Sources and environmental fate of halomethoxybenzenes.

Halomethoxybenzenes are pervasive in the atmosphere at concentration levels that exceed, often by an order of magnitude, those of the persistent organic pollutants with which they share the attributes of persistence and potential for long-range transport, bioaccumulation, and toxic effects. Long ignored by environmental chemists because of their predominantly natural origin-namely, synthesis by terrestrial wood-rotting fungi, marine algae, and invertebrates-knowledge of their environmental pathways remains limited. Through measuring the spatial and seasonal variability of four halomethoxybenzenes in air and precipitation and performing complementary environmental fate simulations, we present evidence that these compounds undergo continental-scale transport in the atmosphere, which they enter largely by evaporation from water. This also applies to halomethoxybenzenes originating in terrestrial environments, such as drosophilin A methyl ether, which reach aquatic environments with runoff, possibly in the form of their phenolic precursors. Our findings contribute substantially to the comprehension of sources and fate of halomethoxybenzenes, illuminating their widespread atmospheric dispersal.

Repeat resection for recurrent glioblastoma in the temozolomide era: a real-world multi-centre study.

INTRODUCTION: In contrast to standard-of-care treatment of newly diagnosed glioblastoma, there is limited consensus on therapy upon disease progression. The role of resection for recurrent glioblastoma remains unclear. This study aimed to identify factors for overall survival (OS) and post-progression survival (PPS) as well as to validate an existing prediction model. METHODS: This was a multi-centre retrospective study that reviewed consecutive adult patients from 2006 to 2019 that received a repeat resection for recurrent glioblastoma. The primary endpoint was PPS defined as from the date of second surgery until death. RESULTS: 1032 glioblastoma patients were identified and 190 (18%) underwent resection for recurrence. Patients that had second surgery were more likely to be younger (<70 years) (adjusted OR: 0.3; 95% CI: 0.1-0.6), to have non-eloquent region tumours (aOR: 1.7; 95% CI: 1.1-2.6) and received temozolomide chemoradiotherapy (aOR: 0.2; 95% CI: 0.1-0.4). Resection for recurrent tumour was an independent predictor for OS (aOR: 1.5; 95% CI: 1.3-1.7) (mOS: 16.9 months versus 9.8 months). For patients that previously received temozolomide chemoradiotherapy and subsequent repeat resection (137, 13%), the median PPS was 9.0 months (IQR: 5.0-17.5). Independent PPS predictors for this group were a recurrent tumour volume of >50cc (aOR: 0.6; 95% CI: 0.4-0.9), local recurrence (aOR: 1.7; 95% CI: 1.1-3.3) and 5-ALA fluorescence-guided resection during second surgery (aOR: 1.7; 95% CI: 1.1-2.8). A National Institutes of Health Recurrent Glioblastoma Multiforme Scale score of 0 conferred an mPPS of 10.0 months, a score of 1-2, 9.0 months and a score of 3, 4.0 months (log-rank test, p-value < 0.05). CONCLUSION: Surgery for recurrent glioblastoma can be beneficial in selected patients and carries an acceptable morbidity rate. The pattern of recurrence influenced PPS and the NIH Recurrent GBM Scale was a reliable prognostication tool.

Neonatal T Helper 17 Responses Are Skewed Towards an Immunoregulatory Interleukin-22 Phenotype.

Newborns are frequently affected by mucocutaneous candidiasis. Th17 cells essentially limit mucosal invasion by commensal Candida spp. Here, we sought to understand the molecular basis for the developmental lack of Th17 cell responses in circulating blood neonatal T cells. Naive cord blood CD4 T cells stimulated in Th17-differentiating conditions inherently produced high levels of the interleukin-22 immunoregulatory cytokine, particularly in the presence of neonatal antigen-presenting cells. A genome-wide transcriptome analysis comparing neonatal and adult naïve CD4 T cells ex vivo revealed major developmental differences in gene networks regulating Small Drosophila Mothers Against Decapentaplegic (SMAD) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling. These changes were functionally validated by experiments showing that the requirement for TGF-ß in human Th17 cell differentiation is age-dependent. Moreover, STAT3 activity was profoundly diminished while overexpression of the STAT3 gene restored Th17 cell differentiation capacity in neonatal T cells. These data reveal that Th17 cell responses are developmentally regulated at the gene expression level in human neonates. These developmental changes may protect newborns against pathological Th17 cell responses, at the same time increasing their susceptibility to mucocutaneous candidiasis.

The Effect of Massage on the Cardiac Autonomic Nervous System and Markers of Inflammation in Night Shift Workers: a Pilot Randomized Crossover Trial.

BACKGROUND: Shift work is a necessary part of many industries; however, it can have detrimental effects on health over time. PURPOSE: This study investigated the effect of a massage intervention on the cardiac autonomic activity and blood inflammatory markers of healthy medical residents working night shifts. SETTING: This trial was conducted at British Columbia Children's and Women's Hospital between February 2014 and June 2016. PARTICIPANTS: Included participants were generally healthy medical residents and were working rotating night shifts on a regular basis. RESEARCH DESIGN: This was a randomized, controlled, crossover, open-label trial (NCT02247089). INTERVENTIONS: Participants received either a 30-min massage intervention or reading control after consecutive periods of night shift. MAIN OUTCOME MEASURES: The primary outcome was high frequency, a proxy for the cardiac parasympathetic activity, measured via heart rate variability. Secondary outcomes included other heart rate variability measures, blood markers of inflammation, and blood pressure. RESULTS: Twelve participants were recruited (nine female) with median age of 28 years. There was no significant difference between the massage intervention and the reading control for the primary outcome, (median relative change between pre- and postmassage [interquartile range]: 62% [-1 to 150], pre- and postreading: 14% [-10 to 51], p = .16). Similarly, there was no difference with respect to blood inflammatory markers and blood pressure. Median high frequency significantly increased between pre- and postmassage (185 vs. 358 ms2, p = .04). CONCLUSION: This pilot study found no statistically significant difference between the massage intervention and the reading control; however, we did observe a significant increase in median high frequency from before massage to after massage, indicative of increased parasympathetic activity. This study may help inform planning of larger trials evaluating massage interventions on the activity of the autonomic nervous system and managing shift work stress.

Cellular metabolism constrains innate immune responses in early human ontogeny.

Pathogen immune responses are profoundly attenuated in fetuses and premature infants, yet the mechanisms underlying this developmental immaturity remain unclear. Here we show transcriptomic, metabolic and polysome profiling and find that monocytes isolated from infants born early in gestation display perturbations in PPAR-γ-regulated metabolic pathways, limited glycolytic capacity and reduced ribosomal activity. These metabolic changes are linked to a lack of translation of most cytokines and of MALT1 signalosome genes essential to respond to the neonatal pathogen Candida. In contrast, they have little impact on house-keeping phagocytosis functions. Transcriptome analyses further indicate a role for mTOR and its putative negative regulator DNA Damage Inducible Transcript 4-Like in regulating these metabolic constraints. Our results provide a molecular basis for the broad susceptibility to multiple pathogens in these infants, and suggest that the fetal immune system is metabolically programmed to avoid energetically costly, dispensable and potentially harmful immune responses during ontogeny.

LRRK2 p.Ile1371Val Mutation in a Case with Neuropathologically Confirmed Multi-System Atrophy.

BACKGROUND: Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are among the most common genetic causes of Lewy body Parkinson's disease (PD). However, LRRK2 mutations can also lead to a variety of pathological phenotypes other than typical PD, including relatively pure nigrostriatal cell loss without alpha-synuclein-positive Lewy bodies or Lewy neurites, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). The mechanisms behind this remarkable pleomorphic pathology are currently unclear. OBJECTIVE: To genetically and pathologically characterize a case with a LRRK2, p.Ile1371Val rare variant and pathologically proven MSA. METHODS: From the brain donation program at the Parkinson's Institute and Clinical Center, we selected 26 brains with family history and a with clinicopathological diagnosis of PD (n = 20), MSA (n = 4), or PSP (n = 2). We performed neuropathological evaluation, including alpha-synuclein and tau immunohistochemistry and sequenced 188 genes that have been reported as causative for or associated with neurodegenerative diseases. RESULTS: We identified a known LRRK2, p.Ile1371Val genetic variant in a case with clinically diagnosed and pathologically proven MSA. Neuropathology revealed that the olivopontocerebellar system was more affected than the striatonigral system. CONCLUSIONS: Our data suggest that genetic variants in the LRRK2 gene can present clinically and neuropathologically as MSA. One other LRRK2 genetic variant (LRRK2, p.Ile2020Thr) has been reported with a neuropathological diagnosis of MSA. Interestingly, the LRRK2 variant (LRRK2, p.Ile1371Val) identified here has been reported previously in a postmortem case with Lewy body PD.Future studies are critical to discover the mechanisms leading to different neurodegenerative trajectories both in neuronal and glial cell populations.

Effects of repetitive transcranial magnetic stimulation on improvement of cognition in elderly patients with cognitive impairment: a systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to examine the effects of repetitive transcranial magnetic stimulation (rTMS) on cognitive function in older patients with cognitive impairment. METHODS: A literature search was performed for articles published in English using the 10 databases (MEDLINE, EMBASE, PsycINFO, INSPEC, the Cumulative Index to Nursing and Allied Health Literature Plus, AMED, Biological Sciences, ClinicalTrials.gov, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews) from their inception to May 2016. The primary outcome was cognitive function as measured by the Mini-Mental State Examination or the Alzheimer's Disease Assessment Scale-cognitive subscale. RESULTS: Seven RCTs were included in the meta-analysis, with a sample of 107 active and 87 sham rTMS. Active rTMS was found to be more effective in improving cognition (Hedges' g = 0.48; 95% confidence interval 0.12 to 0.84). CONCLUSIONS: High-frequency rTMS showed a benefit on cognition amongst older patients with mild to moderate Alzheimer's disease. rTMS was shown to have great potential as a safe and well-tolerated alternative intervention for cognition. Copyright © 2017 John Wiley & Sons, Ltd.

Parkinson's disease associated with pure ATXN10 repeat expansion.

Large, non-coding pentanucleotide repeat expansions of ATTCT in intron 9 of the ATXN10 gene typically cause progressive spinocerebellar ataxia with or without seizures and present neuropathologically with Purkinje cell loss resulting in symmetrical cerebellar atrophy. These ATXN10 repeat expansions can be interrupted by sequence motifs which have been attributed to seizures and are likely to act as genetic modifiers. We identified a Mexican kindred with multiple affected family members with ATXN10 expansions. Four affected family members showed clinical features of spinocerebellar ataxia type 10 (SCA10). However, one affected individual presented with early-onset levodopa-responsive parkinsonism, and one family member carried a large repeat ATXN10 expansion, but was clinically unaffected. To characterize the ATXN10 repeat, we used a novel technology of single-molecule real-time (SMRT) sequencing and CRISPR/Cas9-based capture. We sequenced the entire span of ~5.3-7.0 kb repeat expansions. The Parkinson's patient carried an ATXN10 expansion with no repeat interruption motifs as well as an unaffected sister. In the siblings with typical SCA10, we found a repeat pattern of ATTCC repeat motifs that have not been associated with seizures previously. Our data suggest that the absence of repeat interruptions is likely a genetic modifier for the clinical presentation of l-Dopa responsive parkinsonism, whereas repeat interruption motifs contribute clinically to epilepsy. Repeat interruptions are important genetic modifiers of the clinical phenotype in SCA10. Advanced sequencing techniques now allow to better characterize the underlying genetic architecture for determining accurate phenotype-genotype correlations.

Aggregation and Its Influence on the Immunomodulatory Activity of Synthetic Innate Defense Regulator Peptides.

There is increasing interest in developing cationic host defense peptides (HDPs) and their synthetic derivatives as antimicrobial, immunomodulatory, and anti-biofilm agents. These activities are often evaluated without considering biologically relevant concentrations of salts or serum; furthermore certain HDPs have been shown to aggregate in vitro. Here we examined the effect of aggregation on the immunomodulatory activity of a synthetic innate defense regulator peptide, 1018 (VRLIVAVRIWRR-NH2). A variety of salts and solutes were screened to determine their influence on 1018 aggregation, revealing that this peptide "salts out" of solution in an anion-specific and concentration-dependent manner. Furthermore, the immunomodulatory activity of 1018 was found to be inhibited under aggregation-promoting conditions. A series of 1018 derivatives were synthesized with the goal of disrupting this self-assembly process. Indeed, some derivatives exhibited reduced aggregation while maintaining certain immunomodulatory functions, demonstrating that it is possible to engineer optimized synthetic HDPs to avoid unwanted peptide aggregation.

Derivation of Leptomeninges Explant Cultures from Postmortem Human Brain Donors.

Even though great progress has been made in the clinical characterization of Parkinson's disease, several studies report that the diagnosis of Parkinson's disease is not pathologically confirmed in up to 25% of clinically diagnosed Parkinson's disease. Therefore, tissue collected from clinically diagnosed patients with idiopathic Parkinson's disease can have a high rate of misdiagnosis; hence in vitro studies from such tissues to study Parkinson's disease as a preclinical model can become futile. By collecting postmortem human leptomeninges with a confirmed neuropathological diagnosis of Parkinson's disease and characterized by nigrostriatal cell loss and intracellular protein inclusions called Lewy bodies, one can be certain that clinically observed parkinsonism is not caused by another underlying disease process (e.g. tumor, arteriosclerosis). This protocol presents the dissection and preparation of postmortem human leptomeninges for derivation of a meningeal fibroblast culture. This procedure is robust and has a high success rate. The challenge of the culture is sterility as the brain procurement is generally not performed under sterile conditions. Therefore, it is important to supplement the culture media with a cocktail of penicillin, streptomycin, and amphotericin B. The derivation of meningeal fibroblasts from autopsy-confirmed cases with Parkinson's disease provides the foundation for in vitro modeling of Parkinson's disease. Meningeal fibroblasts appear 3-9 days after sample preparation and about 20-30 million cells can be cryopreserved in 6-8 weeks. The meningeal fibroblast culture is homogenous and the cells express fibronectin, a commonly used marker to identify meninges.

CD44 expression in endothelial colony-forming cells regulates neurovascular trophic effect.

Vascular abnormalities are a common component of eye diseases that often lead to vision loss. Vaso-obliteration is associated with inherited retinal degenerations, since photoreceptor atrophy lowers local metabolic demands and vascular support to those regions is no longer required. Given the degree of neurovascular crosstalk in the retina, it may be possible to use one cell type to rescue another cell type in the face of severe stress, such as hypoxia or genetically encoded cell-specific degenerations. Here, we show that intravitreally injected human endothelial colony-forming cells (ECFCs) that can be isolated and differentiated from cord blood in xeno-free media collect in the vitreous cavity and rescue vaso-obliteration and neurodegeneration in animal models of retinal disease. Furthermore, we determined that a subset of the ECFCs was more effective at anatomically and functionally preventing retinopathy; these cells expressed high levels of CD44, the hyaluronic acid receptor, and IGFBPs (insulin-like growth factor-binding proteins). Injection of cultured media from ECFCs or only recombinant human IGFBPs also rescued the ischemia phenotype. These results help us to understand the mechanism of ECFC-based therapies for ischemic insults and retinal neurodegenerative diseases.

Deep sedation without intubation during second trimester surgical termination in an inpatient hospital setting.

OBJECTIVES: Safety of outpatient dilation and evacuations with intravenous (iv) sedation without intubation has been demonstrated, but there is a paucity of data on deep iv sedation on an inpatient second trimester surgical termination population. The purpose of this study is to evaluate complications of deep sedation with propofol without the use of intubation during second trimester surgical terminations in an inpatient teaching institution. STUDY DESIGN: A retrospective chart review of all obstetrical and anesthetic data from inpatient dilation and evacuations between gestational ages 15 0/7 and 24 0/7 during the years 2002 to 2015. We examined 332 patient charts. Primary outcomes included suspected perioperative pulmonary aspiration and conversion to an intubated general anesthesia. RESULTS: No perioperative pulmonary aspiration cases were either suspected or confirmed. There were a total of 14 (4.2%) patients that had intubation compared to 313 with natural airway (94.3%) or laryngeal mask (1.5%). Of the 14 intubated, 9 (64%) were started with intubation, and 5 (36%) were converted during the procedure (1.7% of those started with nonintubated anesthesia). Cases requiring intubation were associated with longer procedure times (p=<0.001), higher American Society of Anesthesiologists (ASA) class (p=0.038), greater estimated blood loss (p=<0.001) and a primary indication of maternal health (p=<0.001) for the dilation and evacuation. CONCLUSIONS: Deep sedation without intubation appears safe in a hospital setting with few complications reported. IMPLICATIONS: Deep sedation without intubation for operating room dilation and evacuation is a safe option that rarely resulted in conversion to intubation and, in most cases, should be the anesthesia method of choice at initiation in an inpatient setting.