P.330 Role of cerebellum structure as a possible etiopathogenetic cause of the clinical heterogeneity of endogenous psychoses

Owing to the rarity and the biological and clinical heterogeneity of gastroenteropancreatic neuroendocrine neoplasia (GEP NEN), the management of these patients may be challenging for physicians. This review highlights the specific features of GEP NEN with particular attention on the role of Ki67 heterogeneity, the potential prognostic role of novel radiological techniques, and the clinical usefulness of functional imaging, including 68Ga-DOTA-SST PET/CT and 18F-FDG PET/CT. Understanding these specific features may help to plan proper and tailored follow-up programs and therapeutic approaches.

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Models Contribution to the Understanding of Sarcoidosis Pathogenesis: “Are There Good Models of Sarcoidosis?”

Journal of Clinical Medicine ◽

10.3390/jcm9082445 ◽

2020 ◽

Vol 9 (8) ◽

pp. 2445 ◽

Cited By ~ 1

Author(s):

Valérie Besnard ◽

Florence Jeny

Keyword(s):

Mouse Models ◽

Experimental Research ◽

Therapy Response ◽

3D Models ◽

Unknown Etiology ◽

Sarcoidosis Patient ◽

Clinical Heterogeneity ◽

Transgenic Mouse Models

Sarcoidosis is a systemic, granulomatous, and noninfectious disease of unknown etiology. The clinical heterogeneity of the disease (targeted tissue(s), course of the disease, and therapy response) supports the idea that a multiplicity of trigger antigens may be involved. The pathogenesis of sarcoidosis is not yet completely understood, although in recent years, considerable efforts were put to develop novel experimental research models of sarcoidosis. In particular, sarcoidosis patient cells were used within in vitro 3D models to study their characteristics compared to control patients. Likewise, a series of transgenic mouse models were developed to highlight the role of particular signaling pathways in granuloma formation and persistence. The purpose of this review is to put in perspective the contributions of the most recent models in the understanding of sarcoidosis.

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Re-emphasising the importance of histopathological diagnosis in suspected bacterial endocarditis

Perfusion ◽

10.1177/02676591211038886 ◽

2021 ◽

pp. 026765912110388

Author(s):

Hafiz Naderi ◽

Aula Abbara ◽

Alessandro Viviano ◽

Perviz Asaria ◽

Punam A Pabari ◽

...

Keyword(s):

Infective Endocarditis ◽

Patient Outcomes ◽

Bacterial Endocarditis ◽

Histopathological Diagnosis ◽

Team Approach ◽

Clinical Heterogeneity ◽

Diagnostic Uncertainty ◽

Multidisciplinary Team Approach ◽

Atypical Presentations

Infective endocarditis (IE) carries a high risk of morbidity and mortality. Timely diagnosis, effective treatment and prompt recognition of complications are essential to favourable patient outcomes. A collaborative, multidisciplinary team approach to the management of IE has been shown to improve prognosis. However, the clinical heterogeneity of IE and atypical presentations pose challenges to the endocarditis team. We present a case highlighting the role of valve histopathology in suspected IE, where there may be diagnostic uncertainty.

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W12.03 Nosologic differentiation of postpartum psychoses and the role of reproductive functions for the manifestation of endogenous psychoses in women

European Psychiatry ◽

10.1016/s0924-9338(00)93980-4 ◽

2000 ◽

Vol 15 (S2) ◽

pp. 228s-228s

Author(s):

B. Pfuhlmann ◽

G. Althaus

Keyword(s):

Endogenous Psychoses ◽

Postpartum Psychoses

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Genomic sequencing of Lowe syndrome trios reveal a mechanism for the heterogeneity of neurodevelopmental phenotypes

10.1101/2021.06.22.449382 ◽

2021 ◽

Author(s):

Husayn Ahmed P ◽

Pramod Singh ◽

Rajan Thakur ◽

Aastha Kumari ◽

Harini Krishnan ◽

...

Keyword(s):

Brain Development ◽

Lowe Syndrome ◽

Clinical Heterogeneity ◽

Cellular Mechanisms ◽

Monogenic Disorder ◽

Neurodevelopmental Delay ◽

Monogenic Disorders ◽

Ocrl Gene ◽

Neurodevelopmental Phenotype

Lowe syndrome is an X-linked recessive monogenic disorder resulting from mutations in the OCRL gene that encodes a phosphatidylinositol 4,5 bisphosphate 5-phosphatase. The disease affects three organs-the kidney, brain and eye and clinically manifests as proximal renal tubule dysfunction, neurodevelopmental delay and congenital cataract. Although Lowe syndrome is a monogenic disorder, there is considerable heterogeneity in clinical presentation; some individuals show primarily renal symptoms with minimal neurodevelopmental impact whereas others show neurodevelopmental defect with minimal renal symptoms. However, the molecular and cellular mechanisms underlying this clinical heterogeneity remain unknown. Here we analyze a Lowe syndrome family in whom affected members show clinical heterogeneity with respect to the neurodevelopmental phenotype despite carrying an identical mutation in the OCRL gene. Genome sequencing and variant analysis in this family identified a large number of damaging variants in each patient. Using novel analytical pipelines and segregation analysis we prioritize variants uniquely present in the patient with the severe neurodevelopmental phenotype compared to those with milder clinical features. The identity of genes carrying such variants underscore the role of additional gene products enriched in the brain or highly expressed during brain development that may be determinants of the neurodevelopmental phenotype in Lowe syndrome. We also identify a heterozygous variant in CEP290, previously implicated in ciliopathies that underscores the potential role of OCRL in regulating ciliary function that may impact brain development. More generally, our findings demonstrate analytic approaches to identify high-confidence genetic variants that could underpin the phenotypic heterogeneity observed in monogenic disorders.

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Corrigendum to: “Quality of Life in Patients with Neuroendocrine Neoplasms: The Role of Severity, Clinical Heterogeneity, and Resilience”

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab017 ◽

2021 ◽

Keyword(s):

Quality Of Life ◽

Neuroendocrine Neoplasms ◽

Clinical Heterogeneity

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Absence of Caveloin-1 Leads to Delayed Development of Chronic Lymphocytic Leukemia in Eµ-TCL1 Mouse Model

Blood ◽

10.1182/blood.v124.21.2196.2196 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2196-2196

Author(s):

Ashima Shukla ◽

Christine E Cutucache ◽

Karan Rai ◽

Siddharth Rai ◽

Rene Opavsky ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Lymphocytic Leukemia ◽

Lymph Nodes ◽

Lymphocytic Leukemia ◽

Clinical Heterogeneity ◽

Knock Down ◽

Immune Synapses

Abstract Background: Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia in the United States. Clinical heterogeneity, a characteristic feature of CLL is a major problem in the clinical management of this currently incurable leukemia. We and others have demonstrated that the tissue microenvironment, specifically the lymph node (LN), influence the biological and clinical behavior including the clinical heterogeneity of CLL. Using gene expression profiling of CLL cells from peripheral blood (PB), bone marrow (BM) and LNs, we identified Cav-1 a member of the Tolerogenic Signature (genes associated with host immune tolerance) as one of the candidate genes which might be involved in the pathogenesis of CLL. We found that Cav-1 levels were significantly elevated (11 fold) in CLL cells from LNs compared to BM and PB. Cav-1 is the major element of caveolae, which are flask-shaped membrane invaginations. Cav-1 is involved in multiple cellular processes like the regulation and transportation of cellular cholesterol and lipids, clathrin independent endocytosis and signal transduction leading to oncogenesis or tumor suppression. We have previously shown that knock down of Cav-1 results in a significant decrease in cell migration and proliferation of primary human CLL cells in vitro. We have also demonstrated that knock down of Cav-1 prevents CLL cells from forming immune synapses. These immune synapses are important for the interaction between the CLL cells and their tumor microenvironment. These results suggest that Cav-1 protect CLL cells from undergoing apoptosis and enhances their migration in vitro. Objectives and Methodology: To understand the precise role of Cav-1 in leukemic progression in vivo, we crossed Cav-1-/- mice to Eµ-TCL1 mice, which is a well-established transgenic murine model for CLL. The offspring were observed and evaluated for the development of CLL. These mice were sacrificed at the age of 12, 24, 36 and 40+ weeks and peripheral blood, bone marrow and spleen and were examined for the presence of CD5+B220+CD19+ CLL cells using flow cytometry. Spleen, lymph nodes, liver, lungs and kidney were evaluated for the presence of CLL cells using H&E staining of histologic slides. Results: To study the role of Cav-1 in Eµ-TCL1, we isolated splenic B cells and measured the expression of Cav-1. We observed a gradual increase in the expression of Cav-1 in splenic B cells from Eµ-TCL1 mice at age of 12, 24 and 36 weeks when compared with wild type mice. This suggested that Cav-1 might be playing a role in CLL progression in Eµ-TCL1 mice. Therefore, to study the role of Cav-1 in CLL disease progression we decreased the expression of Cav-1 in vivo by breeding Eµ-TCL1 with Cav1 knockout mice. We generated Eµ-TCL1-Cav1-/+ and Eµ-TCL1-Cav1-/- mice to study the effect of Cav-1 knock down in aggressiveness of CLL in vivo. We have shown that Cav-1 is overexpressed in CLL cells from patients with poorer clinical outcome and protects CLL cells from undergoing apoptosis. Therefore, we analyze the number of CLL cells in Eµ-TCL1-Cav1-/+ and Eµ-TCL1-Cav1-/- mice. We observed a significant reduction in the number of B220+CD5+ CLL cells population in bone marrow and spleen of Eµ-TCL1-Cav1-/+ and Eµ-TCL1-Cav1-/- mice when compared with Eµ-TCL1-Cav1wt/wt mice. We have previously shown that Cav-1 is important for CLL cells migration in vitro. Therefore, to study its effect in vivo we analyzed infiltration of CLL cells in spleen, lymph nodes, liver, kidney and lungs in these mice. There was no or significant decrease in tumor infiltration of CLL cells in spleen, lymph nodes, liver, lungs and kidney in Eµ-TCL1-Cav1-/+ and Eµ-TCL1-Cav1-/- mice when compared with Eµ-TCL1-Cav1wt/wt alone. Next, we wanted to examine the effect of Cav-1 knock down on splenomegaly and hepatomegaly. We found that there was a significant decrease in splenomegaly and hepatomegaly in Eµ-TCL1-Cav1-/+ and Eµ-TCL1-Cav1-/- mice. The spleen and liver size of Eµ-TCL1-Cav1-/+ and Eµ-TCL1-Cav1-/- mice was significantly reduced when compared with Eµ-TCL1 mice. Together these results suggest that high expression of Cav-1 in CLL cells leads to enhance proliferation and promotes disease progression in Eµ-TCL1 mice. Disclosures No relevant conflicts of interest to declare.

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