Αρχειοθήκη ιστολογίου

Αλέξανδρος Γ. Σφακιανάκης
ΩτοΡινοΛαρυγγολόγος
Αναπαύσεως 5
Άγιος Νικόλαος Κρήτη 72100
2841026182
6032607174

Δευτέρα 13 Φεβρουαρίου 2023

Current Management of Generalized Pustular Psoriasis

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Abstract

Generalized pustular psoriasis (GPP) is a rare subset of psoriasis involving episodes of sterile pustules accompanied by inflammation and, often, systemic involvement. The inflammatory nature of GPP has potential for severe multisystem complications including high-output cardiac failure, infections, digestive system issues, and disfiguring or lethal acute flare episodes. The disease tends to have higher prevalence in females and Asians. The IL-1/IL-36 inflammatory pathway is a critical facet of GPP's pathology. Genetic mutations that are associated with GPP include modifications of Interleukin 36 Receptor Antagonist (IL36RN), Caspase Recruitment Domain Family Member 14 (CARD14), Adaptor Related Protein Complex 1 Subunit Sigma 3 (AP1S3), Myeloperoxidase (MPO), and Serpin Peptidase Inhibitor Clade A Member 3 (SERPINA3) genes. Treatment guidelines for GPP are not well-entrenched. Currently, only one GPP-specific treatment, the interleukin-36 recepto r antagonist (IL-36Ra) spesolimab, has been approved for use in the United States. Additional anti-IL-36 pathway therapies are currently being developed. Other treatment options include other biologic therapies such as IL-17 inhibitors, IL-23 inhibitors, and TNFα inhibitors. Non-biologic therapeutic options include retinoids, cyclosporine, and methotrexate. Treatment options differ throughout the world; most countries utilize retinoids, cyclosporine, and methotrexate as first-line non-biologic options. China and United Kingdom have no GPP-specific biologic therapies approved for use, while several biologic therapies are approved for use in Japan. This review aims to serve as an update on the current global management of GPP while also including relevant aspects of disease pathogenesis, diagnosis, clinical presentation, histopathology, etiology, and epidemiology.

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A systematic comparison of pan‐Trk immunohistochemistry assays across multiple cancer types

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A systematic comparison of pan-Trk immunohistochemistry assays across multiple cancer types


Aims

NTRK-rearranged tumours are rare but can be successfully treated using anti-TRK–targeted therapies making NTRK testing important for treatment choices in patients with advanced cancers. Pan-Trk immunohistochemistry (IHC) has become a valuable and affordable screening tool in many laboratories. Unfortunately, the choice of antibodies and IHC protocols to investigate biomarkers is not standardized. In this study, we compared the performance of four pan-Trk IHC methods, using three different clones, primarily in NTRK- fusion positive tumours.

Method

We studied the performance of four pan-Trk IHC methods, using three different clones: EPR17341 (Abcam and Ventana), EP1058Y (Abcam), A7H6R (Cell Signaling) in 22 molecularly confirmed NTRK-rearranged tumours. Additionally, selected NTRK-fusion negative tumours were further included: NTRK mutated (n=8) and amplified (N=15) tumours as well as NTRK-fusion negative tumours driven by other gene fusions such as ALK, ROS1 and BCOR (n=20) as well as salivary gland tumours (n=16). Interrater agreement of three pathologist was additionally calculated, including H-score.

Result

With clone EPR17341 (Abcam in house and ready to use Ventana protocol) all molecularly confirmed NTRK 1-3 rearranged tumours were positively detected by immunohistochemistry, while the other clones missed NTRK2-3-rearranged tumours. For the fusion negative cohort we found the best performance (least false positive cases) using the clone A7H6R (Cell Signalling).

Conclusion

Given the therapeutic importance, testing for NTRK rearrangements in daily practice has become necessary and despite IHC being a fast and affordable tool, using it in routine diagnostics is complicated and requires a high level of expertise.

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Transfer RNA halves are found as nicked tRNAs in cells: evidence that nicked tRNAs regulate expression of an RNA repair operon [Report]

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Transfer RNA fragments are proposed to regulate numerous processes in eukaryotes, including translation inhibition, epigenetic inheritance and cancer. In the bacterium Salmonella enterica serovar Typhimurium, 5' tRNA halves ending in 2', 3' cyclic phosphate are proposed to bind the RtcR transcriptional activator, resulting in transcription of an RNA repair operon. However, since 5' and 3' tRNA halves can remain base paired after cleavage, the 5' tRNA halves could potentially bind RtcR as nicked tRNAs. Here we report that nicked tRNAs are ligands for RtcR. By isolating RNA from bacteria under conditions that preserve base pairing, we show that many tRNA halves are in the form of nicked tRNAs. Using a circularly permuted tRNA that mimics a nicked tRNA, we show that nicked tRNA ending in 2', 3' cyclic phosphate is a better ligand for RtcR than the corresponding 5' tRNA half. In human cells, we show that some tRNA halves similarly remain base paired as nicked tR NAs following cleavage by anticodon nucleases. Our work supports a role for the RNA repair operon in repairing nicked tRNAs and has implications for the functions proposed for tRNA fragments in eukaryotes.

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Key Modifiable Factors in Community Participation among Adults with Lower-Limb Amputation

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Objective To identify factors that may predict community participation among adults with lower-limb amputation (LLA). Design This study is a secondary analysis of a cross-sectional dataset, including 126 community-dwelling adults, ≥1 year after unilateral transfemoral- (n = 44; mean age = 59 ± 14 years) or transtibial-level amputation (n = 82; mean age = 59 ± 14 years) seen in an outpatient limb loss clinic. Participation was assessed with the Community Integration Questionnaire (CIQ). Factors, i.e., demographics, comorbidities, prosthesis-use per the Houghton Scale, Socket Comfort Score, assistive device use, falls history, and activity level per General Practice Physical Activity Questionnaire were evaluated. Moreover, balance-confidence per the Activities-Specific Balance Confidence Scale, mobility per the Locomotor Capabilities Index, fast and self-selected gait speed per 10-meter Walk Tests, and functional mobility via Timed Up and Go, were also included. Results Community participation was correlated with several factors (p ≤ 0.050). Stepwise regression of correlated factors found absence of peripheral neuropathy and greater self-reported physical activity, balance-confidence, and prosthesis use, as the strongest correlates, collectively explaining 50.1% of the variance in community participation post-LLA. Conclusions Findings identify key modifiable factors for consideration in future prospective research seeking to enhance community reintegration and participation among adults living with a unilateral transfemoral- or transtibial-level amputation. Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
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Improving trunk postural control facilitates walking in children with cerebral palsy: a pilot study

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Objective The aim of this study was to determine the effects of bilateral trunk support during walking on trunk and leg kinematics and neuromuscular responses in children with cerebral palsy (CP). Design Fourteen children with spastic CP (GMFCS level I to III) participated in this study. Children walked on a treadmill under 4 different conditions, i.e., without support (BASELINE), with bilateral support applied to the upper trunk (UTS), the lower trunk (LTS), and combined upper and lower trunk (CTS). The trunk and leg kinematics and muscle activity were recorded. Results Providing bilateral support to the trunk had a significant impact on the displacement of the pelvis and trunk (p
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Accurate Detection of α‐Synuclein Seeds in Cerebrospinal Fluid from Isolated Rapid Eye Movement Sleep Behavior Disorder and Patients with Parkinson's Disease in the DeNovo Parkinson (DeNoPa) Cohort

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Accurate Detection of α-Synuclein Seeds in Cerebrospinal Fluid from Isolated Rapid Eye Movement Sleep Behavior Disorder and Patients with Parkinson's Disease in the DeNovo Parkinson (DeNoPa) Cohort


ABSTRACT

Background

Misfolded α-synuclein (αSyn) aggregates (αSyn-seeds) in cerebrospinal fluid (CSF) are biomarkers for synucleinopathies such as Parkinson's disease (PD). αSyn-seeds have been detected in prodromal cases with isolated rapid eye movement sleep behavior disorder (iRBD).

Objectives

The objective of this study was to determine the accuracy of the αSyn–seed amplification assay (αS-SAA) in a comprehensively characterized cohort with a high proportion of PD and iRBD CSF samples collected at baseline.

Methods

We used a high-throughput αS-SAA to analyze 233 blinded CSF samples from 206 participants of the DeNovo Parkinson Cohort (DeNoPa) (113 de novo PD, 64 healthy controls, 29 iRBD confirmed by video polysomnography). Results were compared with the final diagnosis, which was determined after up to 10 years of longitudinal clinical evaluations, including dopamine-transporter–single-photon emission computed tomography (DAT-SPECT) at baseline, CSF proteins, Movement Disorder Society–Unified Parkinson's Disease Rating Scale, and various cognitive and nonmotor scales.

Results

αS-SAA detected αSyn-seeds in baseline PD-CSF with 98% accuracy. αSyn-seeds were detected in 93% of the iRBD cases. αS-SAA results showed higher agreement with the final than the initial diagnosis, as 14 patients were rediagnosed as non-αSyn aggregation disorder. For synucleinopathies, αS-SAA showed higher concordance with the final diagnosis than DAT-SPECT. Statistically significant correlations were found between assay parameters and disease progression.

Conclusions

Our results confirm αS-SAA accuracy at the first clinical evaluation when a definite diagnosis is most consequential. αS-SAA conditions reported here are highly sensitive, enabling the detection of αSyn-seeds in CSF from iRBD just months after the first symptoms, suggesting that αSyn-seeds are present in the very early prodromal phase of synucleinopathies. Therefore, αSyn-seeds are clear risk markers for synuclein-related disorders, but not for time of phenoconversion. © 2023 International Parkinson and Movement Disorder Society.

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Plasma Biomarkers and Positron Emission Tomography Tau Pathology in Progressive Supranuclear Palsy

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Plasma Biomarkers and Positron Emission Tomography Tau Pathology in Progressive Supranuclear Palsy

Plasma neurofilament light chain (NfL) is a promising biomarker of progressive supranuclear palsy (PSP) to assist in PSP diagnosis and differential diagnosis from Parkinson's disease (PD) and to monitor disease severity. Pending replication in independent cohorts, plasma glial fibrillary acidic protein (GFAP) holds promise for a PSP diagnosis and a differential diagnosis with multiple system atrophy with predominant parkinsonism (MSA-P) and for detecting brainstem atrophy and tau deposition in PSP.


ABSTRACT

Background

Development of disease-modifying therapeutic trials of progressive supranuclear palsy (PSP) urges the need for sensitive fluid biomarkers.

Objectives

The objectives of this study were to explore the utility of plasma biomarkers in the diagnosis, differential diagnosis, and assessment of disease severity, brain atrophy, and tau deposition in PSP.

Methods

Plasma biomarkers were measured using a single-molecule array in a cohort composed of patients with PSP, Parkinson's disease (PD), multiple system atrophy with predominant parkinsonism (MSA-P), and healthy controls (HCs).

Results

Plasma neurofilament light chain (NfL) outperformed other plasma makers (ie, glial fibrillary acidic protein [GFAP], phosphorylated-tau 181 [p-tau181], amyloid-β 1–40, amyloid-β 1–42) in identifying PSP from HC (area under the curve [AUC] = 0.904) and from MSA-P (AUC = 0.711). Plasma GFAP aided in distinguishing PSP from HC (AUC = 0.774) and from MSA-P (AUC = 0.832). It correlated with brainstem atrophy and higher regional tau accumulation. However, plasma p-tau181 neither helped in diagnosis nor was it associated with clinical or neuroimaging measures.

Conclusions

Plasma NfL and GFAP showed different values in differentiating PSP from HC or controls with other forms of neurodegenerative parkinsonism and detecting disease severity, brain atrophy, or tau deposition in PSP. © 2023 International Parkinson and Movement Disorder Society.

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