Classical Phenotype Research Articles

Variations in the severity of symptoms, DAS28, and Disability Index among different Vata predominant Deha-Prakriti individuals of Amavata (~Rheumatoid Arthritis) - An Analytical Observational Study

Background: Subgrouping of diseased population, based on Deha-Prakriti (DP), phenotypic classification of Ayurveda will explore the variation in the disease severity, which further aid in the management of the disease more precisely and selectively. But there is a paucity in the data generation. Amavata (~Rheumatoid Arthritis) is one of such diseases, resulting from the conglomeration of Ama and aggravated Vata gets lodged in the joints. Aim & Objective: To evaluate variations in the severity of symptoms, duration of morning stiffness, DAS28 (Disease Activity Score in 28 Joints), and Disability Index (DI) among different Vata predominant Deha-Prakriti (DP) individuals of Amavata (~Rheumatoid Arthritis). Materials & Methodology: The study was conducted among 155 clinically diagnosed patients of Amavata, who were screened for DP assessment through the CCRAS-PAS scale. Those who were found to have Vata predominant DP were sub-grouped into Single Vataja (V), Vata-Pittaja (VP), and Vata-Kaphaja (VK) DP, based on the proportion of the doshas in the output of scale. Demographic profile, the severity of the symptoms, duration of the morning stiffness, DAS28, and DI were assessed and calculated using SPSS software version 20.0, p≤0.05 was considered statistically significant. Results: Kruskal-Walli’s test revealed that Single Vata predominant DP patients were found to have severe Sandhi-shula (Joint pain) (p<0.0001), Shunatanga (Numbness of the joint) (p-value at 0.0069), Nidra-Viparyaya (Irregular sleep patterns) (p-value at 0.0012) than VP and VK DP individuals. Sandhi-Shotha (Joint swelling) (p-value at 0.0299), Angamarda (generalized body pains) (p-value at 0.0130), Alasya (laziness) (p<0.0001), Gaurava (Heaviness) (p<0.0001), and Apaka (delayed digestion) (p-value at 0.0254) were found severe in VK DP, whereas Trishna (Thirsty) (p<0.0001), Nidraviparyaya (p-value at 0.0012) were more severe in VP DP individuals. One-way ANOVA revealed that the duration of morning stiffness (2.03±0.2 hours, p-value at 0.446), DAS28 (6.85±0.175, p-value at 0.0035), and DI (1.87±0.54, p-value at 0.0003) were found significantly high in single Vataja than VP and VK Deha-Prakriti. Conclusion: The disease severity in terms of duration of morning stiffness, DAS28, and DI were found more severe in Single Vataja DP. The severity of the signs and symptoms also varied according to DP.

2264P Proteomics-based phenotypic classification of non-smallcell lung cancer

2264P Proteomics-based phenotypic classification of non-smallcell lung cancer

Spatially Resolved Whole Transcriptome Analysis of Histologically-Characterized Tissue Microarray of Patient-Matched Primary and Recurrent Glioblastomas to Identify Underlying Mechanisms of Treatment Resistance

Glioblastoma multiforme (GBM) is a lethal CNS malignancy. Radiation therapy increases overall survival, but tumors often recur in high-radiation dose regions. Additionally, recent investigations have underscored the importance of intra-tumoral heterogeneity as a driver of GBM biology. The purpose of this investigation is to characterize transcriptome differences in primary and recurrent GBM patient clinical samples using a digital spatial profiling approach to better appreciate treatment resistance mechanisms. To address the lack of understanding of molecular mechanisms of resistance in GBM, patient-matched primary and recurrent GBM pathological specimens were identified within the brain tissue biorepository and tissue cores were selected for generation of a tissue microarray (TMA). Hematoxylin and eosin staining with histomorphological (cellular tumor, pseudopalisading necrosis, invasive edge, and perivascular inflammation) scoring were performed in a blinded fashion for every core. This array was then molecularly characterized using digital spatial profiling of the transcriptome. Quality assurance including filtering of lowly expressed genes followed by downstream analyses of the data were performed using the manufacturer's recommended methods within their Bioconductor library. Gene Set Enrichment Analysis (GSEA) was then performed on the ranked gene lists. After recommended filtering, 6171 genes and 248 regions of interest remained for downstream analysis representing 22 unique patients across four different tumor histomorphological types. Significance testing revealed 679 genes that were differentially expressed between primary and recurrent tumor samples (at FDR<1%). On GSEA analysis, the chromosomal positional locus that contains genes most strongly up-regulated is 12q14, a locus that was previously identified as genomically amplified in multiple patient-derived xenograft lines after radiation selection. Additionally, recurrent tumors display a transcriptional profile more similar to the mesenchymal subtype, whereas primary tumors have a more classical transcriptional phenotype. The epithelial-to-mesenchymal transition pathway is particularly strongly up-regulated in recurrent tumors. Recurrent selection at previously identified genomic loci and molecular pathways underscores a possible conserved set of pathways for treatment resistance. This analysis has yielded a set of gene and molecular pathways that will guide future work in our lab targeting treatment resistance using novel therapeutics and radiation techniques in GBM. Future directions include assessing the feasibility of mapping these clinical samples onto our previously generated panel of comprehensively characterized patient-derived xenograft lines.

Shedding Light on Photobiomodulation Therapy for Age-Related Macular Degeneration: A Narrative Review.

Photobiomodulation (PBM) relies on the pathophysiological mechanism whereby red to near-infrared light can target mitochondrial activity and promote ATP synthesis. Preclinical and clinical studies have shown promising results in treating intermediate age-related macular degeneration (AMD), since PBM can produce photochemical reactions in endogenous retinal chromophores. Currently, PBM is approved by the Food and Drug Administration and by the European Medicines Agency for the treatment of intermediate AMD. This narrative review aimed to evaluate the available evidence on the effectiveness and safety of PBM in treating intermediate AMD. A comprehensive search was conducted using the PubMed database, employing the keywords "photobiomodulation" and "age-related macular degeneration." All English-language studies published up to June 2023 were reviewed, and the search was expanded to include relevant references from selected articles. The included publications were analyzed for this review. The available studies on PBM in AMD demonstrated promising but inconsistent results. PBM showed potential in improving best-corrected visual acuity (BCVA) and contrast sensitivity (CS) in patientswith AMD. Some studies also suggested a reduction in AMD lesions, such as drusen volume. However, the long-term efficacy and optimal treatment parameters of PBM in AMD remained to be fully determined due to the limitations of the available studies. These included variations in irradiation techniques, wavelengths, exposure times, and treatment sessions, making it challenging to generalize the effectiveness of PBM. Furthermore, the lack of accurate classification of AMD phenotypes in the available studies hindered the understanding of which phenotypes could truly benefit from this treatment. Finally, the strength of evidence varied among studies, with limited sample sizes, unpublished results, and only three randomized sham-controlled trials. Currently, the effectiveness of PBM in promoting drusen resorption or preventing progression to advanced forms of AMD, as observed in the cited studies, remains uncertain.

A-201 Deriving Information from the Lipid Panel as Spherical Coordinates

Abstract Background Lipid panel assays are used to calculate LDL-C as a proxy for cardiovascular disease risk. Further investigations are required to classify the patient’s dyslipidemia into a phenotype to assist with management. We explored the information contained within the lipid panel with two aims: First, to estimate cardiovascular risk directly, bypassing LDL-C calculation. Second, to provide a novel phenotypic classification system. Methods Various transformations of lipid panel data were explored as inputs to a logistic regression model of cardiovascular risk, and to produce a spherical coordinate system for phenotyping. Area under the receiver operating characteristic (AUROC) curve was used to assess the predictive ability of the model. Clinical utility metrics were calculated and Kaplan-Meier survival curves were used to determine the prognostic value of the model. Results Transforming the lipid panel data into indices allowed derivation of a spherical coordinate system. The spherical coordinates proved to be the best input values for logistic regression to provide the probability of high cardiovascular risk. When we added age, sex and race as variables in the model, the AUROC for predicting cardiovascular events approached that of the American Heart Association’s pooled cohort equation (PCE). The final model was more sensitive than the PCE, and provided greater prognostic ability than LDL-C. The spherical coordinate system classified individuals into “normal” or one of eight phenotypes, which were differentially associated with clinical features such as elevated CRP or metabolic syndrome. Conclusion The new model uses all three lipid panel parameters and other routinely available laboratory data to directly predict cardiovascular risk with similar accuracy to the PCE. Conversion of the parameters to a spherical coordinate system allows classification into one of 9 phenotypic groups, which may alert clinicians to underlying or consequent pathological processes to be managed.

Phenotypic Classification and Clinical Examination of Anemia in Iraqi Water Buffalo in Nasiriyah Governorate

This research aims to classify anemia cases in the Iraqi water buffalo population by collecting 140 blood samples from buffaloes in Nasiriyah Governorate pastures. These samples were collected randomly from three age groups: &gt; 1 year, 1-4 years, and &lt; 5 years. Blood sample analysis revealed 45 anemia cases (32.12%) and 95 healthy cases (67.88%). Phenotypic classification of anemia encompassed microcytic hypochromic (12.14%), macrocytic hypochromic (7.85%), normocytic hypochromic (6.42%), and normocytic normochromic (5.71%) cases. Erythrocyte sedimentation rate (ESR) notably increased in anemic buffaloes, displaying a statistically significant disparity (P&lt; 0.05) compared to healthy counterparts. Anemia cases exhibited higher neutrophil counts in white blood cell relative differentials. For the three age groups, hemoglobin (Hb), packed blood cell volume (PCV), and total red blood cell count (RBC) values indicated significant decreases from normal levels, showcasing statistical significance (P&lt; 0.05) between healthy and anemic buffaloes. While anemia cases generally displayed normal iron concentrations, microcytic anemia demonstrated lower iron levels in the 1-4 and &gt;5 years age groups, with iron levels reaching the minimum global normal range in the &lt;1 year age group. Copper concentrations remained normal in all healthy cases and anemia cases, except for microcytic anemia, which showed reduced levels across age groups.&#x0D; In conclusion, this study comprehensively characterizes anemia in Iraqi water buffaloes through clinical, hematological, and elemental analyses. The findings underscore the prevalence of various anemia types, their age-related variations, and significant hematological deviations in anemic buffaloes compared to healthy counterparts. This research enhances our understanding of anemias' impact on this population and provides valuable insights for future diagnostic and management strategies.

Neuro-otological manifestations in Fabry disease-aretrospective single center study

Fabry disease (FD) is one of the X‑linked lysosomal storage diseases that can affect any organ. They have aspecific lysosomal dysfunction in common, which results in substrate accumulation in lysosomes instead of metabolite degradation. Due to the deficiency/absence of α‑galactosidase, globotriaosylceramides (Gb3) are deposited in lysosomes of the organs. In addition to acroparesthesia, angiokeratomas, autonomic dysfunction, vortex keratopathies, ischemic cerebral or cardiac complications and chronic renal failure, also vestibulocochlear dysfunctions with sudden or progressive asymmetric hearing loss, tinnitus and vertigo may be observed. In this retrospective study, 33patients (men = 16 and women = 17) with FD were evaluated. All patients presented to us in interdisciplinary cooperation as part of routine examinations by the specialized center for lysosomal storage diseases of the in-house department of nephrology. This presentation is carried out as ascreening examination independent of neuro-otological symptoms. The mean age at diagnosis was 34.76 (±11.55) years. The first presentation in our ENT department was at 40.45 (±11.71) years. We were able to demonstrate asignificant correlation between neurological symptoms or apoplexy and hearing loss (p = 0.001) and between cardiac manifestations and hearing loss (p = 0.024). Hearing loss is apotential symptom of Fabry disease and is not limited to the classic male phenotype. Due to possible positive correlations with neurological and cardiological manifestations of the disease, routine ENT screening examinations should be carried out to be able to identify and treat neuro-otological deficits at an early stage. In addition, FD should also be considered and tested as adifferential diagnosis, especially in younger patients with sudden unilateral or bilateral hearing loss and afamily history.

Improved phenotypic classification of male infertility to promote discovery of genetic causes.

An increasing number of genes are being described in the context of non-syndromic male infertility. Linking the underlying genetic causes of non-syndromic male infertility with clinical data from patients is important to establish new genotype-phenotype correlations. This process can be facilitated by using universal nomenclature, but no standardized vocabulary is available in the field of non-syndromic male infertility. The International Male Infertility Genomics Consortium aimed at filling this gap, providing a standardized vocabulary containing nomenclature based on the Human Phenotype Ontology (HPO). The "HPO tree" was substantially revised compared with the previous version and is based on the clinical work-up of infertile men, including physical examination and hormonal assessment. Some causes of male infertility can already be suspected based on the patient's clinical history, whereas in other instances, a testicular biopsy is needed for diagnosis. We assembled 49 HPO terms that are linked in a logical hierarchy and showed examples of morphological features of spermatozoa and testicular histology of infertile men with identified genetic diagnoses to describe the phenotypes. This work will help to record patients' phenotypes systematically and facilitate communication between geneticists and andrologists. Collaboration across institutions will improve the identification of patients with the same phenotypes, which will promote the discovery of novel genetic causes for non-syndromic male infertility.

Proton-Pump Inhibitor Therapy in Patients with Erosive Esophagitis: A Real-World Scenario

Background: Gastroesophageal reflux disease (GERD) has three classical phenotypes, namely erosive esophagitis (EE), nonerosive reflux disease, and Barrett’s esophagus. Patients with GERD are managed with lifestyle changes, dietary interventions, and proton-pump inhibitors (PPI). Aim: To determine the patterns of PPI use in patients with documented EE. Methods: This prospective study recruited all patients with symptoms of GERD (heartburn and/or regurgitation with or without chest pain) and documented significant reflux esophagitis (Los Angeles grading LA-B or beyond on endoscopy). Lifestyle and dietary changes were initiated and all patients were prescribed twice daily PPI for 8 weeks. PPI was tapered as the requirement beyond 8 weeks. Follow-up was done at weeks 8, 12, and 24. The outcomes analysed included number of patients where complete PPI withdrawal was possible at week 24 and determinants of continued PPI use at 24 weeks of therapy. Statistical analysis was performed using Chi-square test, Mann–Whitney U-test, sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio. P &lt; 0.05 was considered statistically significant. Results: The study cohort included 53 patients-42 with reflux esophagitis LA-B and 11 with reflux esophagitis LA-C (median age 46 years [22–77 years]; 28 [52.3%] males). There was significant difference in consumption pattern of PPI between week 12 and 24 (P = 0.008). At week 12, 15.1% were off PPI and 67% required intermittent dosing. At week 24, 45.3% of cases were off PPI therapy and 43.4% required intermittent dosing. Only 11.3% patients continued drug use at once a day dosing. Lower body mass index (BMI) (P 0.01) and age (P 0.01) were linked with complete PPI withdrawal at week 24. Conclusion: The present study highlights that PPI withdrawal is possible in 15.1% and 45.3% cases with EE after week 12 and week 24 of therapy, respectively. Lower BMI and age are likely to be associated with PPI withdrawal at week 24.

Human umbilical cord mesenchymal stem cell-derived exosomes attenuate neuroinflammation and oxidative stress through the NRF2/NF-κB/NLRP3 pathway.

We investigated whether human umbilical cord mesenchymal stem cell (hUC-MSC)-derived exosomes bear therapeutic potential against lipopolysaccharide (LPS)-induced neuroinflammation. Exosomes were isolated from hUC-MSC supernatant by ultra-high-speed centrifugation and characterized by transmission electron microscopy and western blotting. Inflammatory responses were induced by LPS in BV-2 cells, primary microglial cultures, and C57BL/6J mice. H2 O2 was also used to induce inflammation and oxidative stress in BV-2 cells. The effects of hUC-MSC-derived exosomes on inflammatory cytokine expression, oxidative stress, and microglia polarization were studied by immunofluorescence and western blotting. Treatment with hUC-MSC-derived exosomes significantly decreased the LPS- or H2 O2 -induced oxidative stress and expression of pro-inflammatory cytokines (IL-6 and TNF-α) in vitro, while promoting an anti-inflammatory (classical M2) phenotype in an LPS-treated mouse model. Mechanistically, the exosomes increased the NRF2 levels and inhibited the LPS-induced NF-κB p65 phosphorylation and NLRP3 inflammasome activation. In contrast, the reactive oxygen species scavenger NAC and NF-κB inhibitor BAY 11-7082 also inhibited the LPS-induced NLRP3 inflammasome activation and switched to the classical M2 phenotype. Treatment with the NRF2 inhibitor ML385 abolished the anti-inflammatory and anti-oxidative effects of the exosomes. hUC-MSC-derived exosomes ameliorated LPS/H2 O2 -induced neuroinflammation and oxidative stress by inhibiting the microglial NRF2/NF-κB/NLRP3 signaling pathway.

P02.15.A PRONEURAL, CLASSICAL AND MESENCHYMAL PROTEIN SIGNATURES LACK PROGNOSTIC VALUE IN WHO 2021 ADULT TYPE DIFFUSE LOWER-GRADE GLIOMAS

Abstract BACKGROUND Mesenchymal transformation in glioblastomas is associated with therapy resistance and increased aggressiveness. In WHO 2021-defined adult-type diffuse gliomas of lower grade (dLGG), the transition between phenotypic states, has not been studied. Most reports correlating proneural, classical or mesenchymal signatures with outcome in dLGG were made prior to the WHO 2021 classification. Here, we set out to investigate if phenotype as well as the transition of phenotype predicted survival in a clinical cohort of WHO 2021 defined dLGGs. MATERIAL AND METHODS We used a TMA-based approach and five immunohistochemical markers (EGFR, p53, MERTK, CD44 and OLIG2) to examine 183 primary and 49 recurrent tumors from patients with previously diagnosed dLGG. Of the 49 recurrent tumors, nine tumors relapsed a second time, and one a third time. RESULTS In total, 71.0% of all tumors could be subtyped into proneural, classical or mesenchymal. Proneural was the predominant subtype among IDH-mut tumors (78.5%), while in IDH-wt tumors mesenchymal was more common (63.6%). A significant difference in survival was found between subtypes (proneural, classical and mesenchymal) in the total cohort (p&amp;lt;0.001), but not when molecularly stratified (IDH-mut: p=0.220, IDH-wt: p=0.623). Upon relapse, proneural signature was retained in 66.7% of the proneural IDH-mut dLGGs (n=21), whereas IDH-wt tumors (n=10) mainly retained or gained mesenchymal phenotype. There was no significant difference in survival between IDH-mut gliomas remaining proneural and those switching to mesenchymal signature (p=0.347). CONCLUSION Subtyping into proneural, classical and mesenchymal phenotypes by five immunohistochemical markers, was possible for the majority of tumors, but statistical significance between phenotypes and survival was lost after molecular stratification according to the WHO 2021 criteria. IDH-mut tumors mainly remained proneural at recurrence, while IDH-wt tumors mostly retained or gained mesenchymal phenotype. This phenotypic shift, which in glioblastoma is associated with increased aggressiveness, did not affect survival. Sample sizes were, however, too small to draw any firm conclusions on whether this negative finding is due to lack of statistical power or reflects a true biological difference from glioblastomas.

The dual face of microglia (M1/M2) as a potential target in the protective effect of nutraceuticals against neurodegenerative diseases.

The pathophysiology of different neurodegenerative illnesses is significantly influenced by the polarization regulation of microglia and macrophages. Traditional classifications of macrophage phenotypes include the pro-inflammatory M1 and the anti-inflammatory M2 phenotypes. Numerous studies demonstrated dynamic non-coding RNA modifications, which are catalyzed by microglia-induced neuroinflammation. Different nutraceuticals focus on the polarization of M1/M2 phenotypes of microglia and macrophages, offering a potent defense against neurodegeneration. Caeminaxin A, curcumin, aromatic-turmerone, myricetin, aurantiamide, 3,6'-disinapoylsucrose, and resveratrol reduced M1 microglial inflammatory markers while increased M2 indicators in Alzheimer's disease. Amyloid beta-induced microglial M1 activation was suppressed by andrographolide, sulforaphane, triptolide, xanthoceraside, piperlongumine, and novel plant extracts which also prevented microglia-mediated necroptosis and apoptosis. Asarone, galangin, baicalein, and a-mangostin reduced oxidative stress and pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha in M1-activated microglia in Parkinson's disease. Additionally, myrcene, icariin, and tenuigenin prevented the nod-like receptor family pyrin domain-containing 3 inflammasome and microglial neurotoxicity, while a-cyperone, citronellol, nobiletin, and taurine prevented NADPH oxidase 2 and nuclear factor kappa B activation. Furthermore, other nutraceuticals like plantamajoside, swertiamarin, urolithin A, kurarinone, Daphne genkwa flower, and Boswellia serrata extracts showed promising neuroprotection in treating Parkinson's disease. In Huntington's disease, elderberry, curcumin, iresine celosia, Schisandra chinensis, gintonin, and pomiferin showed promising results against microglial activation and improved patient symptoms. Meanwhile, linolenic acid, resveratrol, Huperzia serrata, icariin, and baicalein protected against activated macrophages and microglia in experimental autoimmune encephalomyelitis and multiple sclerosis. Additionally, emodin, esters of gallic and rosmarinic acids, Agathisflavone, and sinomenine offered promising multiple sclerosis treatments. This review highlights the therapeutic potential of using nutraceuticals to treat neurodegenerative diseases involving microglial-related pathways.

Adaptive shift of active electroreception in weakly electric fish for troglobitic life

The adaptive-shift hypothesis for the evolution of cave-dwelling species posits that ancestor species in surface habitats had exaptations for subterranean life that were exploited when individuals invaded caves. Weakly electric Gymnotiform fishes, nocturnal South American teleost fishes, have features that appear to be likely exaptations for troglobitic life. These fishes have active electrosensory systems in which fish generate weak electric fields that are detected by specialized electroreceptors. Gymnotiform fishes use their electric fields for navigation, prey capture (scene analysis), and social communication. Although active electrosensory systems appear to be exaptations for troglobitic life, as fish use these systems to “see in the dark”, producing electric fields is energetically costly. Cave habitats, which often are low in resources, may not be able to support such high energetic demands. Eigenmannia vicentespelaea, a species of weakly electric fish that is endemic to the São Vicente II cave in central Brazil, surprisingly generates stronger electric fields than their surface relatives. The increase in strength of electric fields may result simply from differences in size between cave and surface populations, but may also be due to lack of predation pressure in the cave or increases in “sensory volumes” and acuity that improve prey localization and capture. Eigenmannia vicentespelaea exhibits the classical phenotypes of any troglobitic fish: these fish have small to nonexistent eyes and loss of pigmentation. The closest living surface relative, Eigenmannia trilineata, inhabits streams nearby and has eyes and pigmentation. The electrosensory and locomotor behavior of both species of fish were measured in their natural habitats using a grid recording system. Surface Eigenmannia exhibited dramatic circadian changes in social behavior, such as hiding under rocks during the day and foraging in groups at night, while cave Eigenmannia displayed territorial behavior with no apparent circadian modulations. The territorial behavior involved electrical and movement-based interactions that may be a form of boundary patrolling. Electrosocial behavior and scene analysis are mechanistically interlinked because both stem from active sensing tactics.

Breast Cancer Phenotypes in Africa: A Scoping Review and Meta-Analysis.

Africans have been associated with more aggressive forms of breast cancer (BC). However, there is a lack of data regarding the incidence and distribution of different subtypes on the basis of phenotypic classification. This scoping review and meta-analysis was undertaken to determine the distribution pattern of BC phenotypes (luminal, human epidermal growth factor receptor 2 [HER2]+, and triple-negative breast cancer [TNBC]) across the African region. Four online databases (PubMed, Scopus, ProQuest, and EBSCOhost) were accessed to identify studies published between 2000 and 2022 reporting the representation of receptor status (estrogen receptor, progesterone receptor, and HER2) in African patients with BC. Furthermore, the meta-analysis was carried out using a random-effects model and pooled using the inverse variance method and logit transformation. 95% CI and I2 statistics were calculated using the Clopper-Pearson method to estimate between-study heterogeneity. A total of 2,734 records were retrieved, of which 2,133 were retained for further screening. After the screening, 63 studies were finally selected for the scoping review and meta-analysis. The pooled frequency of luminal, HER2-positive (HER2+), and TNBC was estimated at 56.30%, 12.61%, and 28.10%, respectively. Northern Africa had the highest frequency of the luminal subtype, while West Africa showed higher frequencies of HER2+ and TNBC subtypes. The review also had a representation of only 24 countries in Africa. Our results highlight the disparity in the representation of molecular subtypes among the people in different regions of Africa. There is a need to incorporate routine molecular subtyping into the management of African patients with BC.

Morphological Hallmarks of Classical Fabry Disease: An Ultrastructural Study in a Large Spanish Family.

Fabry disease (FD) is a rare lysosomal disorder caused by α-galactosidase A deficiency, and it leads to the systemic deposition of globotriasylceramide. Demonstrations of the storage material in biopsies support this diagnosis. We report a histological and ultrastructural study of biopsies that were performed on 11 individuals from a family with the variant p.Gln279Arg in GLA, which is associated with the classical phenotype of Fabry disease. Intralysosomal deposits were found in all biopsies, corresponding to the skin, kidney, and endomyocardium in both sexes and at different ages. In nine of the skin biopsies, deposits were analysed by immunofluorescence and quantified at the ultrastructural level. Then, the findings were compared according to sex, genotype, and treatment. The quantification of the deposits in the skin biopsies revealed a broader involvement in men than in women. A significant clearance of the deposits was observed in one case after treatment. Tissue involvement was remarkable at diagnosis in all individuals. The findings from the skin biopsies were demonstrative of classic FD, thus supporting the diagnosis; repeated biopsy analyses suggested the benefit of early treatment.

Alzheimer's disease phenotype based upon the carrier status of the apolipoprotein E ɛ4 allele.

The apolipoprotein E ɛ4 allele (APOE4) is universally acknowledged as the most potent genetic risk factor for Alzheimer's disease (AD). APOE4 promotes the initiation and progression of AD. Although the underlying mechanisms are unclearly understood, differences in lipid-bound affinity among the three APOE isoforms may constitute the basis. The protein APOE4 isoform has a high affinity with triglycerides and cholesterol. A distinction in lipid metabolism extensively impacts neurons, microglia, and astrocytes. APOE4 carriers exhibit phenotypic differences from non-carriers in clinical examinations and respond differently to multiple treatments. Therefore, we hypothesized that phenotypic classification of AD patients according to the status of APOE4 carrier will help specify research and promote its use in diagnosing and treating AD. Recent reviews have mainly evaluated the differences between APOE4 allele carriers and non-carriers from gene to protein structures, clinical features, neuroimaging, pathology, the neural network, and the response to various treatments, and have provided the feasibility of phenotypic group classification based on APOE4 carrier status. This review will facilitate the application of APOE phenomics concept in clinical practice and promote further medical research on AD.

Hidradenitis suppurativa from the typical patient to the new clinical phenotypes

Hidradenitis suppurativa (HS) is a clinically heterogeneous disease with a broad spectrum of clinical features. Attempts to classify HS into distinct clinical phenotypes could lead to a better understanding of the condition and the development of individualized treatment protocols. We summarize some of the existing phenotype classifications and present our experience with 250 patients and their many clinical presentations. We have emphasized the pathophysiologic and clinical overlap between HS and pyoderma gangrenosum. The more severe presentations can include erosive and ulcerative lesions, sometimes associated with vegetative changes leading to diagnostic quandaries. We propose a new phenotype of pyoderma gangrenosum–like HS in which painful ulcerative or vegetative lesions appear in sites affected by HS, their activity coincides with the flareups of classic inflammatory manifestations of HS, and they heal with cribriform or atrophic scars.

Screening for health-related quality of life and its determinants in Fabry disease: A cross-sectional multicenter study

BackgroundFabry disease (FD) is a rare X-linked lysosomal storage disorder caused by α-galactosidase A (α-Gal A) deficiency. The progressive accumulation of globotriaosylceramide results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. In order to improve health care of FD-patients, knowledge of its predictors is important. The aim of our study was to evaluate health-related quality of life (HrQol) in FD and to identify its independent determinants by exploring a wide range of demographic, social and clinical parameters. ResultsIn this cross-sectional multicenter study, 135 adult patients with FD were recruited at three specialized European centers in Germany and Switzerland. Demographics, social status and clinical parameters as well as data on HrQol (EQ5D, EQ VAS) and depression were collected by means of self-reporting questionnaires and confirmed by medical records. HrQol and its predictors were evaluated by univariate and multivariate regression analyses.The study population consisted of 78 female and 57 male FD patients (median age 48 yrs) of whom 80.7% (N = 109) were on enzyme replacement therapy (ERT) and 10.4% (N = 14) were on chaperone treatment. Univariate analysis revealed various factors reducing HrQol such as age > 40 years, classic phenotype, organ involvement (kidney and heart disease, stroke/transient ischemic attack (TIA), gastrointestinal disturbances), depression, and burning limb pain. However, only the following factors were identified as independent predictors of decreased HrQol: classic phenotype, kidney and heart disease, stroke/TIA, depression, and burning limb pain. ERT and chaperone therapy were independent determinants of increased HrQol. ConclusionsModifiable factors, such as burning limb pain and depression, identified as independent predictors of HrQol-deterioration should be addressed in programs aiming to improve HrQol in FD. A multidisciplinary approach is essential in FD-patients since diverse organ involvement prominently compromises HrQol in affected patients. Our findings showed that the classic phenotype is a strong predictor of worsening HrQol.

Assessment tools and phenotype classification for hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a heterogeneous chronic relapsing skin disease. Several assessment tools are used to assess disease severity and to classify disease phenotype; however, no consensus exists. This review evaluates the various assessment tools and phenotypes, assessing their validity and reliability. Numerous assessment tools and phenotype classifications have been proposed for identifying various subtypes within the hidradenitis suppurativa disease spectrum. Each has a different purpose, such as use in daily practice or in clinical trial settings. Several assessment tools and phenotype classifications have been validated but not always with satisfactory results and often with studies showing divergent intra-rater reliability results. A consensus is needed for a validated, easy-to-use, and timesaving assessment tool for routine daily practice. For clinical trials, a validated and extensive assessment tool that also measures response to treatment is also needed.

Emerging cellular and immunotherapies for systemic sclerosis: from mesenchymal stromal cells to CAR-T cells and vaccine-based approaches.

Although two targeted therapies have received recent approval for systemic sclerosis (SSc)-associated interstitial lung disease, they do not show major disease-modifying activity, highlighting the need for novel therapies and innovative paradigms. To that end, cellular therapies may represent a new opportunity for the treatment of SSc. The purpose of this review is to provide an up-to-date overview of emerging cell-based disease-modifying therapies in SSc. Initial small studies in patients with severe refractory systemic lupus erythematosus (SLE) using engineered regulatory cells show promising results. CD19-directed CAR-T have shown promising results in one case report of refractory diffuse cutaneous SSc patients. T cells engineered to express a chimeric autoantibody receptor (CAAR-T cells) may be even more relevant via the specific elimination of auto-reactive B cells. Targeting pro-fibrotic or senescence-related pathways may also constitute promising approaches in SSc. Building on the classification of the clinical phenotype and prediction of clinical trajectory based on individual patients' autoantigen and/or autoantibody profile, cellular therapies targeting the same autoantigen or related autoreactive cells may represent an unprecedented opportunity to implement personalized medicine in SSc.