Reevaluating the relevance of 18F-FDG PET findings for diagnosis of neurosarcoidosis: a case series.

OBJECTIVE: The diagnosis of neurosarcoidosis (NS) remains challenging due to the difficulty to obtain central nervous system (CNS) biopsies. Various diagnostic parameters are considered for the definition of possible, probable and definite NS. Magnetic resonance imaging (MRI) is the imaging gold standard and considered in diagnostic criteria. Fluorodeoxyglucose positron emission (18F-FDG PET) is sometimes performed additionally to identify possible systemic biopsy targets. However, at present, its findings are not incorporated into the diagnostic criteria for neurosarcoidosis (NS). METHODS: We conducted a single center retrospective search for the period 2020-2022, for patients with neurological symptoms in a diagnostic context of suspected NS who underwent MRI and additional 18F-FDG PET scans to identify potential hypermetabolism in the CNS and biopsy targets. RESULTS: We identified three cases of NS, where Gadolinium-enhanced MRI scans did not show abnormalities while 18F-FDG PET revealed hypermetabolic lesions in areas of the CNS. Additional MRI scans were still inconclusive for structural changes. We diagnosed a "probable" NS in all cases with histopathological confirmation of systemic sarcoidosis which led to an intensified therapy regime. DISCUSSION: 18F-FDG PET is an early indicator for metabolic changes. It appears to be a useful add-on to improve accuracy of diagnostic criteria in suspected NS without MRI findings.

HIF prolyl hydroxylase 2/3 deletion disrupts astrocytic integrity and exacerbates neuroinflammation.

Astrocytes constitute the parenchymal border of the blood-brain barrier (BBB), modulate the exchange of soluble and cellular elements, and are essential for neuronal metabolic support. Thus, astrocytes critically influence neuronal network integrity. In hypoxia, astrocytes upregulate a transcriptional program that has been shown to boost neuroprotection in several models of neurological diseases. We investigated transgenic mice with astrocyte-specific activation of the hypoxia-response program by deleting the oxygen sensors, HIF prolyl-hydroxylase domains 2 and 3 (Phd2/3). We induced astrocytic Phd2/3 deletion after onset of clinical signs in experimental autoimmune encephalomyelitis (EAE) that led to an exacerbation of the disease mediated by massive immune cell infiltration. We found that Phd2/3-ko astrocytes, though expressing a neuroprotective signature, exhibited a gradual loss of gap-junctional Connexin-43 (Cx43), which was induced by vascular endothelial growth factor-alpha (Vegf-a) expression. These results provide mechanistic insights into astrocyte biology, their critical role in hypoxic states, and in chronic inflammatory CNS diseases.

Mepolizumab as an effective treatment in a case of hypophysitis in eosinophilic granulomatosis with polyangiitis.

Granulomatosis or eosinophilic granulomatosis with polyangiitis (GPA/EGPA) can affect multiple organs resulting in heterogeneous symptoms and phenotypes. Pituitary gland dysfunction rarely occurs in GPA (1-3%) and even less in EGPA (two case reports). Here, we report a case of a 51-year-old female patient with a four-year history of EGPA who presented with new polydipsia and polyuria. Laboratory testing and magnetic resonance imaging (MRI) confirmed pituitary gland dysfunction caused by a hypophysitis. Therapeutic adjustment with a switch from dupilumab to mepolizumab resulted in a decrease in clinical symptoms, inflammation in MRI, and normalization of C-reactive protein in serum. This case underlines hypophysitis as a rare organ involvement also in EGPA. Moreover, this case demonstrates the responsiveness of neuroinflammatory manifestations to the recently approved anti-interleukin-5 monoclonal antibody mepolizumab as a new potential treatment option.

CaM Kinase II-δ Is Required for Diabetic Hyperglycemia and Retinopathy but Not Nephropathy.

Type 2 diabetes has become a pandemic and leads to late diabetic complications of organs, including kidney and eye. Lowering hyperglycemia is the typical therapeutic goal in clinical medicine. However, hyperglycemia may only be a symptom of diabetes but not the sole cause of late diabetic complications; instead, other diabetes-related alterations could be causative. Here, we studied the role of CaM kinase II-δ (CaMKIIδ), which is known to be activated through diabetic metabolism. CaMKIIδ is expressed ubiquitously and might therefore affect several different organ systems. We crossed diabetic leptin receptor-mutant mice to mice lacking CaMKIIδ globally. Remarkably, CaMKIIδ-deficient diabetic mice did not develop hyperglycemia. As potential underlying mechanisms, we provide evidence for improved insulin sensing with increased glucose transport into skeletal muscle and also reduced hepatic glucose production. Despite normoglycemia, CaMKIIδ-deficient diabetic mice developed the full picture of diabetic nephropathy, but diabetic retinopathy was prevented. We also unmasked a retina-specific gene expression signature that might contribute to CaMKII-dependent retinal diabetic complications. These data challenge the clinical concept of normalizing hyperglycemia in diabetes as a causative treatment strategy for late diabetic complications and call for a more detailed analysis of intracellular metabolic signals in different diabetic organs.

Phosphorylation of T107 by CamKIIδ Regulates the Detoxification Efficiency and Proteomic Integrity of Glyoxalase 1.

The glyoxalase system is a highly conserved and ubiquitously expressed enzyme system, which is responsible for the detoxification of methylglyoxal (MG), a spontaneous by-product of energy metabolism. This study is able to show that a phosphorylation of threonine-107 (T107) in the (rate-limiting) Glyoxalase 1 (Glo1) protein, mediated by Ca2+/calmodulin-dependent kinase II delta (CamKIIδ), is associated with elevated catalytic efficiency of Glo1 (lower KM; higher Vmax). Additionally, we observe proteasomal degradation of non-phosphorylated Glo1 via ubiquitination does occur more rapidly as compared with native Glo1. The absence of CamKIIδ is associated with poor detoxification capacity and decreased protein content of Glo1 in a murine CamKIIδ knockout model. Therefore, phosphorylation of T107 in the Glo1 protein by CamKIIδ is a quick and precise mechanism regulating Glo1 activity, which is experimentally linked to an altered Glo1 status in cancer, diabetes, and during aging.

Heidelberger Interprofessionelle Ausbildungsstation (HIPSTA): a practice- and theory-guided approach to development and implementation of Germany's first interprofessional training ward.

Background: Deficits in care and impaired patient-safety have been linked to inefficient interprofessional collaborative practice. Interprofessional training wards (IPTW) are an interprofessional educational intervention which aim to enable students and trainees from different health professions to work self-responsibly in order to manage the medical treatment and rehabilitation of real-life patients together as an interprofessional team. We aimed to develop and implement Germany´s first IPTW at the department of Surgery at Heidelberg University Hospital. Methods: The Kern cycle was used to develop an ITPW curriculum. Practical as well as theoretical considerations guided the design of the IPTW. Common project management tools including blueprinting and RASCI (Responsibility, Approval, Support, Consultation, Information) matrix were applied. Results: Since April 2017, 7 cohorts of students and trainees have had four-week long placements on HIPSTA. They run the IPTW in early and late shifts. Nursing and medical facilitators are supporting the IP team as needed. Learning objectives are operationalized as EPAs (entrustable professional activities) and interprofessional learning goals. Since initiation only minor modifications to the curriculum have been necessary and satisfaction of students/trainees, facilitators and patients is high. Conclusion: IPTWs can be established and run in the German health care system even in a complex clinical setting. The early involvement of all professions in a steering group seems to be key to success. Nursing and medical facilitators are of utmost importance for daily routine. The experiences outlined here could help others aiming to implement IPTWs at their sites. IPTWs might address a number of hitherto unaddressed educational needs. Trial registration: Not applicable.