Cardioprotection by Preconditioning with Intralipid Is Sustained in a Model of Endothelial Dysfunction for Isolated-Perfused Hearts.

Endothelial dysfunction (ED) is closely associated with most cardiovascular diseases. Experimental models are needed to analyze the potential impact of ED on cardioprotection in constant pressure Langendorff systems (CPLS). One cardioprotective strategy against ischemia/reperfusion injury (I/RI) is conditioning with the lipid emulsion Intralipid (IL).

Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies.

CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12).

Riboflavin 1 Transporter Deficiency: Novel Variants and Expansion of the Phenotypic Spectrum.

Riboflavin transporter 1 (RFVT1) deficiency is an ultrarare metabolic disorder due to autosomal dominant pathogenic variants in . The RFVT1 protein is mainly expressed in the placenta and intestine. To our knowledge, only five cases of RFVT1 deficiency from three families have been reported so far.

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Hyperammonemia is a life-threatening condition, the prognosis of which depends on a rapid reduction of ammonia. If a hepatic cause is excluded, the differential diagnosis is broad and even in adulthood includes hereditary metabolic diseases. Here, the case of a 25-year-old female patient with severe hyperammonemia refractory to standard therapy is described and the relevance of extracorporeal elimination of ammonia emphasized.

Extracellular flux analysis in intact cardiac tissue slices-A novel tool to investigate cardiac substrate metabolism in mouse myocardium.

Aim: Cardiac pathologies are accompanied by alterations in substrate metabolism, and extracellular flux analysis is a standard tool to investigate metabolic disturbances, especially in immortalized cell lines. However, preparations of primary cells, such as adult cardiomyocytes require enzymatic dissociation and cultivation affecting metabolism. Therefore, we developed a flux analyzer-based method for the assessment of substrate metabolism in intact vibratome-sliced mouse heart tissue.

The T-cell-directed vaccine BNT162b4 encoding conserved non-spike antigens protects animals from severe SARS-CoV-2 infection.

T cell responses play an important role in protection against beta-coronavirus infections, including SARS-CoV-2, where they associate with decreased COVID-19 disease severity and duration. To enhance T cell immunity across epitopes infrequently altered in SARS-CoV-2 variants, we designed BNT162b4, an mRNA vaccine component that is intended to be combined with BNT162b2, the spike-protein-encoding vaccine. BNT162b4 encodes variant-conserved, immunogenic segments of the SARS-CoV-2 nucleocapsid, membrane, and ORF1ab proteins, targeting diverse HLA alleles.

Transition for adolescents with a rare disease: results of a nationwide German project.

Purpose: The transition process from paediatric/adolescent to adult medical care settings is of utmost importance for the future health of adolescents with chronic diseases and poses even more difficulties in the context of rare diseases (RDs). Paediatric care teams are challenged to deliver adolescent-appropriate information and structures. Here we present a structured transition pathway which is patient-focused and adoptable for different RDs.

IL-17 Signaling in Keratinocytes Orchestrates the Defense against Staphylococcus aureus Skin Infection.

Keratinocytes (KCs) form the outer epithelial barrier of the body, protecting against invading pathogens. Mice lacking the IL-17RA or both IL-17A and IL-17F develop spontaneous Staphylococcusaureus skin infections. We found a marked expansion of T cells, comprised of RORγt-expressing γδ T cells and T helper 17 cells in the skin-draining lymph nodes of these mice.

Cardioprotective efficacy of limb remote ischaemic preconditioning in rats: discrepancy between a meta-analysis and a three-centre in vivo study.

Aims: Remote ischaemic preconditioning (RIPC) is a robust cardioprotective intervention in preclinical studies. To establish a working and efficacious RIPC protocol in our laboratories, we performed randomized, blinded in vivo studies in three study centres in rats, with various RIPC protocols. To verify that our experimental settings are in good alignment with in vivo rat studies showing cardioprotection by limb RIPC, we performed a systematic review and meta-analysis.

Modulation of Specific Sphingosine-1-Phosphate Receptors Augments a Repair Mediating Schwann Cell Phenotype.

Transdifferentiation of Schwann cells is essential for functional peripheral nerve regeneration after injury. By activating a repair program, Schwann cells promote functional axonal regeneration and remyelination. However, chronic denervation, aging, metabolic diseases, or chronic inflammatory processes reduce the transdifferentiation capacity and thus diminish peripheral nerve repair.

Insulin-Like Growth Factor 1 Attenuates the Pro-Inflammatory Phenotype of Neutrophils in Myocardial Infarction.

Acute myocardial infarction (MI) induces an extensive sterile inflammation, which is dominated in the early phase by invading neutrophils and monocytes/macrophages. The inflammatory response after MI critically affects infarct healing and cardiac remodeling. Therefore, modulation of cardiac inflammation may improve outcome post MI.

Limited waiting areas in outpatient clinics: an intervention to incorporate the effect of bridging times in blueprint schedules.

Background: Distancing measures enforced by the COVID-19 pandemic impose a restriction on the number of patients simultaneously present in hospital waiting areas.

Objective: Evaluate waiting area occupancy of an intervention that designs clinic blueprint schedules, in which all appointments of the pre-COVID-19 case mix are scheduled either digitally or in person under COVID-19 distancing measures, whereby the number of in-person appointments is maximised.

Methods: Preintervention analysis and prospective assessment of intervention outcomes were used to evaluate the outcomes on waiting area occupancy and number of in-person consultations (postintervention only) using descriptive statistics, for two settings in the Rheumatology Clinic of Sint Maartenskliniek (SMK) and Medical Oncology & Haematology Outpatient Clinic of University Medical Center Utrecht (UMCU).

Ibrutinib plus Obinutuzumab as Frontline Therapy for Chronic Lymphocytic Leukemia Is Associated with a Lower Rate of Infusion-Related Reactions and with Sustained Remissions after Ibrutinib Discontinuation: A Single-Arm, Open-Label, Phase 1b/2 Clinical Trial NCT0231576.

Ibrutinib-based therapies are costly and require continuous administration. We hypothesized combining BTK inhibition with anti-CD20 monoclonal antibodies would yield deep remissions allowing discontinuation. We enrolled 32 therapy-naïve CLL patients to receive ibrutinib plus obinutuzumab, followed by single-agent ibrutinib.

Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases.

The osmodiuretic agent Mannitol exerts cardioprotection against ischemia and reperfusion (I/R) injury when applied as a pre- and/or postconditioning stimulus. Previously, we demonstrated that these properties are mediated via the activation of mitochondrial ATP-sensitive potassium (mK) channels. However, considering Mannitol remains in the extracellular compartment, the question arises as to which receptor and intracellular signaling cascades are involved in myocardial protection by the osmodiuretic substance.

Understanding health anxiety in the COVID-19 pandemic.

Background: The COVID-19 pandemic continues to be one of the greatest public health challenges faced by the UK. Reported rates of psychiatric difficulties have increased and the mechanisms by which the pandemic has affected mental health requires investigation.

Aims: The aim of the study was to understand the psychological impact of the COVID-19 pandemic on health anxiety in the general population, with a focus on Oxford Health NHS Foundation Trust, which provides specialist mental health care within Oxfordshire and Buckinghamshire.

Mitochondrial Telomerase Reverse Transcriptase Protects From Myocardial Ischemia/Reperfusion Injury by Improving Complex I Composition and Function.

Background: The catalytic subunit of telomerase, telomerase reverse transcriptase (TERT), has protective functions in the cardiovascular system. TERT is not only present in the nucleus but also in mitochondria. However, it is unclear whether nuclear or mitochondrial TERT is responsible for the observed protection, and the appropriate tools are missing to dissect this.

Influence of Hyperglycemia and Diabetes on Cardioprotection by Humoral Factors Released after Remote Ischemic Preconditioning (RIPC).

Remote ischemic preconditioning (RIPC) protects hearts from ischemia-reperfusion (I/R) injury in experimental studies; however, clinical RIPC trials were unsatisfactory. This discrepancy could be caused by a loss of cardioprotection due to comorbidities in patients, including diabetes mellitus (DM) and hyperglycemia (HG). RIPC is discussed to confer protective properties by release of different humoral factors activating cardioprotective signaling cascades.

Recurrent missense variants in can cause syndromic intellectual disability.

Purpose: Binding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A missense variant in was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism.

Combination of Cyclosporine A and Levosimendan Induces Cardioprotection under Acute Hyperglycemia.

Prognosis of patients with myocardial infarction is detrimentally affected by comorbidities like diabetes mellitus. In the experimental setting, not only diabetes mellitus but also acute hyperglycemia is shown to hamper cardioprotective properties by multiple pharmacological agents. For Levosimendan-induced postconditioning, a strong infarct size reducing effect is demonstrated in healthy myocardium.

Remote ischemic preconditioning does not induce activation of Akt and STAT5 in the rat heart.

Remote ischemic preconditioning (RIPC) is hypothesized to be a promising cardioprotective strategy to protect hearts against ischemia and reperfusion (I/R) injury; however, the current understanding of the underlying signal transduction pathways involved remains unclear. It has been previously demonstrated that protein kinase B/AKT, which is a crucial protein of the reperfusion injury salvage kinases pathway, and STAT5, which is a member of the survivor activating factor enhancement pathway, serve a pivotal role in cardioprotection. However, whether and at what time-points (TPs) RIPC leads to the activation of AKT and STAT5 in a rat model of RIPC and I/R injury remains to be determined.

Cardioprotective Properties of Mannitol-Involvement of Mitochondrial Potassium Channels.

Cardiac preconditioning (PC) and postconditioning (PoC) are powerful measures against the consequences of myocardial ischemia and reperfusion (I/R) injury. Mannitol-a hyperosmolar solution-is clinically used for treatment of intracranial and intraocular pressure or promotion of diuresis in renal failure. Next to these clinical indications, different organ-protective properties-e.

4-hydroxytamoxifen does not deteriorate cardiac function in cardiomyocyte-specific MerCreMer transgenic mice.

Conditional, cell-type-specific transgenic mouse lines are of high value in cardiovascular research. A standard tool for cardiomyocyte-restricted DNA editing is the αMHC-MerCreMer/loxP system. However, there is an ongoing debate on the occurrence of cardiac side effects caused by unspecific Cre activity or related to tamoxifen/oil overload.

BNT162b vaccines protect rhesus macaques from SARS-CoV-2.

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD-foldon).