Cholinergic basal forebrain neurons of the nucleus basalis of Meynert (nbM) regulate attentional and memory function and are exquisitely prone to tau pathology and neurofibrillary tangle (NFT) ...formation during the progression of Alzheimer's disease (AD). nbM neurons require the neurotrophin nerve growth factor (NGF), its cognate receptor TrkA, and the pan-neurotrophin receptor p75NTR for their maintenance and survival. Additionally, nbM neuronal activity and cholinergic tone are regulated by the expression of nicotinic (nAChR) and muscarinic (mAChR) acetylcholine receptors as well as receptors modulating glutamatergic and catecholaminergic afferent signaling. To date, the molecular and cellular relationships between the evolution of tau pathology and nbM neuronal survival remain unknown. To address this knowledge gap, we profiled cholinotrophic pathway genes within nbM neurons immunostained for pS422, a pretangle phosphorylation event preceding tau C-terminal truncation at D421, or dual-labeled for pS422 and TauC3, a later stage tau neo-epitope revealed by this same C-terminal truncation event, via single-population custom microarray analysis. nbM neurons were obtained from postmortem tissues from subjects who died with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. Quantitative analysis revealed significant downregulation of mRNAs encoding TrkA as well as TrkB, TrkC, and the Trk-mediated downstream pro-survival kinase Akt in pS422+ compared to unlabeled, pS422-negative nbM neurons. In addition, pS422+ neurons displayed a downregulation of transcripts encoding NMDA receptor subunit 2B, metabotropic glutamate receptor 2, D2 dopamine receptor, and β1 adrenoceptor. By contrast, transcripts encoding p75NTR were downregulated in dual-labeled pS422+/TauC3+ neurons. Appearance of the TauC3 epitope was also associated with an upregulation of the α7 nAChR subunit and differential downregulation of the β2 nAChR subunit. Notably, we found that gene expression patterns for each cell phenotype did not differ with clinical diagnosis. However, linear regression revealed that global cognition and Braak stage were predictors of select transcript changes within both unlabeled and pS422+/TauC3− neurons. Taken together, these cell phenotype-specific gene expression profiling data suggest that dysregulation of neurotrophic and neurotransmitter signaling is an early pathogenic mechanism associated with NFT formation in vulnerable nbM neurons and cognitive decline in AD, which may be amenable to therapeutic intervention early in the disease process.
•Downregulation of high affinity neurotrophin receptors coincides with pretangle pathology in cholinergic nbM neurons.•Dysregulation of select neurotransmitter receptors coincides with pretangle pathology in cholinergic nbM neurons.•Gene dysregulation within nbM neurons is related to tau pathological status, global cognition, and Braak stage.•Pathological dysregulation of neurotrophic and neurotransmitter signaling is associated with pretangle formation.
Widespread occurrence of emerging contaminants in Great Lakes tributaries led to the development and publication of a vulnerability index (VI) to assess the potential exposure of aquatic communities ...to chemicals of emerging concern (CEC) in the Great Lakes basin. The robust nature of the VI was tested to evaluate the underlying statistical model and expand the spatial domain of the index. Data collected at 131 new sampling sites (Test 1) and published data from independent studies (Test 2) were used to test the model predictions. Test 1 water and sediment samples were analyzed for the same classes of CEC chemicals and compared to the predictions for the original VI. Concentrations and numbers of unique CECs detected in water and sediment samples were similar between the original data and the two test datasets, although CECs tended to have higher detection frequencies in the original dataset compared to the Test 1 and Test 2 datasets. For example, 69 CECs were detected in ≥30% of water samples in the original dataset compared with 17 CECs in the Test 1 data and 59 in the Test 2 data. Predicted vulnerability for test sites agreed with actual vulnerability 64% of the time for water and 71% of the time for sediment. Agreement percentage results were greater when individual sites were grouped by river, with 82% agreement between predictions and actual vulnerability for water and 78% agreement for sediment. For the entire dataset, the VI ranks correlated with an independent estimate of potential biological impact. Agreement percentage was the greatest for low or high vulnerability index values but highly variable for sites that are classified as having medium vulnerability. Despite the underlying variability, there is a significant correlation (R2 = 0.26; p < 0.01) between the VI ranking of tributaries and the independent ranking of potential negative biological impact.
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•Chemicals of emerging concern (CEC) occur throughout Great Lakes tributaries.•Vulnerability index (VI) created to assess exposure of aquatic communities to CECs.•We tested VI predictions throughout the Great Lakes basin.•VI predictions and observed CEC presence agreed for water (64%) and sediment (78%).•VI compared favorably with independent assessment of biological effects.
Highlights • Diaphragm muscle (DIAm) sarcopenia impairs higher force required for airway clearance. • Sarcopenia decreases force of more fatigable DIAm motor units-type IIx/IIb fibers. • Sarcopenia ...reflects reduced neurotrophic influence at motor neurons and DIAm fibers. • Reduced NRG/ErbB signaling underlies IIx/IIb fiber atrophy and reduced force in DIAm. • Reduced BDNF/TrkB signaling underlies phrenic motor neuron loss triggering sarcopenia.
Urinary Soluble CD163 in Active Renal Vasculitis O'Reilly, Vincent P; Wong, Limy; Kennedy, Claire ...
Journal of the American Society of Nephrology,
09/2016, Letnik:
27, Številka:
9
Journal Article
Recenzirano
Odprti dostop
A specific biomarker that can separate active renal vasculitis from other causes of renal dysfunction is lacking, with a kidney biopsy often being required. Soluble CD163 (sCD163), shed by monocytes ...and macrophages, has been reported as a potential biomarker in diseases associated with excessive macrophage activation. Thus, we hypothesized that urinary sCD163 shed by crescent macrophages correlates with active glomerular inflammation. We detected sCD163 in rat urine early in the disease course of experimental vasculitis. Moreover, microdissected glomeruli from patients with small vessel vasculitis (SVV) had markedly higher levels of CD163 mRNA than did those from patients with lupus nephritis, diabetic nephropathy, or nephrotic syndrome. Both glomeruli and interstitium of patients with SVV strongly expressed CD163 protein. In 479 individuals, including patients with SVV, disease controls, and healthy controls, serum levels of sCD163 did not differ between the groups. However, in an inception cohort, including 177 patients with SVV, patients with active renal vasculitis had markedly higher urinary sCD163 levels than did patients in remission, disease controls, or healthy controls. Analyses in both internal and external validation cohorts confirmed these results. Setting a derived optimum cutoff for urinary sCD163 of 0.3 ng/mmol creatinine for detection of active renal vasculitis resulted in a sensitivity of 83%, specificity of 96%, and a positive likelihood ratio of 20.8. These data indicate that urinary sCD163 level associates very tightly with active renal vasculitis, and assessing this level may be a noninvasive method for diagnosing renal flare in the setting of a known diagnosis of SVV.
Abstract
(Forensic) toxicology has faced many challenges, both analytically and interpretatively, especially in relation to an increase in potential drugs of interest. Analytical toxicology and its ...application to medicine and forensic science have progressed rapidly within the past centuries. Technological innovations have enabled detection of more substances with increasing sensitivity in a variety of matrices. Our understanding of the effects (both intended and unintended) have also increased along with determination and degree of toxicity. However, it is clear there is even more to understand and consider. The analytical focus has been on typical matrices such as blood and urine but other matrices could further increase our understanding, especially in postmortem (PM) situations. Within this context, the role of PM changes and potential redistribution of drugs requires further research and identification of markers of its occurrence and extent. Whilst instrumentation has improved, in the future, nanotechnology may play a role in selective and sensitive analysis as well as bioassays. Toxicologists often only have an advisory impact on pre-analytical and pre-interpretative considerations. The collection of appropriate samples at the right time in an appropriate way as well as obtaining sufficient circumstance background is paramount in ensuring an effective analytical strategy to provide useful results that can be interpreted within context. Nevertheless, key interpretative considerations such as pharmacogenomics and drug–drug interactions as well as determination of tolerance remain and in the future, analytical confirmation of an individual’s metabolic profile may support a personalized medicine and judicial approach. This should be supported by the compilation and appropriate application of drug data pursuant to the situation. Specifically, in PM circumstances, data pertaining to where a drug was not/may have been/was contributory will be beneficial with associated pathological considerations. This article describes the challenges faced within toxicology and discusses progress to a future where they are being addressed.
Genetic disorders are one of the leading causes of infant mortality and are frequent in neonatal intensive care units (NICUs). Rapid genome-wide sequencing (GWS; whole genome or exome sequencing ...(ES)), due to its diagnostic capabilities and immediate impacts on medical management, is becoming an appealing testing option in the NICU setting. RAPIDOMICS was a trio-based rapid ES pilot study of 25 babies with suspected genetic disorders in the BC Women’s Hospital NICU. ES and bioinformatic analysis were performed after careful patient ascertainment. Trio analysis was performed using an in-house pipeline reporting variants in known disease-causing genes. Variants interpreted by the research team as definitely or possibly causal of the infant’s phenotype were Sanger validated in a clinical laboratory. The average time to preliminary diagnosis was 7.2 days. Sanger validation was pursued in 15 patients for 13 autosomal dominant and 2 autosomal recessive disorders, with an overall diagnostic rate (partial or complete) of 60%.
Conclusion
: In total, 72% of patients enrolled had a genomic diagnosis achieved through ES, multi-gene panel testing or chromosomal microarray analysis. Among these, there was an 83% rate of significant and immediate impact on medical decision-making directly related to new knowledge of the diagnosis
.
Health service implementation challenges and successes are discussed.
What is Known:
•
Rapid genome-wide sequencing in the neonatal intensive care setting has a greater diagnostic hit rate and impact on medical management than conventional genetic testing. However, the impact of consultation with genetics and patient ascertainment requires further investigation.
What is New:
•
This study demonstrates the importance of genetic consultation and careful patient selection prior to pursuing exome sequencing (ES).
•
In total, 15/25 (60%) patients achieved a diagnosis through ES and 18/25 (72%) through ES, multi-gene panel testing or chromosomal microarray analysis with 83% of those having immediate effects on medical management.
The COVID-19 pandemic prompted healthcare professionals to implement service delivery adaptations to remain in compliance with safety regulations. Though many adaptations in service delivery were ...reported throughout the literature, a wide variety of terminology and definitions were used.
To address this, we conducted a PRISMA review to identify service delivery adaptations across behavioral healthcare services in the United States from March 2020 to May 2022 and to identify variations in terminology used to describe these adaptations. We identified 445 initial articles for our review across eight databases using predetermined keywords. Using a two-round screening process, authors used a team approach to identify the most appropriate articles for this review.
Our results suggested that a total of 14 different terms were used to describe service modality changes, with the most frequent term being
(63%). Each term found in our review and the frequency of use across identified articles is described in detail.
Implications of this review such as understanding modality changes during the COVID-19 pandemic and beyond are discussed. Our findings illustrate the importance of standardizing terminology to enhance communication and understanding among professionals.
In the present study, a patient-derived orthotopic xenograft (PDOX) model of recurrent cisplatinum (CDDP)-resistant metastatic osteosarcoma was treated with Salmonella typhimurium A1-R (S. ...typhimurium A1-R), which decoys chemoresistant quiescent cancer cells to cycle, and recombinant methioninase (rMETase), which selectively traps cancer cells in late S/G
, and chemotherapy. The PDOX models were randomized into the following groups 14 days after implantation: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks). G4, S. typhimurium A1-R (5 × 10
CFU/100 μl, i.v., weekly, for 2 weeks); G5, S. typhimurium A1-R (5 × 10
CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G6, S. typhimurium A1-R (5 × 10
CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks) and CDDP (6 mg/kg, i.p. injection, weekly, for 2 weeks). On day 14 after initiation, all treatments except CDDP alone, significantly inhibited tumor growth compared to untreated control: (CDDP: p = 0.586; rMETase: p = 0.002; S. typhimurium A1-R: p = 0.002; S. typhimurium A1-R combined with rMETase: p = 0.0004; rMETase combined with both S. typhimurium A1-R and CDDP: p = 0.0001). The decoy, trap and kill combination of S. typhimurium A1-R, rMETase and CDDP was the most effective of all therapies and was able to eradicate the metastatic osteosarcoma PDOX.
In recent years, numerous studies have reported the prevalence of organic micropollutants in natural waters. There is an increasing interest in assessing the occurrence and transport of these ...contaminants in groundwater because a large number of people in the United States rely on groundwater for their drinking water. However, commonly used mass-spectrometry-based analytical methods are expensive and time-consuming. The enzyme-linked immunosorbent assay (ELISA) method offers an inexpensive analytical alternative that provides semi-quantitative results in a relatively quick timeframe. We investigated the use of ELISA for two commonly detected micropollutants, sulfamethoxazole (SMX) and carbamazepine (CBZ), in groundwater collected as part of two different studies, one in Minnesota and the other in Iowa. The ELISA results were compared with two mass-spectrometry-based methods: (1) direct aqueous injection-high performance liquid chromatography/tandem mass spectrometry (HPLC) and (2) online solid-phase extraction with liquid chromatography/electrospray ionization-mass spectrometry (SPE LC). Differences in SMX and CBZ observations between ELISA and both HPLC and SPE LC were analyzed using the Paired Prentice-Wilcoxon test. Estimates of bias and limits of agreement between paired observations also were calculated. The SMX determinations by ELISA yielded results that were 30 and 14% greater than HPLC and SPE LC, respectively. The CBZ determinations by ELISA yielded results that were 25 and 9% greater than HPLC and SPE LC, respectively. The ELISA determinations were in presence-absence agreement with HPLC for 83% of samples for SMX and CBZ; and with SPE LC for 76 and 80% of samples for SMX and CBZ, respectively. Results indicate that ELISA for SMX and CBZ is a reliable and cost effective screening-tool alternative to more commonly used mass spectrometry-based analytical methods.
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•ELISA is an inexpensive and time-saving analytical option for some micropollutants.•Presence-absence agreement between ELISA and mass spectrometry methods was >75%.•ELISA concentrations were slightly higher than mass spectrometry methods.•Paired differences fell within limits of agreement with no apparent bias.
Enzyme-linked immunosorbent assay methods produce results for sulfamethoxazole and carbamazepine that are comparable to more commonly used mass-spectrometry-based methods.
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