Atrophic Lesions Research Articles

CKD, Brain Atrophy, and White Matter Lesion Volume: The Japan Prospective Studies Collaboration for Aging and Dementia

Chronic kidney disease, defined by albuminuria and/or reduced estimated glomerular filtration rate (eGFR), has been reported to be associated with brain atrophy and/or higher white matter lesion volume (WMLV), but there are few large-scale population-based studies assessing this issue. This study aimed to examine the associations between the urinary albumin-creatinine ratio (UACR) and eGFR levels and brain atrophy and WMLV in a large-scale community-dwelling older population of Japanese. Population-based cross-sectional study. A total of 8,630 dementia-free community-dwelling Japanese aged greater than or equal to 65 years underwent brain magnetic resonance imaging scanning and screening examination of health status in 2016-2018. UACR and eGFR levels. The total brain volume (TBV)-to-intracranial volume (ICV) ratio (TBV/ICV), the regional brain volume-to-TBV ratio, and the WMLV-to-ICV ratio (WMLV/ICV). The associations of UACR and eGFR levels with the TBV/ICV, the regional brain volume-to-TBV ratio, and the WMLV/ICV were assessed by using an analysis of covariance. Higher UACR levels were significantly associated with lower TBV/ICV and higher geometric mean values of the WMLV/ICV (P for trend= 0.009 and <0.001, respectively). Lower eGFR levels were significantly associated with lower TBV/ICV, but not clearly associated with WMLV/ICV. In addition, higher UACR levels, but not lower eGFR, were significantly associated with lower temporal cortex volume-to-TBV ratio and lower hippocampal volume-to-TBV ratio. Cross-sectional study, misclassification of UACR or eGFR levels, generalizability to other ethnicities and younger populations, and residual confounding factors. The present study demonstrated that higher UACR was associated with brain atrophy, especially in the temporal cortex and hippocampus, and with increased WMLV. These findings suggest that chronic kidney disease is involved in the progression of morphologic brain changes associated with cognitive impairment.

A novel eye-movement impairment in multiple sclerosis indicating widespread cortical damage.

In multiple sclerosis, remyelination trials have yet to deliver success like that achieved for relapse rates with disease course modifying treatment trials. The challenge is to have a clinical, functional outcome measure. Currently, there are none that have been validated, other than visual evoked potentials in optic neuritis. Like vision, quick eye movements (saccades) are heavily dependent on myelination. We proposed that it is possible to extrapolate from demyelination of the medial longitudinal fasciculus in the brainstem to quantitative assessment of cortical networks governing saccadic eye movements in multiple sclerosis. We have developed and validated a double-step saccadic test, which consists of a pair of eye movements towards two stimuli presented in quick succession (the demonstrate eye movement networks with saccades protocol). In this single-centre, cross-sectional cohort study we interrogated the structural and functional relationships of double-step saccades in multiple sclerosis. Data were collected for double-step saccades, cognitive function (extended Rao's Brief Repeatable Battery), disability (Expanded Disability Status Scale) and visual functioning in daily life (National Eye Institute Visual Function Questionnaire). MRI was used to quantify grey matter atrophy and multiple sclerosis lesion load. Multivariable linear regression models were used for analysis of the relationships between double-step saccades and clinical and MRI metrics. We included 209 individuals with multiple sclerosis (mean age 54.3 ± 10.5 years, 58% female, 63% relapsing-remitting multiple sclerosis) and 60 healthy control subjects (mean age 52.1 ± 9.2 years, 53% female). The proportion of correct double-step saccades was significantly reduced in multiple sclerosis (mean 0.29 ± 0.22) compared to controls (0.45 ± 0.22, P < 0.001). Consistent with this, there was a significantly larger double-step dysmetric saccadic error in multiple sclerosis (mean vertical error -1.18 ± 1.20°) compared to controls (-0.54 ± 0.86°, P < 0.001). Impaired double-step saccadic metrics were consistently associated with more severe global and local grey matter atrophy (correct responses-cortical grey matter: β = 0.42, P < 0.001), lesion load (vertical error: β = -0.28, P < 0.001), progressive phenotypes, more severe physical and cognitive impairment (correct responses-information processing: β = 0.46, P < 0.001) and visual functioning. In conclusion, double-step saccades represent a robust metric that revealed a novel eye-movement impairment in individuals with multiple sclerosis. Double-step saccades outperformed other saccadic tasks in their statistical relationship with clinical, cognitive and visual functioning, as well as global and local grey matter atrophy. Double-step saccades should be evaluated longitudinally and tested as a potential novel outcome measure for remyelination trials in multiple sclerosis.

The value of dermoscopy and high-frequency ultrasound in staging morphea.

Morphea is an autoimmune disease characterized by skin sclerosis. According to the disease progression, morphea can be divided into inflammatory, sclerotic, and atrophic stages. Dermoscopy and high-frequency ultrasound (HF-US) have been applied in the noninvasive evaluation of many inflammatory diseases, but studies on the skin imaging features of the different stages of morphea are limited. To analyze the dermoscopic and HF-US features of the different stages of morphea and explore their auxiliary value in staging the disease, we followed 34 patients with histopathology-confirmed morphea between April 2018 and July 2021 who underwent dermoscopy and 50 and 20 MHz HF-US. Fisher's exact test was used to assess the differences in dermoscopic and HF-US features among patients with different stages of morphea. Seven patients were classified as the inflammatory stage, 20 as the sclerotic stage, and seven as the atrophic stage by histopathology. The most common dermoscopic features of inflammatory lesions were red structureless areas (100%) and linear curved vessels (85.7%). White clouds and shiny white streaks could be seen in 100% and 90% of sclerotic lesions, respectively. Among atrophic lesions, pigmentary structures (100%) and red structureless areas (85.7%) were the main features. In the HF-US examination, inflammatory lesions showed hypoechogenicity around the appendages (85.7%), a hypoechogenic dermis (71.4%), and an unclear boundary between the dermis and the subcutaneous fat (71.4%). Among lesions of the sclerotic stage, the main HF-US characteristics included a hyperechogenic dermis (85.0%), acoustic attenuation of the dermis (70.0%), and an unclear boundary between the dermis and the subcutaneous fat (85.0%). All atrophic lesions showed a hyperechogenic dermis, and 28.6% showed an unclear boundary between the dermis and the subcutaneous fat. Dermoscopy and HF-US can reveal the characteristic features of the different stages of morphea and show good correspondence with the histopathology. Dermoscopy and HF-US can provide important information for the staging of morphea.

Impact of obesity and diet on brain structure and function: a gut-brain-body crosstalk.

Most societies witness an ever increasing prevalence of both obesity and dementia, a scenario related to often underestimated individual and public health burden. Overnutrition and weight gain have been linked with abnormal functionality of homoeostasis brain networks and changes in higher cognitive functions such as reward evaluation, executive functions and learning and memory. In parallel, evidence has accumulated that modifiable factors such as obesity and diet impact the gut-brain axis and modulate brain health and cognition through various pathways. Using neuroimaging data from epidemiological studies and randomised clinical trials, we aim to shed light on the underlying mechanisms and to determine both determinants and consequences of obesity and diet at the level of human brain structure and function. We analysed multimodal 3T MRI of about 2600 randomly selected adults (47 % female, 18-80 years of age, BMI 18-47 kg/m2) of the LIFE-Adult study, a deeply phenotyped population-based cohort. In addition, brain MRI data of controlled intervention studies on weight loss and healthy diets acquired in lean, overweight and obese participants may help to understand the role of the gut-brain axis in food craving and cognitive ageing. We find that higher BMI and visceral fat accumulation correlate with accelerated brain age, microstructure of the hypothalamus, lower thickness and connectivity in default mode- and reward-related areas, as well as with subtle grey matter atrophy and white matter lesion load in non-demented individuals. Mediation analyses indicated that higher visceral fat affects brain tissue through systemic low-grade inflammation, and that obesity-related regional changes translate into cognitive disadvantages. Considering longitudinal studies, some, but not all data indicate beneficial effects of weight loss and healthy diets such as plant-based nutrients and dietary patterns on brain ageing and cognition. Confounding effects of concurrent changes in other lifestyle factors or false positives might help to explain these findings. Therefore a more holistic intervention approach, along with open science tools such as data and code sharing, in-depth pre-registration and pooling of data could help to overcome these limitations. In addition, as higher BMI relates to increased head micro-movements during MRI, and as head motion in turn systematically induces image artefacts, future studies need to rigorously control for head motion during MRI to enable valid neuroimaging results. In sum, our results support the view that overweight and obesity are intertwined with markers of brain health in the general population, and that weight loss and plant-based diets may help to promote brain plasticity. Meta-analyses and longitudinal cohort studies are underway to further differentiate causation from correlation in obesity- and nutrition-brain research.

Cerebrospinal Fluid Alpha-Synuclein Improves the Differentiation between Dementia with Lewy Bodies and Alzheimer's Disease in Clinical Practice.

Alpha-synuclein, abnormally aggregated in Dementia with Lewy Bodies (DLB), could represent a potential biomarker to improve the differentiation between DLB and Alzheimer's disease (AD). Our main objective was to compare Cerebrospinal Fluid (CSF) alpha-synuclein levels between patients with DLB, AD and Neurological Control (NC) individuals. In a monocentric retrospective study, we assessed CSF alpha-synuclein concentration with a validated ELISA kit (ADx EUROIMMUN) in patients with DLB, AD and NC from a tertiary memory clinic. Between-group comparisons were performed, and Receiver Operating Characteristic analysis was used to identify the best CSF alpha-synuclein threshold. We examined the associations between CSF alpha-synuclein, other core AD CSF biomarkers and brain MRI characteristics. We included 127 participants (mean age: 69.3 ± 8.1, Men: 41.7%). CSF alpha-synuclein levels were significantly lower in DLB than in AD (1.28 ± 0.52 ng/mL vs. 2.26 ± 0.91 ng/mL, respectively, p &lt; 0.001) without differences due to the stage of cognitive impairment. The best alpha-synuclein threshold was characterized by an Area Under the Curve = 0.85, Sensitivity = 82.0% and Specificity = 76.0%. CSF alpha-synuclein was associated with CSF AT(N) biomarkers positivity (p &lt; 0.01) but not with hippocampal atrophy or white matter lesions. CSF Alpha-synuclein evaluation could help to early differentiate patients with DLB and AD in association with existing biomarkers.

Benefits of early treatment with natalizumab: a real-world study

BackgroundThe impact of early versus later high-efficacy disease-modifying therapy (DMT) in patients with multiple sclerosis (MS) is uncertain. This study reported the association of early versus later natalizumab treatment with real-world clinical outcomes in MS patients. MethodsThe study included 661 participants diagnosed with MS in 1994 or later from 7 US centers participating in the MS Partners Advancing Technology for Health Solutions (MS PATHS) network. Time to natalizumab treatment between diagnosis and first infusion (TTNT) was determined from the Tysabri Outreach: Unified Commitment to Health (TOUCH) registry. Clinical outcomes were defined using neuroperformance tests included in the Multiple Sclerosis Performance Test. Associations were tested using TTNT as a categorical and continuous variable. Linear mixed models addressed within-subject and within-site clustering. ResultsTTNT varied from 0.1 to 19.8 years (median [interquartile range] 4.2 [1.8, 9.0] years). A significant association between later natalizumab use and worse outcomes was demonstrated for walking speed (p < 0.001), processing speed (p < 0.001), manual dexterity (p < 0.001), brain atrophy (p = 0.001), and T2 lesion volume (p = 0.02). Covariate-adjusted modelling of a sensitivity population diagnosed with MS in 2006 or later (n = 424) demonstrated significant associations between longer TTNT and worse walking speed (p < 0.05), processing speed (p < 0.001), and manual dexterity (p < 0.001). ConclusionLater initiation of natalizumab was associated with worse clinical and radiologic imaging outcomes. Thus, high-efficacy DMT may have greater benefit when started earlier in MS patients. These results provide a rationale for randomized controlled trials to further assess the impact of early highly-effective DMT use versus later escalation of therapy.

Occurrences and phenotypes of RIPK3-positive gastric cells in Helicobacter pylori infected gastritis and atrophic lesions.

Research evidences suggest that diverse forms of programmed cell death (PCD) are involved in the helicobacter pylori (H. pylori)-induced gastric inflammation and disorders. To characterize occurrences and phenotypes of necroptosis in gastric cells in H. pylori infected gastritis and atrophic specimens. Occurrences and phenotypes of necroptosis in gastric cells were immunohistochemically characterized with receptor-interacting protein kinase 3 (RIPK3) antibody in both human H. pylori infected gastric gastritis, atrophic specimens, and transgenic mice. Increased populations of RIPK3-positive cells were observed in both gastric glands and lamina propria in H. pylori infected human oxyntic gastritis and atrophic specimens. Phenotypic analysis revealed that many RIPK3-positive cells were H+K+ ATPase-positive parietal cells in the gastric glands and were predominantly CD3-positive T lymphocytes, CD68-positive macrophages, and SMA-alpha-positive stromal cells in the lamina propria. Furthermore, we found an increased expression of RIPK3-positive gastric glandular cells along with the histological process of hyperplasia-atrophy-dysplasia progression in hypergastrinemic INS-GAS mice. An increased population of RIPK3-positive cells was observed in several types of gastric cells, future studies that define the effects and mechanisms of PCD implicated in the development of H. pylori induced gastric disorders are needed.

The Diagnostic Dilemma of Rothmund-Thomson Syndrome Type II: A Rare Disorder with a Novel Mutation in the RECQL4 Gene in an Indian Boy

Abstract Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous mutations in RECQL4 gene and has characteristic clinical features of poikiloderma, congenital bone defects, gastrointestinal disturbances such as chronic diarrhea and vomiting, and an increased susceptibility to malignancy. A 2½-year-old Indian boy presented with reticulate hyperpigmented erythema with superimposed hypopigmented atrophic macular lesions over the cheeks and diffuse background hyperpigmentation with multiple discrete atrophic hypopigmented macules of variable size over the abdomen and extensor aspects of the forearms. X-rays suggested metaphyseal irregularity around knee joint and radioulnar synostosis. Whole-exome sequencing was suggestive of a de novo novel RECQL4 gene mutation causing RTS Type II. There is an overlapping of clinical features of the group of syndrome associated with skin lesions, skeletal, and gastric manifestations. All these conditions present a challenge to the clinician. Thus, molecular diagnosis is the only way to resolve these phenotypically similar conditions. This report expands the RECQL4 gene pathogenic mutations spectrum.

Risk factors for myopic choroidal neovascularization-related macular atrophy after anti-VEGF treatment.

PurposeThe study aimed to evaluate risk factors for macular atrophy (MA) associated with myopic choroidal neovascularization (mCNV) during long-term follow-up after intravitreal anti-vascular endothelial growth factor (VEGF) treatment in highly myopic eyes.MethodsThe medical records of patients who received intravitreal injection of anti-VEGF agents as mCNV treatment and were followed-up for more than 36 months were retrospectively reviewed. The risk factors for the development of mCNV-MA, which is the fovea-involving patchy atrophy lesion adjacent to mCNV, were investigated using the Cox proportional hazard model.ResultsA total of 82 eyes (74 patients) were included in the study. The mean age at anti-VEGF treatment was 56.3 ± 12.5 years (range, 26–77), and the mean follow-up period was 76.3 ± 33.5 months (range, 36–154). During follow-up, mCNV-MA developed in 27 eyes (32.9%), and its occurrence was estimated to be 24.5% at 3 years and 37.3% at 5 years after the first anti-VEGF treatment. Old age (hazard ratio [HR] = 1.054, 95% confidence interval [CI]: 1.018–1.091; P = 0.003) and greater CNV size at baseline (HR = 2.396, CI: 1.043–5.504; P = 0.040) were significant factors for mCNV-MA development. Eyes with a thinner subfoveal choroid were more likely to show faster enlargement of the mCNV-MA during follow-up.ConclusionsIn mCNV eyes treated with intravitreal anti-VEGF agents, older age and greater mCNV size at baseline were risk factors for the development of MA during long-term follow-up, which was associated with a poor visual prognosis.

Automated segmentation and feature discovery of age-related macular degeneration and Stargardt disease via self-attended neural networks

Age-related macular degeneration (AMD) and Stargardt disease are the leading causes of blindness for the elderly and young adults respectively. Geographic atrophy (GA) of AMD and Stargardt atrophy are their end-stage outcomes. Efficient methods for segmentation and quantification of these atrophic lesions are critical for clinical research. In this study, we developed a deep convolutional neural network (CNN) with a trainable self-attended mechanism for accurate GA and Stargardt atrophy segmentation. Compared with traditional post-hoc attention mechanisms which can only visualize CNN features, our self-attended mechanism is embedded in a fully convolutional network and directly involved in training the CNN to actively attend key features for enhanced algorithm performance. We applied the self-attended CNN on the segmentation of AMD and Stargardt atrophic lesions on fundus autofluorescence (FAF) images. Compared with a preexisting regular fully convolutional network (the U-Net), our self-attended CNN achieved 10.6% higher Dice coefficient and 17% higher IoU (intersection over union) for AMD GA segmentation, and a 22% higher Dice coefficient and a 32% higher IoU for Stargardt atrophy segmentation. With longitudinal image data having over a longer time, the developed self-attended mechanism can also be applied on the visual discovery of early AMD and Stargardt features.

SEVERE MUCOSITIS AND ORAL COMPLICATIONS IN A LEUKEMIC PEDIATRIC PATIENT

The aim of this study is to report a case of a pediatric patient with severe oral mucositis, toothache, and gingivitis as a consequence of chemotherapy (CTX) treatment. An 11-year-old female patient diagnosed with acute lymphocytic leukemia was referred to the dentistry service because of suspension of CTX due to oral lesions. The patient reported oral pain and toothache and was not performing oral hygiene tasks. On intraoral examination, there were erythematous, atrophic, desquamative, and ulcerated lesions with pseudomembrane on the tongue and buccal and labial mucosa. There was also gingival bleeding, decayed teeth, and pulp exposure in the upper left first molar. Oral hygiene instructions, prescription of salivary substitute, topical antifungal, and low-level laser therapy were performed. The complete adequacy of oral cavity was assessed. The introduction of dentistry in the multidisciplinary treatment of patients with cancer is extremely important for the prevention, control, and treatment of oral complications from CTX.

Association of the prefrailty with global brain atrophy and white matter lesions among cognitively unimpaired older adults: the Nakajima study

Physical frailty has been associated with adverse outcomes such as dementia. However, the underlying structural brain abnormalities of physical frailty are unclear. We investigated the relationship between physical frailty and structural brain abnormalities in 670 cognitively unimpaired individuals (mean age 70.1 years). Total brain volume (TBV), hippocampal volume (HV), total white matter hypointensities volume (WMHV), and estimated total intracranial volume (eTIV) on the 3D T1-weighted images were automatically computed using FreeSurfer software. Participants were divided into two states of physical frailty (robust vs. prefrail) based on the revised Japanese version of the Cardiovascular Health Study criteria. The multivariable-adjusted mean values of the TBV-to-eTIV ratio was significantly decreased, whereas that of the WMHV-to-eTIV ratio was significantly increased in the prefrail group compared with the robust group. Slowness, one of the components of physical frailty, was significantly associated with reduced TBV-to-eTIV and HV-to-eTIV ratios, and slowness and weakness were significantly associated with an increased WMHV-to-eTIV ratio. Our results suggest that the prefrail state is significantly associated with global brain atrophy and white matter hypointensities. Furthermore, slowness was significantly associated with hippocampal atrophy.

Delineating the Clinical Phenotype of Patients With the c.629C>G, p.Pro210Arg Mutation in Peripherin-2.

PurposeMore than 200 different mutations in peripherin-2 (PRPH2) are associated with multiple subtypes of inherited retinal diseases (IRDs), including retinitis pigmentosa and cone or macular diseases. Our goal was to understand how the poorly characterized PRPH2 mutation p.Pro210Arg (P210R) affects visual function and retinal structure as well as gain insight into the mechanism driving the clinical pathology.MethodsEleven patients had clinical assessments including best-corrected visual acuity (BCVA), full field and multifocal electroretinography (ERG), static (spot size V) and kinetic perimetry (Octopus 900), and dark-adapted chromatic (DAC; Medmont; spot size V) perimetry. Images were acquired with the Optos ultra-wide field camera and spectral-domain optical coherence tomography (SD-OCT). Molecular characteristics of the P210R mutant protein were evaluated in vitro.ResultsPatients with the P210R mutation had BCVA (Snellen) ranging from 20/15 to 20/80. Perimetry showed a reduction in sensitivity, while ERG findings suggested that cone function was more impaired than rod function. Scotomas were identified corresponding to atrophic retinal lesions. Imaging revealed heterogeneous outer retinal changes such as hyperfluorescent flecks, hypo-autofluorescence (AF) regions of atrophy, and thinning of the photoreceptor layer on SD-OCT. In vitro findings suggested that P210R-Prph2 retains the ability to interact with binding partner Rom1 but abnormally accumulates in the endoplasmic reticulum (ER), suggesting the protein does not fold properly.ConclusionsRod and cone sensitivities were decreased in subjects with the P210R mutation in PRPH2. There was scotomatous vision loss that occurred within the macula, likely due to atrophy that occurs after drusen have formed and have begun to resolve. This suggests that although rod and cone photoreceptors are dependent on PRPH2, preventing blindness in this specific subgroup of patients could involve therapeutics that impede the formation or lifecycle of drusen.

Nomenclature and Definition of Atrophic Lesions in Small Bowel Capsule Endoscopy: A Delphi Consensus Statement of the International CApsule endoscopy REsearch (I-CARE) Group.

(1) Background: Villous atrophy is an indication for small bowel capsule endoscopy (SBCE). However, SBCE findings are not described uniformly and atrophic features are sometimes not recognized; (2) Methods: The Delphi technique was employed to reach agreement among a panel of SBCE experts. The nomenclature and definitions of SBCE lesions suggesting the presence of atrophy were decided in a core group of 10 experts. Four images of each lesion were chosen from a large SBCE database and agreement on the correspondence between the picture and the definition was evaluated using the Delphi method in a broadened group of 36 experts. All images corresponded to histologically proven mucosal atrophy; (3) Results: Four types of atrophic lesions were identified: mosaicism, scalloping, folds reduction, and granular mucosa. The core group succeeded in reaching agreement on the nomenclature and the descriptions of these items. Consensus in matching the agreed definitions for the proposed set of images was met for mosaicism (88.9% in the first round), scalloping (97.2% in the first round), and folds reduction (94.4% in the first round), but granular mucosa failed to achieve consensus (75.0% in the third round); (4) Conclusions: Consensus among SBCE experts on atrophic lesions was met for the first time. Mosaicism, scalloping, and folds reduction are the most reliable signs, while the description of granular mucosa remains uncertain.

"Atypical" Mild Clinical Presentation in Elderly Patients With Ruptured Intracranial Aneurysm: Causes and Clinical Characteristics.

ObjectiveThunderclap-like severe headache or consciousness disturbance is the common “typical” clinical presentation after aneurysmal subarachnoid hemorrhage (aSAH); however, a slowly developing “atypical” clinical pattern, with mild headache, vomiting, or dizziness, is frequently noted in elderly patients. The aim of this study was to evaluate the clinical characteristics of this “atypical” subgroup, as well as related factors associated with the presence of these mild symptoms.MethodsThe data of 176 elderly patients (≥70 years old) with ruptured intracranial aneurysms (IAs) treated at our center from January 2016 to January 2020 were retrospectively collected and analyzed. The patients were divided into “typical” and “atypical” groups based on their initial and development of clinical symptoms after the diagnosis of aSAH. Intergroup differences were analyzed, and factors related to the presence of these two clinical patterns were explored through multiple logistic regression analyses.ResultsDespite significant admission delay (P < 0.001) caused by mild initial symptoms with slow development, patients in the “atypical” group achieved better clinical prognosis, as indicated by a significantly higher favourable outcome ratio and lower death rate upon discharge and at different time points during the 1-year follow-up, than the “typical” group (P < 0.05). Multiple logistic regression analysis revealed that modified Fisher grade III-IV (OR = 11.182, P = 0.003), brain atrophy (OR = 10.010, P = 0.001), a larger lesion diameter (OR = 1.287, P < 0.001) and current smoking (OR = 5.728, P < 0.001) were independently associated with the presence of “typical” symptoms. Aneurysms with wide necks (OR = 0.013, P < 0.001) were independently associated with the presence of “atypical” symptoms.Conclusions“Atypical” presentations, with mild clinical symptoms and slow development, were commonly recorded in elderly patients after the onset of aSAH. Despite the prolonged admission delay, these “atypical” patients achieved better clinical outcomes than those with “typical” symptoms. Modified Fisher grade (III-IV), current smoking, brain atrophy and larger lesion diameter were factors predictive of “typical” symptoms, while aneurysms with wide necks were independently associated with “atypical” symptoms.

How Does Helicobacter pylori Infection Cause Gastric Mucosal Atrophy.

ObjectiveTo investigate the occurrence and development of gastric mucosal atrophy due to Helicobacter pylori (Hp) infection and the accompanying histomorphological features.MethodsDetailed histological observations and immunohistochemical examinations were conducted via 197 endoscopic biopsies and endoscopic submucosal dissection specimens of gastric mucosal atrophic lesions with gastric Hp infection. Detailed observation was made of columnar cells in the proliferative region of the deep gastric pit and the isthmus of the gastric gland, as well as the upper part of the glandular cervix.ResultsThe infection of the gastric mucosa by Hp firstly led to the proliferative disorder of stem cells in the normal proliferative region of the gastric mucosa. This caused substantial propagation of cells in the proliferative region of the deep gastric pit and the isthmus of the gastric gland, as well as the upper part of the glandular cervix, as a means to replenish the damaged surface mucus cells. However, the propagation of stem cells in the proliferative region was insufficient for downward migration, and the normal physiological process of differentiation into fundic/pyloric gland cells was disrupted, resulting in glandular atrophy of the intrinsic layer of the gastric mucosa. Persistent Hp infection and disruption of stem cell proliferation in the proliferative region subsequently resulted in extensive segmental hyperplasia of the gastric mucosa and glandular atrophy of the lamina propria.ConclusionThe occurrence, development, and histomorphological features of gastric mucosal atrophy due to gastric Hp infection provide a reliable pathological basis for precise treatment by clinicians and are of great significance for controlling the development of gastric cancer.

Grey-matter sodium concentration as an individual marker of multiple sclerosis severity

Objective: Quantification of brain injury in patients with variable disability despite similar disease duration may be relevant to identify the mechanisms underlying disability in multiple sclerosis (MS). We aimed to compare grey-matter sodium abnormalities (GMSAs), a parameter reflecting neuronal and astrocyte dysfunction, in MS patients with benign multiple sclerosis (BMS) and non-benign multiple sclerosis (NBMS). Methods: We identified never-treated BMS patients in our local MS database of 1352 patients. A group with NBMS was identified with same disease duration. All participants underwent 23Na magnetic resonance imaging (MRI). The existence of GMSA was detected by statistical analysis. Results: In total, 102 individuals were included (21 BMS, 25 NBMS and 56 controls). GMSA was detected in 10 BMS and 19 NBMS (11/16 relapsing-remitting multiple sclerosis (RRMS) and 8/9 secondary progressive multiple sclerosis (SPMS) patients) (p = 0.05). On logistic regression including the presence or absence of GMSA, thalamic volume, cortical grey-matter volume and T2-weighted lesion load, thalamic volume was independently associated with BMS status (odds ratio (OR) = 0.64 for each unit). Nonetheless, the absence of GMSA was independently associated when excluding patients with significant cognitive alteration (n = 7) from the BMS group (OR = 4.6). Conclusion: Detection of GMSA in individuals and thalamic volume are promising to differentiate BMS from NBMS as compared with cortical or whole grey-matter atrophy and T2-weighted lesions.

Focal facial dermal dysplasias type III: Two families with Setleis syndrome in China.

Focal facial dermal dysplasias type III (FFDD III), commonly known as Setleis syndrome (SS; Online Mendelian Inheritance in Man #227260), is a type of focal facial dermal dysplasia, characterized by bitemporal atrophic skin lesion. The homozygous mutations in the TWIST2 gene and copy number variants (CNV) at chromosome 1p36.22p36.21 were reported as the pathogenic mechanism. In this study, we collected DNA samples from a large Chinese family affected by FFDD and found no mutation of TWSIT2. To determine the underlying genetic cause, we performed a multipoint parameter linkage analysis and haplotype analysis of the family 1 and mapped SS to a region Chr1:14.074-20.524cM (rs2401090-rs2294642). Copy number variant was identified by Sanger sequencing, which breakpoints were Chr1:11695972 and Chr1:11829858. The region contains eight genes, including FBXO2, FBXO44, FBXO6, MAD2L2, DRAXIN, AK125437, AGTRAP, and C1orf167. There were no candidate gene mutations of the second family with SS. Our study further reduced the size of CNV resulting in SS (Chr1:11696993-11829858) and focused on eight genes.

Abstract 3734: Progressive spreading of CpG methylation in the CpG island of Glutathione S-Transferase pi 1 (GSTP1) alleles across transitions from precursor to invasive prostate cancer

Abstract Glutathione S-transferase pi 1 (GSTP1) is expressed at low levels in normal prostate luminal cells and becomes induced in most proliferative inflammatory atrophy lesions (PIA). GSTP1 becomes silenced in prostatic intraepithelial neoplasia (PIN) and prostate adenocarcinoma (CaP) via CpG island promoter hypermethylation. However, the specific methylation patterns in CaP and its precursors have not been investigated. We used bisulfite genomic sequencing to examine methylation of 39 CpG sites in the GSTP1 promoter. Radical prostatectomy specimens were selected from 32 subjects that underwent treatment for CaP. Serial sections were subjected to laser capture microdissection for enrichment of epithelial cells from benign, PIA, PIN, and CaP regions. Isolated DNA was bisulfite converted. Sequences corresponding to the GSTP1 promoter CpG island were amplified with nested PCR, and PCR products were cloned. 10 independent clones were sequenced and analyzed with a Java program, DNAMethylMap, to determine the methylation pattern of 39 CpG sites of the GSTP1 promoter in each lesion. The extent of methylation on an individual allele was classified as negative (&amp;lt;10% CpGs), mild (10-25%), moderate (25-50%), or high (&amp;gt;50%). 212 clones from 24 normal epithelium regions, 327 clones from 37 PIA regions, 167 clones from 18 PIN regions, and 202 clones from 23 CaP regions were sequenced, totaling 34863 CpG sites. Normal and PIA lesions were mostly unmethylated with 0.52% and 1.3% of total CpG sites methylated, respectively. Methylated PIA lesions were adjacent to CaP or PIN regions significantly more often than unmethylated PIA lesions (χ2, p = 0.012). PIN and CaP lesions had greater methylation with 24% and 51% of total CpG sites methylated, respectively. PIN lesions generally showed partial methylation with 28.7% of alleles in PIN having mild/moderate methylation density compared to 5.5% in PIA and 11% in CaP. PIA and PIN lesions were enriched for methylation changes at 6 CpG sites that aligned with AP1 and SP1 binding sites. Among 16 PIN and CaP lesions with an overall intermediate level of methylation, 5 of the lesions had clones that clustered into either fully methylated or unmethylated. One patient with 3 CaP lesions displayed significant heterogeneity in methylation patterns: full, moderate, or no methylation across all clones in a given lesion. The results demonstrate that methylation density in the GSTP1 CpG island from PIN was intermediate between normal prostate epithelium/PIA and CaP lesions. The observed methylation in PIA and PIN was enriched at binding sites of key transcription factors, AP1 and SP1. The results are consistent with gradual spreading of DNA methylation centered at the transcription factor binding sites in the putative precursor lesions, with subsequent spreading of methylation across the entire CpG island in transition to CaP. Citation Format: Harshath Gupta, Hitoshi Inoue, Yasutomo Nakai, Masashi Nakayama, William G. Nelson, Angelo M. De Marzo, Srinivasan Yegnasubramanian. Progressive spreading of CpG methylation in the CpG island of Glutathione S-Transferase pi 1 (GSTP1) alleles across transitions from precursor to invasive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3734.

Recombinant characteristics, pathogenicity, and viral shedding of a novel PRRSV variant derived from twice inter-lineage recombination

Porcine reproductive and respiratory syndrome (PRRS), caused by the PRRS virus (PRRSV), is a significant threat to the global pig industry. In this study, a novel recombinant PRRSV, SD043, was isolated from a pig farm experiencing disease in 2019. Phylogenetic analysis revealed that SD043 belonged to lineage 1 of PRRSV-2 while recombination analyses revealed that it is a recombinant virus from lineage 1 and lineage 8 strains. Based on further analysis, SD043 underwent recombination twice. Pathogenicity studies revealed that SD043 causes mild clinical symptoms, thymus atrophy, and severe histopathological lesions in the lungs. Notably, virus shedding in SD043-infected piglets was detectable at 10 days post-inoculation with a high viral load in the respiratory or digestive tract, indicating that the recombinant PRRSV appears to shed higher numbers of virus. Furthermore, genomic surveillance based on all available PRRSVs circulating in Shandong province revealed an increasing increase in recombinant PRRSV since 2015, with the recombinant pattern (between lineages 1 and 8) being the same as that of SD043. These findings enable a better understanding of the process of twice recombination and virus shedding of recombinant PRRSV and can strengthen the prevention and control of the PRRSV epidemic.