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Transplantation Jan 2024This review outlines the molecular disease states in kidney transplant biopsies as documented in the development of the Molecular Microscope Diagnostic System (MMDx).... (Review)
Review
This review outlines the molecular disease states in kidney transplant biopsies as documented in the development of the Molecular Microscope Diagnostic System (MMDx). These states include T cell-mediated rejection (TCMR), antibody-mediated rejection (AMR), recent parenchymal injury, and irreversible atrophy-fibrosis. The MMDx project, initiated through a Genome Canada grant, is a collaboration involving many centers. MMDx uses genome-wide microarrays to measure transcript expression, interprets the results using ensembles of machine learning algorithms, and generates a report. Experimental studies in mouse models and cell lines were extensively used to annotate molecular features and interpret the biopsy results. Over time, MMDx revealed unexpected aspects of the disease states: for example, AMR is usually C4d-negative and often DSA-negative, and subtle "Minor" AMR-like states are frequent. Parenchymal injury correlates with both reduced glomerular filtration rate and increased risk of graft loss. In kidneys with rejection, injury features, not rejection activity, are the strongest predictors of graft survival. Both TCMR and AMR produce injury, but TCMR induces immediate nephron injury and accelerates atrophy-fibrosis, whereas AMR induces microcirculation and glomerular damage that slowly leads to nephron failure and atrophy-fibrosis. Plasma donor-derived cell-free DNA levels correlate strongly with AMR activity, acute kidney injury, and in a complex way with TCMR activity. Thus, the MMDx project has documented the molecular processes that underlie the clinical and histologic states in kidney transplants, and provides a diagnostic tool that can be used to calibrate biomarkers, optimize histology interpretation, and guide clinical trials.
Topics: Animals; Mice; Kidney Transplantation; Kidney; Antibodies; Phenotype; Fibrosis; Atrophy; Graft Rejection; Biopsy
PubMed: 37310258
DOI: 10.1097/TP.0000000000004624 -
The British Journal of General Practice... Dec 2021
Topics: Atrophy; Humans; Urogenital System
PubMed: 34824066
DOI: 10.3399/bjgp21X717725 -
Seminars in Cutaneous Medicine and... Dec 2018Genitourinary syndrome of menopause (GSM), encompassing the disorders of atrophic vaginitis, urinary incontinence, and pelvic prolapse, affects the majority of... (Review)
Review
Genitourinary syndrome of menopause (GSM), encompassing the disorders of atrophic vaginitis, urinary incontinence, and pelvic prolapse, affects the majority of postmenopausal women, as well as patients who are undergoing breast cancer treatement, post-ovarectomy, post-radiation, and breast-feeding. There is a need for better treatment options for these common conditions that adversely affect physical function and quality of life and that are often underserved by existing options. Lasers have been used to treat genitourinary tissue for over 40 years, and over the past decade, several lasers and radiofrequency devices have been developed and clinically tested for the treatment of GSM, with an accumulating body of evidence demonstrating their safety and efficacy. Fractional lasers, including carbon dioxide, erbium: YAG and hybrid technologies, as well as monopolar radiofrequency devices, work by resurfacing and/or stimulating via heat the vaginal lining resulting in a re-epithelialization, neovascularization, and remodeling of the vaginal tissue from an atrophic postmenopausal state to a thickened, glycogen-rich and well-vascularized state similar to premenopausal vaginal lining. These changes are correlated clinically with improved function on a variety of validated vaginal health scales and urinary incontinence tests. Currently cleared for general application to genitourinary tissue, clinical trials are underway for FDA clearance or approval for specific GSM indications.
Topics: Atrophy; Catheter Ablation; Female; Humans; Laser Therapy; Menopause; Quality of Life; Vagina; Vaginal Diseases; Women's Health
PubMed: 30475926
DOI: 10.12788/j.sder.2018.052 -
Translational Neurodegeneration Dec 2023TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal...
BACKGROUND
TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS-FTD spectrum.
METHODS
We used a data-driven procedure to identify 13 anatomic clusters of brain volume for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS-FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS-FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease.
RESULTS
SuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy in either prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 types B, E and C. In contrast, the prefrontal/somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS-FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. The overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King's stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology.
CONCLUSIONS
Our findings suggest distinct neurodegenerative subtypes of disease along the ALS-FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns.
Topics: Humans; Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; Neurodegenerative Diseases; Brain; DNA-Binding Proteins; Atrophy
PubMed: 38062485
DOI: 10.1186/s40035-023-00389-3 -
Tidsskrift For Den Norske Laegeforening... Jun 2015Posterior cortical atrophy is a neurodegenerative condition with atrophy of posterior parts of the cerebral cortex, including the visual cortex and parts of the parietal... (Review)
Review
BACKGROUND
Posterior cortical atrophy is a neurodegenerative condition with atrophy of posterior parts of the cerebral cortex, including the visual cortex and parts of the parietal and temporal cortices. It presents early, in the 50s or 60s, with nonspecific visual disturbances that are often misinterpreted as ophthalmological, which can delay the diagnosis. The purpose of this article is to present current knowledge about symptoms, diagnostics and treatment of this condition.
METHOD
The review is based on a selection of relevant articles in PubMed and on the authors' own experience with the patient group.
RESULTS
Posterior cortical atrophy causes gradually increasing impairment in reading, distance judgement, and the ability to perceive complex images. Examination of higher visual functions, neuropsychological testing, and neuroimaging contribute to diagnosis. In the early stages, patients do not have problems with memory or insight, but cognitive impairment and dementia can develop. It is unclear whether the condition is a variant of Alzheimer's disease, or whether it is a separate disease entity. There is no established treatment, but practical measures such as the aid of social care workers, telephones with large keypads, computers with voice recognition software and audiobooks can be useful.
INTERPRETATION
Currently available treatment has very limited effect on the disease itself. Nevertheless it is important to identify and diagnose the condition in its early stages in order to be able to offer patients practical assistance in their daily lives.
Topics: Aged; Atrophy; Cerebral Cortex; Disease Progression; Humans; Middle Aged; Neurodegenerative Diseases; Positron-Emission Tomography; Vision Disorders
PubMed: 26037756
DOI: 10.4045/tidsskr.14.1127 -
CNS Spectrums Aug 2021Brain-derived neurotrophic factor (BDNF) is involved in neurogenesis and in the protection against oxidative damage and neuronal apoptosis. After exercise, there is an...
BACKGROUND
Brain-derived neurotrophic factor (BDNF) is involved in neurogenesis and in the protection against oxidative damage and neuronal apoptosis. After exercise, there is an increased expression of this myokine, especially in skeletal muscle and brain. Low BDNF levels have been described in neurodegenerative diseases. Alcoholics show both muscle atrophy and brain atrophy. Thus, this study was performed in order to analyze serum BDNF levels among alcoholics and their associations with brain atrophy and muscle strength.
METHODS
Serum BDNF values were determined to 82 male alcoholics and 27 age-matched controls, and compared with handgrip strength, with the presence of brain atrophy, assessed by computed tomography, and with the intensity of alcoholism and liver function derangement.
RESULTS
BDNF levels and handgrip strength were significantly lower among patients. Handgrip strength was correlated with BDNF values, both in the whole population and in alcoholics, especially in patients over 59 years of age. BDNF was poorly related to liver dysfunction but showed no relationship with brain atrophy or age.
CONCLUSION
Chronic alcoholics show decreased BDNF serum levels that are related to muscle function impairment rather than to age, brain atrophy, liver dysfunction, or the amount of ethanol consumed.
Topics: Aged; Alcoholism; Atrophy; Brain; Brain-Derived Neurotrophic Factor; Humans; Male; Middle Aged; Tomography, X-Ray Computed
PubMed: 32423492
DOI: 10.1017/S1092852920001431 -
Clinical Obstetrics and Gynecology Sep 2015Vulvovaginal atrophy is a common condition associated with decreased estrogenization of the vaginal tissue. Symptoms include vaginal dryness, irritation, itching,... (Review)
Review
Vulvovaginal atrophy is a common condition associated with decreased estrogenization of the vaginal tissue. Symptoms include vaginal dryness, irritation, itching, soreness, burning, dyspareunia, discharge, urinary frequency, and urgency. It can occur at any time in a woman's life cycle, although more commonly in the postmenopausal phase, during which the prevalence is approximately 50%. Despite the high prevalence and the substantial effect on quality of life, vulvovaginal atrophy often remains underreported and undertreated. This article aims to review the physiology, clinical presentation, assessment, and current recommendations for treatment, including aspects of effectiveness and safety of local vaginal estrogen therapies.
Topics: Administration, Cutaneous; Administration, Intravaginal; Aging; Atrophy; Estrogen Replacement Therapy; Female; Humans; Lubricants; Menopause; Vagina; Vaginal Diseases; Vulva; Vulvar Diseases
PubMed: 26125962
DOI: 10.1097/GRF.0000000000000126 -
La Revue de Medecine Interne Jul 2021
Topics: Atrophy; Glucocorticoids; Humans; Hypopigmentation; Skin
PubMed: 33280839
DOI: 10.1016/j.revmed.2020.11.004 -
American Journal of Physiology.... Jul 2022Skeletal muscle is an integral tissue system that plays a crucial role in the physical function of all vertebrates and is a key target for maintaining or improving... (Review)
Review
Skeletal muscle is an integral tissue system that plays a crucial role in the physical function of all vertebrates and is a key target for maintaining or improving health and performance across the lifespan. Based largely on cellular and animal models, there is some evidence that various forms of heat stress with or without resistance exercise may enhance skeletal muscle growth or reduce its loss. It is not clear whether these stimuli are similarly effective in humans or meaningful compared with exercise alone across various heating methodologies. Furthermore, the magnitude by which heat stress may influence whole body thermoregulatory responses and the connection to skeletal muscle adaptation remains ambiguous. Finally, the underlying mechanisms, which may include interaction between relevant heat shock proteins and intracellular hypertrophy and atrophy related factors, remain unclear. In this narrative review, we examine the relevant literature regarding heat stress alone or in combination with resistance exercise emphasizing skeletal muscle hypertrophy and atrophy across cellular and animal models, as well as human investigations. In addition, we present working mechanistic theories for heat shock protein-mediated signaling effects regarding hypertrophy and atrophy-related signaling processes. Importantly, continued research is necessary to determine the practical effects and mechanisms of heat stress with and without resistance exercise on skeletal muscle function via growth and maintenance.
Topics: Animals; Atrophy; Exercise; Heat-Shock Proteins; Heat-Shock Response; Hypertrophy; Muscle, Skeletal; Muscular Atrophy
PubMed: 35536704
DOI: 10.1152/ajpregu.00048.2022 -
Current Opinion in Gastroenterology May 2024Persistent villous atrophy is associated with morbidity in coeliac disease and most commonly due to ongoing gluten ingestion. Current methods for assessing gluten... (Review)
Review
PURPOSE OF REVIEW
Persistent villous atrophy is associated with morbidity in coeliac disease and most commonly due to ongoing gluten ingestion. Current methods for assessing gluten exposure and persisting villous atrophy include dietary questionnaires and repeat duodenal biopsy, which have limited accuracy or are invasive. This review discusses adjunctive and/or novel tests that could be used to overcome these challenges.
RECENT FINDINGS
Small bowel capsule endoscopy is well tolerated and helps to evaluate for persisting villous atrophy and importantly, complications associated with coeliac disease. Testing for urinary and/or stool gluten immunogenic peptides may help identify recent gluten exposure, but further studies are still warranted to evaluate the accuracy and applicability of this approach. Measuring spikes in circulating Interleukin-2 following gluten challenge has shown promise for coeliac disease diagnosis, and thus may serve as a useful confirmatory test in those with persisting symptoms but provides no information on mucosal inflammation. No specific gut microbial signature has been identified in coeliac disease; however, studies have shown a reduced microbial diversity in active disease, which with future refinement may prove clinically useful.
SUMMARY
There is no evidence to support alternative methods for assessing persisting villous atrophy in coeliac disease over performing an up-to-date duodenal biopsy. Monitoring for adherence to a gluten-free diet remains clinically challenging and should be a priority for future research.
Topics: Humans; Celiac Disease; Intestine, Small; Glutens; Biopsy; Diet, Gluten-Free; Atrophy; Intestinal Mucosa
PubMed: 38547329
DOI: 10.1097/MOG.0000000000001009