ability to absorb light in the visible range. The nanocomposite exhibited better visible light-mediated photocatalytic activity than TiO₂ (Degussa P25) in terms of degradation of Reactive Blue (RB-19) dye. The photocatalysis was favoured under initial acidic pH, and complete degradation of 50 mg/L dye could be achieved at optimum catalyst loading of 1 g/L. The kinetics of degradation followed the Langmuir-Hinshelhood model. PANI-TiO₂ nanocomposite showed almost similar photocatalytic activity under UV and visible light as well as in the solar light which comprises of radiation in both UV and visible light range. Chemical oxygen demand removal of 86% could also be achieved under visible light, confirming that simultaneous mineralization of the dye occurred during photocatalysis. PANI-TiO₂ nanocomposites are promising photocatalysts for the treatment of industrial wastewater containing RB-19 dye.

Following logical realism where it leads

Abstract

Logical realism is the view that there is logical structure in the world. I argue that, if logical realism is true, then we are deeply ignorant of that logical structure: either we can't know which of our logical concepts accurately capture it, or none of our logical concepts accurately capture it at all. I don't suggest abandoning logical realism, but instead discuss how realists should adjust their methodology in the face of this ignorance.

Geographic Distribution of Nonphysicians Who Billed Medicare for Dermatologic Services

This study uses Medicare and US Census data to discover which dermatology-related services are independently billed by nonphysician clinicians treating Medicare beneficiaries, and where these clinicians are located.

Hair Repigmentation With Anti–PD-1 and Anti–PD-L1 Immunotherapy—Reply

In Reply We read with interest the letter by Manson et al. They describe another case of hair repigmentation (HR) in a male patient with concomitant advanced colorectal cancer and Hodgkin lymphoma treated with nivolumab and showing a good response. Interestingly, this new case seems to support the association between a good response and HR.

Hair Repigmentation With Anti–PD-1 and Anti–PD-L1 Immunotherapy

To the Editor We read with great interest the article by Rivera and colleagues reporting on hair repigmentation in patients receiving immunotherapy with anti–programmed cell death 1 (PD-1) and anti–programmed cell death 1 ligand 1 (PD-L1) immunotherapy.

Reticular Hyperpigmented Eruption in a Young Woman

A woman in her 20s was seen with a 6-year history of recurrent, pruritic skin eruptions involving the middle and lower back. Physical examination showed several discrete, erythematous, scaly papules admixed with light brown reticulated macules and patches. What is your diagnosis?

Hair Repigmentation With Anti–PD-1 and Anti–PD-L1 Immunotherapy

To the Editor The article by Rivera et al is the first report of a previously undescribed side effect of checkpoint inhibitors: hair repigmentation (HR). In this significant case series of 14 patients, all patients received an anti–programmed cell death 1 (PD-1) and anti–programmed cell death 1 ligand 1 (PD-L1) antibody for the treatment of a lung cancer.

Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients

This cohort study addresses whether current skin surveillance intervals and threshold for biopsy of suspicious lesions are adequate for the increased tendency of solid organ transplant recipients to develop potentially aggressive cutaneous squamous cell carcinomas.

Treatment of Refractory Mycosis Fungoides With Brentuximab Vedotin

This case report describes the treatment of CD30-negative refractory mycosis fungoides with brentuximab vedotin.

Antimicrobial Photodynamic Therapy Associated with Conventional Endodontic Treatment: A Clinical and Molecular Microbiological Study

Abstract

This study evaluated antimicrobial photodynamic therapy (aPDT) as an adjunct to endodontic treatment. Ten uniradicular teeth (control group (CG)= 4 (2 and test group (TG)= 6) with primary endodontic infections, from both genders, between 17 and 65 years old, were analyzed. Microbiological samples were collected before and after chemical-mechanical instrumentation (CMI), after aPDT (for the TG), and after the removal of the temporary restorations (second session). In TG, the aPDT was performed with 100 μg/mL methylene blue and irradiated with low power laser (InGaAIP, 660 nm; 100 mW; 40 sec) with a fiber-coupled optical laser. Another irradiation (3 J; 30 sec; spot size of 3 mm²) was performed in the gingiva close to the apical foramen. The PCR was performed, after previous whole-genome amplification, for Enterococcus faecalis, Candida genus and Bacteria domain. For TG, a positive tooth for Candida spp. before of the CMI presented negative results in subsequent samples. Additionally, E. faecalis species was present in four samples before CMI, two after CMI, in one after the aPDT and was not detected at the second session. aPDT may be an effective adjunct therapy, resulting in a reduction (p=0.0286) of the incidence of E. faecalis before root canal obturation.

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PhotochemCAD 3: Diverse Modules for Photophysical Calculations with Multiple Spectral Databases

Abstract

The PhotochemCAD program, developed over 30 years, is described comprehensively with focus on features of the most recent version (PhotochemCAD 3). The program is equipped with a streamlined user interface and provisions for handling multiple spectral databases. Eight modules enable calculations to be performed on the basis of the spectra in the databases. The calculational modules provide results concerning properties of individual compounds (oscillator strength, transition dipole moment, natural radiative lifetime), interactions of multiple compounds (Förster energy transfer, Dexter energy transfer, analysis of energy transfer among an array of chromophores), and composition of mixtures (multicomponent analysis). Synthetic spectra (blackbody radiator, Gaussian and Lorentzian curves, and delta functions) also can be generated. For comparison and calculation, synthetic and experimental spectra can be shifted along both coordinate axes and combined by addition, subtraction, and use of multiplicative factors. The core databases (described in the companion paper) have been expanded to 339 compounds for which absorption spectra (including molar absorption coefficient, ε), fluorescence spectra (including fluorescence quantum yield, Φ_f) and references to the primary literature have been included where available (551 spectra altogether). A database of 31 solar spectra also is included. Each calculational module is described along with illustrative examples.

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Database of Absorption and Fluorescence Spectra of >300 Common Compounds for use in PhotochemCAD

Abstract

The design of new molecules for photochemical studies typically requires knowledge of spectral features of pertinent chromophores beginning with the absorption spectrum (λ_abs) and accompanying molar absorption coefficient (ε, M⁻¹cm⁻¹) and often extending to the fluorescence spectrum (λ_em) and fluorescence quantum yield (Φ_f), where the fluorescence properties may be of direct relevance or useful as proxies to gain insight into the nature of the first excited singlet state. PhotochemCAD databases, developed over a period of 30 years, are described here. The previous databases for 150 compounds have been expanded to encompass 339 compounds for which absorption spectra (including ε values), fluorescence spectra (including Φ_f values) and references to the primary literature have been included where available (551 spectra altogether). The compounds exhibit spectra in the ultraviolet, visible, and/or near-infrared spectral regions. The compound classes and number of members include acridines (21), aromatic hydrocarbons (41), arylmethane dyes (11), azo dyes (18), biomolecules (18), chlorins/bacteriochlorins (16), coumarins (14), cyanine dyes (19), dipyrrins (7), heterocycles (26), miscellaneous dyes (13), oligophenylenes (13), oligopyrroles (6), perylenes (5), phthalocyanines (11), polycyclic aromatic hydrocarbons (16), polyenes/polyynes (10), porphyrins (34), quinones (24), and xanthenes (15). A database of 31 solar spectra also is included.

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Efficacy and Safety of Titanium Miniplates in Septorhinoplasty

This case series evaluates the efficacy and safety of titanium miniplates for cartilaginous graft fixation in patients undergoing septorhinoplasty.

Hybrid Cartilage-Modifying Otoplasty Technique and Outcomes

This observational study compares preoperative and postoperative measurements of the ears of patients who underwent hybrid cartilage-modifying otoplasty.

Seizures and Sleep in the Thalamus: Focal Limbic Seizures Show Divergent Activity Patterns in Different Thalamic Nuclei

The thalamus plays diverse roles in cortical-subcortical brain activity patterns. Recent work suggests that focal temporal lobe seizures depress subcortical arousal systems and convert cortical activity into a pattern resembling slow-wave sleep. The potential simultaneous and paradoxical role of the thalamus in both limbic seizure propagation, and in sleep-like cortical rhythms has not been investigated. We recorded neuronal activity from the central lateral (CL), anterior (ANT), and ventral posteromedial (VPM) nuclei of the thalamus in an established female rat model of focal limbic seizures. We found that population firing of neurons in CL decreased during seizures while the cortex exhibited slow waves. In contrast, ANT showed a trend toward increased neuronal firing compatible with polyspike seizure discharges seen in the hippocampus. Meanwhile, VPM exhibited a remarkable increase in sleep spindles during focal seizures. Single-unit juxtacellular recordings from CL demonstrated reduced overall firing rates, but a switch in firing pattern from single spikes to burst firing during seizures. These findings suggest that different thalamic nuclei play very different roles in focal limbic seizures. While limbic nuclei, such as ANT, appear to participate directly in seizure propagation, arousal nuclei, such as CL, may contribute to depressed cortical function, whereas sleep spindles in relay nuclei, such as VPM, may interrupt thalamocortical information flow. These combined effects could be critical for controlling both seizure severity and impairment of consciousness. Further understanding of differential effects of seizures on different thalamocortical networks may lead to improved treatments directly targeting these modes of impaired function.

SIGNIFICANCE STATEMENT Temporal lobe epilepsy has a major negative impact on quality of life. Previous work suggests that the thalamus plays a critical role in thalamocortical network modulation and subcortical arousal maintenance, but its precise seizure-associated functions are not known. We recorded neuronal activity in three different thalamic regions and found divergent activity patterns, which may respectively participate in seizure propagation, impaired level of conscious arousal, and altered relay of information to the cortex during focal limbic seizures. These very different activity patterns within the thalamus may help explain why focal temporal lobe seizures often disrupt widespread network function, and can help guide future treatments aimed at restoring normal thalamocortical network activity and cognition.

Serotonin Decreases the Gain of Visual Responses in Awake Macaque V1

Serotonin, an important neuromodulator in the brain, is implicated in affective and cognitive functions. However, its role even for basic cortical processes is controversial. For example, in the mammalian primary visual cortex (V1), heterogenous serotonergic modulation has been observed in anesthetized animals. Here, we combined extracellular single-unit recordings with iontophoresis in awake animals. We examined the role of serotonin on well-defined tuning properties (orientation, spatial frequency, contrast, and size) in V1 of two male macaque monkeys. We find that in the awake macaque the modulatory effect of serotonin is surprisingly uniform: it causes a mainly multiplicative decrease of the visual responses and a slight increase in the stimulus-selective response latency. Moreover, serotonin neither systematically changes the selectivity or variability of the response, nor the interneuronal correlation unexplained by the stimulus ("noise-correlation"). The modulation by serotonin has qualitative similarities with that for a decrease in stimulus contrast, but differs quantitatively from decreasing contrast. It can be captured by a simple additive change to a threshold-linear spiking nonlinearity. Together, our results show that serotonin is well suited to control the response gain of neurons in V1 depending on the animal's behavioral or motivational context, complementing other known state-dependent gain-control mechanisms.

SIGNIFICANCE STATEMENT Serotonin is an important neuromodulator in the brain and a major target for drugs used to treat psychiatric disorders. Nonetheless, surprisingly little is known about how it shapes information processing in sensory areas. Here we examined the serotonergic modulation of visual processing in the primary visual cortex of awake behaving macaque monkeys. We found that serotonin mainly decreased the gain of the visual responses, without systematically changing their selectivity, variability, or covariability. This identifies a simple computational function of serotonin for state-dependent sensory processing, depending on the animal's affective or motivational state.

Rethinking the Role of Thought Suppression in Psychological Models and Treatment

Development of the Visual Word Form Area Requires Visual Experience: Evidence from Blind Braille Readers

Learning to read causes the development of a letter- and word-selective region known as the visual word form area (VWFA) within the human ventral visual object stream. Why does a reading-selective region develop at this anatomical location? According to one hypothesis, the VWFA develops at the nexus of visual inputs from retinotopic cortices and linguistic input from the frontotemporal language network because reading involves extracting linguistic information from visual symbols. Surprisingly, the anatomical location of the VWFA is also active when blind individuals read Braille by touch, suggesting that vision is not required for the development of the VWFA. In this study, we tested the alternative prediction that VWFA development is in fact influenced by visual experience. We predicted that in the absence of vision, the "VWFA" is incorporated into the frontotemporal language network and participates in high-level language processing. Congenitally blind (n = 10, 9 female, 1 male) and sighted control (n = 15, 9 female, 6 male), male and female participants each took part in two functional magnetic resonance imaging experiments: (1) word reading (Braille for blind and print for sighted participants), and (2) listening to spoken sentences of different grammatical complexity (both groups). We find that in blind, but not sighted participants, the anatomical location of the VWFA responds both to written words and to the grammatical complexity of spoken sentences. This suggests that in blindness, this region takes on high-level linguistic functions, becoming less selective for reading. More generally, the current findings suggest that experience during development has a major effect on functional specialization in the human cortex.

SIGNIFICANCE STATEMENT The visual word form area (VWFA) is a region in the human cortex that becomes specialized for the recognition of written letters and words. Why does this particular brain region become specialized for reading? We tested the hypothesis that the VWFA develops within the ventral visual stream because reading involves extracting linguistic information from visual symbols. Consistent with this hypothesis, we find that in congenitally blind Braille readers, but not sighted readers of print, the VWFA region is active during grammatical processing of spoken sentences. These results suggest that visual experience contributes to VWFA specialization, and that different neural implementations of reading are possible.

Perspectives on Treatment of Alzheimer's Disease: A Closer Look into EphB2 Depletion

A Subconscious Interaction between Fixation and Anticipatory Pursuit

Ocular smooth pursuit and fixation are typically viewed as separate systems, yet there is evidence that the brainstem fixation system inhibits pursuit. Here we present behavioral evidence that the fixation system modulates pursuit behavior outside of conscious awareness. Human observers (male and female) either pursued a small spot that translated across a screen, or fixated it as it remained stationary. As shown previously, pursuit trials potentiated the oculomotor system, producing anticipatory eye velocity on the next trial before the target moved that mimicked the stimulus-driven velocity. Randomly interleaving fixation trials reduced anticipatory pursuit, suggesting that a potentiated fixation system interacted with pursuit to suppress eye velocity in upcoming pursuit trials. The reduction was not due to passive decay of the potentiated pursuit signal because interleaving "blank" trials in which no target appeared did not reduce anticipatory pursuit. Interspersed short fixation trials reduced anticipation on long pursuit trials, suggesting that fixation potentiation was stronger than pursuit potentiation. Furthermore, adding more pursuit trials to a block did not restore anticipatory pursuit, suggesting that fixation potentiation was not overridden by certainty of an imminent pursuit trial but rather was immune to conscious intervention. To directly test whether cognition can override fixation suppression, we alternated pursuit and fixation trials to perfectly specify trial identity. Still, anticipatory pursuit did not rise above that observed with an equal number of random fixation trials. The results suggest that potentiated fixation circuitry interacts with pursuit circuitry at a subconscious level to inhibit pursuit.

SIGNIFICANCE STATEMENT When an object moves, we view it with smooth pursuit eye movements. When an object is stationary, we view it with fixational eye movements. Pursuit and fixation are historically regarded as controlled by different neural circuitry, and alternating between invoking them is thought to be guided by a conscious decision. However, our results show that pursuit is actively suppressed by prior fixation of a stationary object. This suppression is involuntary, and cannot be avoided even if observers are certain that the object will move. The results suggest that the neural fixation circuitry is potentiated by engaging stationary objects, and interacts with pursuit outside of conscious awareness.

Delayed Maturation of Fast-Spiking Interneurons Is Rectified by Activation of the TrkB Receptor in the Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is a leading cause of inherited intellectual disability, and the most common known cause of autism spectrum disorder. FXS is broadly characterized by sensory hypersensitivity and several developmental alterations in synaptic and circuit function have been uncovered in the sensory cortex of the mouse model of FXS (Fmr1 KO). GABA-mediated neurotransmission and fast-spiking (FS) GABAergic interneurons are central to cortical circuit development in the neonate. Here we demonstrate that there is a delay in the maturation of the intrinsic properties of FS interneurons in the sensory cortex, and a deficit in the formation of excitatory synaptic inputs on to these neurons in neonatal Fmr1 KO mice. Both these delays in neuronal and synaptic maturation were rectified by chronic administration of a TrkB receptor agonist. These results demonstrate that the maturation of the GABAergic circuit in the sensory cortex is altered during a critical developmental period due in part to a perturbation in BDNF-TrkB signaling, and could contribute to the alterations in cortical development underlying the sensory pathophysiology of FXS.

SIGNIFICANCE STATEMENT Fragile X (FXS) individuals have a range of sensory related phenotypes, and there is growing evidence of alterations in neuronal circuits in the sensory cortex of the mouse model of FXS (Fmr1 KO). GABAergic interneurons are central to the correct formation of circuits during cortical critical periods. Here we demonstrate a delay in the maturation of the properties and synaptic connectivity of interneurons in Fmr1 KO mice during a critical period of cortical development. The delays both in cellular and synaptic maturation were rectified by administration of a TrkB receptor agonist, suggesting reduced BDNF-TrkB signaling as a contributing factor. These results provide evidence that the function of fast-spiking interneurons is disrupted due to a deficiency in neurotrophin signaling during early development in FXS.

Domain Specificity of Oculomotor Learning after Changes in Sensory Processing

Humans visually process the world with varying spatial resolution and can program their eye movements optimally to maximize information acquisition for a variety of everyday tasks. Diseases such as macular degeneration can change visual sensory processing, introducing central vision loss (a scotoma). However, humans can learn to direct a new preferred retinal location to regions of interest for simple visual tasks. Whether such learned compensatory saccades are optimal and generalize to more complex tasks, which require integrating information across a large area of the visual field, is not well understood. Here, we explore the possible effects of central vision loss on the optimal saccades during a face identification task, using a gaze-contingent simulated scotoma. We show that a new foveated ideal observer with a central scotoma correctly predicts that the human optimal point of fixation to identify faces shifts from just below the eyes to one that is at the tip of the nose and another at the top of the forehead. However, even after 5000 trials, humans of both sexes surprisingly do not change their initial fixations to adapt to the new optimal fixation points to faces. In contrast, saccades do change for tasks such as object following and to a lesser extent during search. Our findings argue against a central brain motor-compensatory mechanism that generalizes across tasks. They instead suggest task specificity in the learning of oculomotor plans in response to changes in front-end sensory processing and the possibility of separate domain-specific representations of learned oculomotor plans in the brain.

SIGNIFICANCE STATEMENT The mechanism by which humans adapt eye movements in response to central vision loss is still not well understood and carries importance for gaining a fundamental understanding of brain plasticity. We show that although humans adapt their eye movements for simpler tasks such as object following and search, these adaptations do not generalize to more complex tasks such as face identification. We provide the first computational model to predict where humans with central vision loss should direct their eye movements in face identification tasks, which could become a critical tool in making patient-specific recommendations. Based on these results, we suggest a novel theory for oculomotor learning: a distributed representation of learned eye-movement plans represented in domain-specific areas of the brain.

{alpha}II Spectrin Forms a Periodic Cytoskeleton at the Axon Initial Segment and Is Required for Nervous System Function

Spectrins form a submembranous cytoskeleton proposed to confer strength and flexibility to neurons and to participate in ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Neuronal spectrin cytoskeletons consist of diverse β subunits and αII spectrin. Although αII spectrin is found in neurons in both axonal and somatodendritic domains, using proteomics, biochemistry, and superresolution microscopy, we show that αII and βIV spectrin interact and form a periodic AIS cytoskeleton. To determine the role of spectrins in the nervous system, we generated Sptan1^f/f mice for deletion of CNS αII spectrin. We analyzed αII spectrin-deficient mice of both sexes and found that loss of αII spectrin causes profound reductions in all β spectrins. αII spectrin-deficient mice die before 1 month of age and have disrupted AIS and many other neurological impairments including seizures, disrupted cortical lamination, and widespread neurodegeneration. These results demonstrate the importance of the spectrin cytoskeleton both at the AIS and throughout the nervous system.

SIGNIFICANCE STATEMENT Spectrin cytoskeletons play diverse roles in neurons, including assembly of excitable domains such as the axon initial segment (AIS) and nodes of Ranvier. However, the molecular composition and structure of these cytoskeletons remain poorly understood. Here, we show that αII spectrin partners with βIV spectrin to form a periodic cytoskeleton at the AIS. Using a new αII spectrin conditional knock-out mouse, we show that αII spectrin is required for AIS assembly, neuronal excitability, cortical lamination, and to protect against neurodegeneration. These results demonstrate the broad importance of spectrin cytoskeletons for nervous system function and development and have important implications for nervous system injuries and diseases because disruption of the spectrin cytoskeleton is a common molecular pathology.

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An {alpha}II Spectrin-Based Cytoskeleton Protects Large-Diameter Myelinated Axons from Degeneration

Axons must withstand mechanical forces, including tension, torsion, and compression. Spectrins and actin form a periodic cytoskeleton proposed to protect axons against these forces. However, because spectrins also participate in assembly of axon initial segments (AISs) and nodes of Ranvier, it is difficult to uncouple their roles in maintaining axon integrity from their functions at AIS and nodes. To overcome this problem and to determine the importance of spectrin cytoskeletons for axon integrity, we generated mice with αII spectrin-deficient peripheral sensory neurons. The axons of these neurons are very long and exposed to the mechanical forces associated with limb movement; most lack an AIS, and some are unmyelinated and have no nodes. We analyzed αII spectrin-deficient mice of both sexes and found that, in myelinated axons, αII spectrin forms a periodic cytoskeleton with βIV and βII spectrin at nodes of Ranvier and paranodes, respectively, but that loss of αII spectrin disrupts this organization. Avil-cre;Sptan1^f/f mice have reduced numbers of nodes, disrupted paranodal junctions, and mislocalized Kv1 K⁺ channels. We show that the density of nodal βIV spectrin is constant among axons, but the density of nodal αII spectrin increases with axon diameter. Remarkably, Avil-cre;Sptan1^f/f mice have intact nociception and small-diameter axons, but severe ataxia due to preferential degeneration of large-diameter myelinated axons. Our results suggest that nodal αII spectrin helps resist the mechanical forces experienced by large-diameter axons, and that αII spectrin-dependent cytoskeletons are also required for assembly of nodes of Ranvier.

SIGNIFICANCE STATEMENT A periodic axonal cytoskeleton consisting of actin and spectrin has been proposed to help axons resist the mechanical forces to which they are exposed (e.g., compression, torsion, and stretch). However, until now, no vertebrate animal model has tested the requirement of the spectrin cytoskeleton in maintenance of axon integrity. We demonstrate the role of the periodic spectrin-dependent cytoskeleton in axons and show that loss of αII spectrin from PNS axons causes preferential degeneration of large-diameter myelinated axons. We show that nodal αII spectrin is found at greater densities in large-diameter myelinated axons, suggesting that nodes are particularly vulnerable domains requiring a specialized cytoskeleton to protect against axon degeneration.

Pathological Tau Strains from Human Brains Recapitulate the Diversity of Tauopathies in Nontransgenic Mouse Brain

Pathological tau aggregates occur in Alzheimer's disease (AD) and other neurodegenerative tauopathies. It is not clearly understood why tauopathies vary greatly in the neuroanatomical and histopathological patterns of tau aggregation, which contribute to clinical heterogeneity in these disorders. Recent studies have shown that tau aggregates may form distinct structural conformations, known as tau strains. Here, we developed a novel model to test the hypothesis that cell-to-cell transmission of different tau strains occurs in nontransgenic (non-Tg) mice, and to investigate whether there are strain-specific differences in the pattern of tau transmission. By injecting pathological tau extracted from postmortem brains of AD (AD-tau), progressive supranuclear palsy (PSP-tau), and corticobasal degeneration (CBD-tau) patients into different brain regions of female non-Tg mice, we demonstrated the induction and propagation of endogenous mouse tau aggregates. Specifically, we identified differences in tau strain potency between AD-tau, CBD-tau, and PSP-tau in non-Tg mice. Moreover, differences in cell-type specificity of tau aggregate transmission were observed between tau strains such that only PSP-tau and CBD-tau strains induce astroglial and oligodendroglial tau inclusions, recapitulating the diversity of neuropathology in human tauopathies. Furthermore, we demonstrated that the neuronal connectome, but not the tau strain, determines which brain regions develop tau pathology. Finally, CBD-tau- and PSP-tau-injected mice showed spatiotemporal transmission of glial tau pathology, suggesting glial tau transmission contributes to the progression of tauopathies. Together, our data suggest that different tau strains determine seeding potency and cell-type specificity of tau aggregation that underlie the diversity of human tauopathies.

SIGNIFICANCE STATEMENT Tauopathies show great clinical and neuropathological heterogeneity, despite the fact that tau aggregates in each disease. This heterogeneity could be due to tau aggregates forming distinct structural conformations, or strains. We now report the development of a sporadic tauopathy model to study human tau strains by intracerebrally injecting nontransgenic mice with pathological tau enriched from human tauopathy brains. We show human tau strains seed different types and cellular distributions of tau neuropathology in our model that recapitulate the heterogeneity seen in these human diseases.

Ablation of TFR1 in Purkinje Cells Inhibits mGlu1 Trafficking and Impairs Motor Coordination, But Not Autistic-Like Behaviors

Group 1 metabotropic glutamate receptors (mGlu1/5s) are critical to synapse formation and participate in synaptic LTP and LTD in the brain. mGlu1/5 signaling alterations have been documented in cognitive impairment, neurodegenerative disorders, and psychiatric diseases, but underlying mechanisms for its modulation are not clear. Here, we report that transferrin receptor 1 (TFR1), a transmembrane protein of the clathrin complex, modulates the trafficking of mGlu1 in cerebellar Purkinje cells (PCs) from male mice. We show that conditional knock-out of TFR1 in PCs does not affect the cytoarchitecture of PCs, but reduces mGlu1 expression at synapses. This regulation by TFR1 acts in concert with that by Rab8 and Rab11, which modulate the internalization and recycling of mGlu1, respectively. TFR1 can bind to Rab proteins and facilitate their expression at synapses. PC ablation of TFR1 inhibits parallel fiber–PC LTD, whereas parallel fiber–LTP and PC intrinsic excitability are not affected. Finally, we demonstrate that PC ablation of TFR1 impairs motor coordination, but does not affect social behaviors in mice. Together, these findings underscore the importance of TFR1 in regulating mGlu1 trafficking and suggest that mGlu1- and mGlu1-dependent parallel fiber–LTD are associated with regulation of motor coordination, but not autistic behaviors.

SIGNIFICANCE STATEMENT Group 1 metabotropic glutamate receptor (mGlu1/5) signaling alterations have been documented in cognitive impairment, neurodegenerative disorders, and psychiatric diseases. Recent work suggests that altered mGlu1 signaling in Purkinje cells (PCs) may be involved in not only motor learning, but also autistic-like behaviors. We find that conditional knock-out of transferrin receptor 1 (TFR1) in PCs reduces synaptic mGlu1 by tethering Rab8 and Rab11 in the cytosol. PC ablation of TFR1 inhibits parallel fiber–PC LTD, whereas parallel fiber–PC LTP and PC intrinsic excitability are intact. Motor coordination is impaired, but social behaviors are normal in TFR1^flox/flox;pCP2-cre mice. Our data reveal a new regulator for trafficking and synaptic expression of mGlu1 and suggest that mGlu1-dependent LTD is associated with motor coordination, but not autistic-like behaviors.

Cortical Regulation of Nociception of the Trigeminal Nucleus Caudalis

Pain perception is strongly influenced by descending pathways from "higher" brain centers that regulate the activity of spinal circuits. In addition to the extensively studied descending system originating from the medulla, the neocortex provides dense anatomical projections that directly target neurons in the spinal cord and the spinal trigeminal nucleus caudalis (SpVc). Evidence exists that these corticotrigeminal pathways may modulate the processing of nociceptive inputs by SpVc, and regulate pain perception. We demonstrate here, with anatomical and optogenetic methods, and using both rats and mice (of both sexes), that corticotrigeminal axons densely innervate SpVc, where they target and directly activate inhibitory and excitatory neurons. Electrophysiological recordings reveal that stimulation of primary somatosensory cortex potently suppresses SpVc responses to noxious stimuli and produces behavioral hypoalgesia. These findings demonstrate that the corticotrigeminal pathway is a potent modulator of nociception and a potential target for interventions to alleviate chronic pain.

SIGNIFICANCE STATEMENT Many chronic pain conditions are resistant to conventional therapy. Promising new approaches to pain management capitalize on the brain's own mechanisms for controlling pain perception. Here we demonstrate that cortical neurons directly innervate the brainstem to drive feedforward inhibition of nociceptive neurons. This corticotrigeminal pathway suppresses the activity of these neurons and produces analgesia. This corticotrigeminal pathway may constitute a therapeutic target for chronic pain.

Gaze-Stabilizing Central Vestibular Neurons Project Asymmetrically to Extraocular Motoneuron Pools

Within reflex circuits, specific anatomical projections allow central neurons to relay sensations to effectors that generate movements. A major challenge is to relate anatomical features of central neural populations, such as asymmetric connectivity, to the computations the populations perform. To address this problem, we mapped the anatomy, modeled the function, and discovered a new behavioral role for a genetically defined population of central vestibular neurons in rhombomeres 5–7 of larval zebrafish. First, we found that neurons within this central population project preferentially to motoneurons that move the eyes downward. Concordantly, when the entire population of asymmetrically projecting neurons was stimulated collectively, only downward eye rotations were observed, demonstrating a functional correlate of the anatomical bias. When these neurons are ablated, fish failed to rotate their eyes following either nose-up or nose-down body tilts. This asymmetrically projecting central population thus participates in both upward and downward gaze stabilization. In addition to projecting to motoneurons, central vestibular neurons also receive direct sensory input from peripheral afferents. To infer whether asymmetric projections can facilitate sensory encoding or motor output, we modeled differentially projecting sets of central vestibular neurons. Whereas motor command strength was independent of projection allocation, asymmetric projections enabled more accurate representation of nose-up stimuli. The model shows how asymmetric connectivity could enhance the representation of imbalance during nose-up postures while preserving gaze stabilization performance. Finally, we found that central vestibular neurons were necessary for a vital behavior requiring maintenance of a nose-up posture: swim bladder inflation. These observations suggest that asymmetric connectivity in the vestibular system facilitates representation of ethologically relevant stimuli without compromising reflexive behavior.

SIGNIFICANCE STATEMENT Interneuron populations use specific anatomical projections to transform sensations into reflexive actions. Here we examined how the anatomical composition of a genetically defined population of balance interneurons in the larval zebrafish relates to the computations it performs. First, we found that the population of interneurons that stabilize gaze preferentially project to motoneurons that move the eyes downward. Next, we discovered through modeling that such projection patterns can enhance the encoding of nose-up sensations without compromising gaze stabilization. Finally, we found that loss of these interneurons impairs a vital behavior, swim bladder inflation, that relies on maintaining a nose-up posture. These observations suggest that anatomical specialization permits neural circuits to represent relevant features of the environment without compromising behavior.

Concerted Interneuron Activity in the Cerebellar Molecular Layer During Rhythmic Oromotor Behaviors

Molecular layer interneurons (MLIs, stellate and basket cells) of the cerebellar cortex are linked together by chemical and electrical synapses and exert a potent feedforward inhibition on Purkinje cells. The functional role of MLIs during specific motor tasks is uncertain. Here, we used two-photon imaging to study the patterns of activity of neighboring individual MLIs in the Crus II region of awake female mice during two types of oromotor activity, licking and bruxing, using specific expression of the genetically encoded calcium indicator protein GCaMP6s. We found that both stellate and basket cells engaged in synchronized waves of calcium activity during licking and bruxing, with high degrees of correlation among the signals collected in individual MLIs. In contrast, no calcium activity was observed during whisking. MLI activity tended to lag behind the onset of sustained licking episodes, indicating a regulatory action of MLIs during licking. Furthermore, during licking, stellate cell activity was anisotropic: the coordination was constant along the direction of parallel fibers (PFs), but fell off with distance along the orthogonal direction. These results suggest a PF drive for Ca²⁺ signals during licking. In contrast, during bruxing, MLI activity was neither clearly organized spatially nor temporally correlated with oromotor activity. In conclusion, MLI activity exhibits a high degree of correlation both in licking and in bruxing, but spatiotemporal patterns of activity display significant differences for the two types of behavior.

SIGNIFICANCE STATEMENT It is known that, during movement, the activity of molecular layer interneurons (MLIs) of the cerebellar cortex is enhanced. However, MLI–MLI interactions are complex because they depend both from excitatory electrical synapses and from potentially inhibitory chemical synapses. Accordingly, the pattern of MLI activity during movement has been unclear. Here, during two oromotor tasks, licking and bruxism, individual neighboring MLIs displayed highly coordinated activity, showing that the positive influences binding MLIs together are predominant. We further find that spatiotemporal patterns differ between licking and bruxing, suggesting that the precise pattern of MLI activity depends on the nature of the motor task.

Parkinson's Disease-Associated LRRK2 Hyperactive Kinase Mutant Disrupts Synaptic Vesicle Trafficking in Ventral Midbrain Neurons

Parkinson's disease (PD) is characterized pathologically by the selective loss of substantia nigra (SN) dopaminergic (DAergic) neurons. Recent evidence has suggested a role of LRRK2, linked to the most frequent familial PD, in regulating synaptic vesicle (SV) trafficking. However, the mechanism whereby LRRK2 mutants contribute to nigral vulnerability remains unclear. Here we show that the most common PD mutation LRRK2 G2019S impairs SV endocytosis in ventral midbrain (MB) neurons, including DA neurons, and the slowed endocytosis can be rescued by inhibition of LRRK2 kinase activity. A similar endocytic defect, however, was not observed in LRRK2 mutant neurons from the neocortex (hereafter, cortical neurons) or the hippocampus, suggesting a brain region-specific vulnerability to the G2019S mutation. Additionally, we found MB-specific impairment of SV endocytosis in neurons carrying heterozygous deletion of SYNJ1 (PARK20), a gene that is associated with recessive Parkinsonism. Combining SYNJ1^+/– and LRRK2 G2019S does not exacerbate SV endocytosis but impairs sustained exocytosis in MB neurons and alters specific motor functions of 1-year-old male mice. Interestingly, we show that LRRK2 directly phosphorylates synaptojanin1 in vitro, resulting in the disruption of endophilin-synaptojanin1 interaction required for SV endocytosis. Our work suggests a merge of LRRK2 and SYNJ1 pathogenic pathways in deregulating SV trafficking in MB neurons as an underlying molecular mechanism of early PD pathogenesis.

SIGNIFICANCE STATEMENT Understanding midbrain dopaminergic (DAergic) neuron-selective vulnerability in PD is essential for the development of targeted therapeutics. We report, for the first time, a nerve terminal impairment in SV trafficking selectively in MB neurons but not cortical neurons caused by two PARK genes: LRRK2 (PARK8) and SYNJ1 (PARK20). We demonstrate that the enhanced kinase activity resulting from the most frequent G2019S mutation in LRRK2 is the key to this impairment. We provide evidence suggesting that LRRK2 G2019S and SYNJ1 loss of function share a similar pathogenic pathway in deregulating DAergic neuron SV endocytosis and that they play additive roles in facilitating each other's pathogenic functions in PD.

GFP-Mutant Human Tau Transgenic Mice Develop Tauopathy Following CNS Injections of Alzheimer's Brain-Derived Pathological Tau or Synthetic Mutant Human Tau Fibrils

Neurodegenerative proteinopathies characterized by intracellular aggregates of tau proteins, termed tauopathies, include Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-tau), and related disorders. Pathological tau proteins derived from human AD brains (AD-tau) act as proteopathic seeds that initiate the templated aggregation of soluble tau upon intracerebral injection into tau transgenic (Tg) and wild-type mice, thereby modeling human tau pathology. In this study, we found that aged Tg mice of both sexes expressing human tau proteins harboring a pathogenic P301L MAPT mutation labeled with green fluorescent protein (T40PL-GFP Tg mouse line) exhibited hyperphosphorylated tau mislocalized to the somatodentritic domain of neurons, but these mice did not develop de novo insoluble tau aggregates, which are characteristic of human AD and related tauopathies. However, intracerebral injections of either T40PL preformed fibrils (PFFs) or AD-tau seeds into T40PL-GFP mice induced abundant intraneuronal pathological inclusions of hyperphosphorylated T40PL-GFP. These injections of pathological tau resulted in the propagation of tau pathology from the injection site to neuroanatomically connected brain regions, and these tau inclusions consisted of both T40PL-GFP and WT endogenous mouse tau. Primary neurons cultured from the brains of neonatal T40PL-GFP mice provided an informative in vitro model for examining the uptake and localization of tau PFFs. These findings demonstrate the seeded aggregation of T40PL-GFP in vivo by synthetic PFFs and human AD-tau and the utility of this system to study the neuropathological spread of tau aggregates.

SIGNIFICANCE STATEMENT The stereotypical spread of pathological tau protein aggregates have recently been attributed to the transmission of proteopathic seeds. Despite the extensive use of transgenic mouse models to investigate the propagation of tau pathology in vivo, details of the aggregation process such as the early seeding events leading to new tau pathology have remained elusive. This study validates the use of GFP-labeled tau expressed by neurons in vivo and in vitro as models for investigating mechanisms underlying the seeded transmission of tau pathology as well as tau-focused drug discovery to identify disease-modifying therapies for AD and related tauopathies.