Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype (“SPGn” designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life.

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Distinct extracellular-matrix remodeling events precede symptoms of inflammation

10.1101/665653 ◽

2019 ◽

Cited By ~ 1

Author(s):

Elee Shimshoni ◽

Idan Adir ◽

Ran Afik ◽

Inna Solomonov ◽

Anjana Shenoy ◽

...

Keyword(s):

Extracellular Matrix ◽

Clinical Symptoms ◽

Human Subjects ◽

Disease Onset ◽

Matrix Remodeling ◽

Cellular Processes ◽

Wide Range ◽

The Matrix ◽

Bowel Diseases ◽

Clinical Potential

AbstractIdentification of early processes leading to complex tissue pathologies, such as inflammatory bowel diseases, poses a major scientific and clinical challenge that is imperative for improved diagnosis and treatment. Most studies of inflammation onset focus on cellular processes and signaling molecules, while overlooking the environment in which they take place, the continuously remodeled extracellular matrix. In this study, we used colitis models for investigating extracellular-matrix dynamics during disease onset, while treating the matrix as a complete and defined entity. Through the analysis of matrix structure, stiffness and composition, we unexpectedly revealed that even prior to the first clinical symptoms, the colon displays its own unique extracellular-matrix signature and found specific markers of clinical potential, which were also validated in human subjects. We also show that the emergence of this pre-symptomatic matrix is mediated by sub-clinical infiltration of neutrophils and monocytes bearing remodeling enzymes. Remarkably, whether the inflammation is chronic or acute, its matrix signature converges at pre-symptomatic states. We suggest that the existence of a pre-symptomatic extracellular-matrix is general and relevant to a wide range of diseases.

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Celiac Disease in Kosovar Albanian Children: Evaluation of Clinical Features and Diagnosis

Current Pediatric Reviews ◽

10.2174/1573396316666200116093753 ◽

2020 ◽

Vol 16 (3) ◽

pp. 241-247

Author(s):

Atifete Ramosaj-Morina ◽

Alije Keka-Sylaj ◽

Arbana Baloku Zejnullahu ◽

Lidvana Spahiu ◽

Virgjina Hasbahta ◽

...

Keyword(s):

Celiac Disease ◽

Disease Onset ◽

Clinical Manifestations ◽

Gastrointestinal Symptoms ◽

Dominant Mode ◽

Primary School Children ◽

Cross Sectional ◽

Classical Form ◽

Wide Range ◽

The Mean

Background: Celiac disease is an immune-mediated disorder characterized by variable clinical manifestations, specific antibodies, HLA-DQ2/DQ8 haplotypes, and enteropathy. Objectives: The aim of this study was to present the clinical spectrum and patterns of celiac disease in Kosovar Albanian children. Methods: A cross-sectional retrospective study was performed with Albanian children aged 0-18 years, treated for celiac disease in the Pediatric Clinic, University Clinical Center of Kosovo from 2005 to 2016. Results: During the study period, 63 children were treated for celiac disease. The mean age at diagnosis was 5.5 years (SD ± 3.31). The mean age at celiac disease onset was 3.3 years (SD ± 2.02), while the mean delay from the first symptoms indicative of celiac disease to diagnosis was 2.2 years (SD ± 2.09). More than 70% of the patients were diagnosed in the first 7 years of life, mainly presented with gastrointestinal symptoms, while primary school children and adolescents mostly showed atypical symptoms (p<0.001). The classical form of celiac disease occurred in 78% of the cases. Sixty (95%) patients carried HLA-DQ2.5, DQ2.2 and/or HLA-DQ8 heterodimers, and only three of them tested negative. Conclusions: Kosovo, as the majority of developing countries, is still facing the classical form of celiac disease as the dominant mode of presentation; as a result, most children with other forms of the celiac disease remain undiagnosed. : Physicians should be aware of the wide range of clinical presentations and utilize low testing thresholds in order to prevent potential long-term problems associated with untreated celiac disease.

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Vitiligo: An Updated Narrative Review

Current Pediatric Reviews ◽

10.2174/1573396316666201210125858 ◽

2020 ◽

Vol 16 ◽

Author(s):

Alexander K. C. Leung ◽

Joseph M. Lam ◽

Kin Fon Leong ◽

Kam Lun Hon

Keyword(s):

Present Article ◽

English Literature ◽

Disease Onset ◽

Clinical Manifestations ◽

Calcineurin Inhibitors ◽

Ultraviolet B ◽

Lower Limbs ◽

Treatment Modalities ◽

Topical Corticosteroids ◽

Topical Calcineurin Inhibitors

Background: Vitiligo is a relatively common acquired pigmentation disorder that can cause significant psychological stress and stigmatism. Objective: This article aims to familiarize physicians with the clinical manifestations, evaluation, diagnosis, and management of vitiligo. Methods: A Pubmed search was conducted in Clinical Queries using the key term "vitiligo". The search included metaanalyses, randomized controlled trials, clinical trials, observational studies, and reviews. The search was restricted to the English literature. The information retrieved from the above search was used in the compilation of the present article. The information retrieved from the above search was used in the compilation of the present article. Results: Approximately one quarter of patients with vitiligo have the onset before 10 years of age. Genetic, immunological, neurogenic and environmental factors may have a role to play in the pathogenesis. Vitiligo typically presents as acquired depigmented, well-demarcated macules/patches that appear milk- or chalk-white in color. Lesions tend to increase in number and enlarge centrifugally in size with time. Sites of predilection include the face, followed by the neck, lower limbs, trunk, and upper limbs. The clinical course is generally unpredictable. In children with fair skin, no active treatment is usually necessary other than the use of sunscreens and camouflage cosmetics. If treatment is preferred for cosmesis, topical corticosteroids, topical calcineurin inhibitors, and narrowband ultraviolet B phototherapy are the mainstays of treatment. Conclusion: The therapeutic effect of all the treatment modalities varies considerably from individual to individual. As such, treatment must be individualized. In general, the best treatment response is seen in younger patients, recent disease onset, darker skin types, and head and neck lesions. Topical corticosteroids and calcineurin inhibitors are the treatment of choice for those with localized disease. Topical calcineurin inhibitors are generally preferred for lesions on genitalia, intertriginous areas, face, and neck. Narrowband ultraviolet B phototherapy should be considered in patients who have widespread vitiligo or those with localized vitiligo associated with a significant impact on the quality of life who do not respond to treatment with topical corticosteroids and calcineurin inhibitors.

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Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms22147281 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7281

Author(s):

Benoit R. Gauthier ◽

Valentine Comaills

Keyword(s):

Nuclear Envelope ◽

Clinical Symptoms ◽

Genome Instability ◽

Chromosomal Rearrangements ◽

Wide Range ◽

Complex Chromosomal Rearrangements ◽

Health And Disease ◽

Dna Release ◽

Sting Pathway ◽

Eukaryote Genome

The dynamic nature of the nuclear envelope (NE) is often underestimated. The NE protects, regulates, and organizes the eukaryote genome and adapts to epigenetic changes and to its environment. The NE morphology is characterized by a wide range of diversity and abnormality such as invagination and blebbing, and it is a diagnostic factor for pathologies such as cancer. Recently, the micronuclei, a small nucleus that contains a full chromosome or a fragment thereof, has gained much attention. The NE of micronuclei is prone to collapse, leading to DNA release into the cytoplasm with consequences ranging from the activation of the cGAS/STING pathway, an innate immune response, to the creation of chromosomal instability. The discovery of those mechanisms has revolutionized the understanding of some inflammation-related diseases and the origin of complex chromosomal rearrangements, as observed during the initiation of tumorigenesis. Herein, we will highlight the complexity of the NE biology and discuss the clinical symptoms observed in NE-related diseases. The interplay between innate immunity, genomic instability, and nuclear envelope leakage could be a major focus in future years to explain a wide range of diseases and could lead to new classes of therapeutics.

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What Do Meditators Do When They Meditate? Proposing a Novel Basis for Future Meditation Research

Mindfulness ◽

10.1007/s12671-021-01641-5 ◽

2021 ◽

Author(s):

Karin Matko ◽

Ulrich Ott ◽

Peter Sedlmeier

Keyword(s):

Qualitative Study ◽

Quantitative Study ◽

Literature Search ◽

Comprehensive Overview ◽

Contemplative Practices ◽

Comprehensive List ◽

Scientific Investigations ◽

Wide Range ◽

Vast Range ◽

Selection Of

Abstract Objectives Meditation is an umbrella term for a vast range of contemplative practices. Former proposals have struggled to do justice to this variety. To our knowledge, there is to date no comprehensive overview of meditation techniques spanning all major traditions. The present studies aimed at providing such a comprehensive list of meditation techniques. Methods In a qualitative study, we compiled a collection of 309 meditation techniques through a literature search and interviews with 20 expert meditators. Then, we reduced this collection to 50 basic meditation techniques. In a second, quantitative study, 635 experienced meditators from a wide range of meditative backgrounds indicated how much experience they had with each of these 50 meditation techniques. Results Meditators’ responses indicated that our choice of techniques had been adequate and only two techniques had to be added. Our additional statistical and cluster analyses illustrated preferences for specific techniques across and within diverse traditions as well as sets of techniques commonly practiced together. Body-centered techniques stood out in being of exceptional importance to all meditators. Conclusions In conclusion, we found an amazing variety of meditation techniques, which considerably surpasses previous collections. Our selection of basic meditation techniques might be of value for future scientific investigations and we encourage researchers to use this set.

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UV Nanoimprint Lithography: Geometrical Impact on Filling Properties of Nanoscale Patterns

Nanomaterials ◽

10.3390/nano11030822 ◽

2021 ◽

Vol 11 (3) ◽

pp. 822

Author(s):

Christine Thanner ◽

Martin Eibelhuber

Keyword(s):

Layer Thickness ◽

Process Parameters ◽

Nanoimprint Lithography ◽

Failure Modes ◽

Production Method ◽

Efficient Production ◽

Comprehensive Overview ◽

Replication Method ◽

Wide Range ◽

Pattern Size

Ultraviolet (UV) Nanoimprint Lithography (NIL) is a replication method that is well known for its capability to address a wide range of pattern sizes and shapes. It has proven to be an efficient production method for patterning resist layers with features ranging from a few hundred micrometers and down to the nanometer range. Best results can be achieved if the fundamental behavior of the imprint resist and the pattern filling are considered by the equipment and process parameters. In particular, the material properties and pattern size and shape play a crucial role. For capillary force-driven filling behavior it is important to understand the influencing parameters and respective failure modes in order to optimize the processes for reliable full wafer manufacturing. In this work, the nanoimprint results obtained for different pattern geometries are compared with respect to pattern quality and residual layer thickness: The comprehensive overview of the relevant process parameters is helpful for setting up NIL processes for different nanostructures with minimum layer thickness.

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Occupational hazard in Malaysian traffic police: special focus on air pollutants

Reviews on Environmental Health ◽

10.1515/reveh-2020-0107 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Putri Anis Syahira Mohamad Jamil ◽

Karmegam Karuppiah ◽

Irniza Rasdi ◽

Vivien How ◽

Shamsul Bahri Mohd Tamrin ◽

...

Keyword(s):

Occupational Injuries ◽

Indicator System ◽

Control Measures ◽

Special Focus ◽

Safety Measures ◽

Traffic Police ◽

Wide Range ◽

And Control ◽

Risk Occupation ◽

High Risk Occupation

Abstract This paper provides a specific deliberation on occupational hazards confronted daily by Malaysian Traffic Police. Traffic police is a high-risk occupation that involves a wide range of tasks and, indirectly, faced with an equally wide variety of hazards at work namely, physical, biological, psychosocial, chemical, and ergonomic hazards. Thereupon, occupational injuries, diseases, and even death are common in the field. The objective of this paper is to collate and explain the major hazards of working as Malaysian traffic police especially in Point Duty Unit, their health effects, and control measures. There are many ways in which these hazards can be minimised by ensuring that sufficient safety measures are taken such as a wireless outdoor individual exposure indicator system for the traffic police. By having this system, air monitoring among traffic police may potentially be easier and accurate. Other methods of mitigating these unfortunate events are incorporated and addressed in this paper according to the duty and needs of traffic police.

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One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation

Genetics in Medicine ◽

10.1038/s41436-021-01187-w ◽

2021 ◽

Author(s):

Stephen E. Lincoln ◽

Tina Hambuch ◽

Justin M. Zook ◽

Sara L. Bristow ◽

Kathryn Hatchell ◽

...

Keyword(s):

Diagnostic Yield ◽

Copy Number Variants ◽

Low Complexity ◽

Clinical Genetic ◽

Clinical Sensitivity ◽

Pathogenic Variants ◽

Wide Range ◽

Large Indels ◽

Next Generation Sequencing Ngs ◽

The Impact

Abstract Purpose To evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small copy-number variants (CNVs), complex alterations, and variants in low-complexity or segmentally duplicated regions. Methods An interlaboratory pilot study used synthetic specimens to assess detection of challenging variant types by various next-generation sequencing (NGS)–based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients. Results In the interlaboratory study, only 2 of 13 challenging variants were detected by all 10 workflows, and just 3 workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests. Conclusion The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.

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Prodromal Dementia With Lewy Bodies: Evolution of Symptoms and Predictors of Dementia Onset

Journal of Geriatric Psychiatry and Neurology ◽

10.1177/08919887211023586 ◽

2021 ◽

pp. 089198872110235

Author(s):

Kathryn A. Wyman-Chick ◽

Lauren R. O’Keefe ◽

Daniel Weintraub ◽

Melissa J. Armstrong ◽

Michael Rosenbloom ◽

...

Keyword(s):

Clinical Features ◽

Dementia With Lewy Bodies ◽

Clinical Symptoms ◽

Neuropsychiatric Symptoms ◽

Lewy Bodies ◽

Rem Sleep Behavior Disorder ◽

Data Set ◽

Wide Range ◽

Prodromal Dementia ◽

Dementia Onset

Background: Research criteria for prodromal dementia with Lewy bodies (DLB) were published in 2020, but little is known regarding prodromal DLB in clinical settings. Methods: We identified non-demented participants without neurodegenerative disease from the National Alzheimer’s Coordinating Center Uniform Data Set who converted to DLB at a subsequent visit. Prevalence of neuropsychiatric and motor symptoms were examined up to 5 years prior to DLB diagnosis. Results: The sample included 116 participants clinically diagnosed with DLB and 348 age and sex-matched (1:3) Healthy Controls. Motor slowing was present in approximately 70% of participants 3 years prior to DLB diagnosis. In the prodromal phase, 50% of DLB participants demonstrated gait disorder, 70% had rigidity, 20% endorsed visual hallucinations, and over 50% of participants endorsed REM sleep behavior disorder. Apathy, depression, and anxiety were common prodromal neuropsychiatric symptoms. The presence of 1+ core clinical features of DLB in combination with apathy, depression, or anxiety resulted in the greatest AUC (0.815; 95% CI: 0.767, 0.865) for distinguishing HC from prodromal DLB 1 year prior to diagnosis. The presence of 2+ core clinical features was also accurate in differentiating between groups (AUC = 0.806; 95% CI: 0.756, 0.855). Conclusion: A wide range of motor, neuropsychiatric and other core clinical symptoms are common in prodromal DLB. A combination of core clinical features, neuropsychiatric symptoms and cognitive impairment can accurately differentiate DLB from normal aging prior to dementia onset.

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Electrospun Fiber Scaffolds for Engineering Glial Cell Behavior to Promote Neural Regeneration

Bioengineering ◽

10.3390/bioengineering8010004 ◽

2020 ◽

Vol 8 (1) ◽

pp. 4

Author(s):

Devan L. Puhl ◽

Jessica L. Funnell ◽

Derek W. Nelson ◽

Manoj K. Gottipati ◽

Ryan J. Gilbert

Keyword(s):

Nervous System ◽

Glial Cell ◽

Cell Response ◽

Electrospun Fiber ◽

Neural Regeneration ◽

Cell Phenotype ◽

Comprehensive Overview ◽

Fiber Alignment ◽

Wide Range ◽

Fiber Scaffolds

Electrospinning is a fabrication technique used to produce nano- or micro- diameter fibers to generate biocompatible, biodegradable scaffolds for tissue engineering applications. Electrospun fiber scaffolds are advantageous for neural regeneration because they mimic the structure of the nervous system extracellular matrix and provide contact guidance for regenerating axons. Glia are non-neuronal regulatory cells that maintain homeostasis in the healthy nervous system and regulate regeneration in the injured nervous system. Electrospun fiber scaffolds offer a wide range of characteristics, such as fiber alignment, diameter, surface nanotopography, and surface chemistry that can be engineered to achieve a desired glial cell response to injury. Further, electrospun fibers can be loaded with drugs, nucleic acids, or proteins to provide the local, sustained release of such therapeutics to alter glial cell phenotype to better support regeneration. This review provides the first comprehensive overview of how electrospun fiber alignment, diameter, surface nanotopography, surface functionalization, and therapeutic delivery affect Schwann cells in the peripheral nervous system and astrocytes, oligodendrocytes, and microglia in the central nervous system both in vitro and in vivo. The information presented can be used to design and optimize electrospun fiber scaffolds to target glial cell response to mitigate nervous system injury and improve regeneration.

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