Disease burden among patients with Arginase 1 deficiency and their caregivers: A multinational, cross-sectional survey.

Arginase 1 deficiency (ARG1-D) is an ultrarare, metabolic disease which may cause spastic paraplegia, cognitive deficiency, seizures, and ultimately severe disability. The aim of this study was to assess disease burden in ARG1-D by performing a cross-sectional survey of patients with ARG1-D and their caregivers in four European countries (France, Portugal, Spain, and the United Kingdom). Patients were enrolled at participating clinics and data were collected using a web-based questionnaire.

Societal costs and quality of life associated with arginase 1 deficiency in a European setting - a multinational, cross-sectional survey.

Background And Aims: Arginase 1 deficiency (ARG1-D) is a ultrarare disease with manifestations that cause mobility and cognitive impairment that progress over time and may lead to early mortality. Diseases such as ARG1-D have a major impact also outside of the health care sector and the aim of this study was to estimate the current burden of disease associated with ARG1-D from a societal perspective.

Methods: The study was performed as a web-based survey of patients with ARG1-D and their caregivers in four European countries (France, Portugal, Spain, United Kingdom).

Molecularly targeted protease-activated probes for visualization of glioblastoma: a comparison with 5-ALA.

Objective: The highly infiltrative growth of glioblastoma (GBM) makes distinction between the tumor and normal brain tissue challenging. Therefore, fluorescence-guided surgery is often used to improve visual identification of radiological tumor margins. The aim of this study was to evaluate the ability of recently developed molecularly targeted near-infrared (NIR) protease-activated probes to visualize GBM tissue and to compare the most promising candidate with the gold standard, 5-aminolevulinic acid (5-ALA).

Diagnosis of external ventricular drainage related infections with real-time 16S PCR and third-generation 16S sequencing.

Objective: Investigate the performance of real-time 16S PCR and third-generation 16S sequencing in the diagnosis of external ventricular drain related infections (EVDRI).

Methods: Subjects with suspected EVDRI were prospectively included at Uppsala University Hospital. Subjects were included into three groups: subjects with negative CSF culture with and without antibiotic treatment and subjects with positive CSF culture, respectively.

A retrospective observational study of 1000 consecutive patients tested with the FilmArray® Meningitis/Encephalitis panel: clinical diagnosis at discharge and microbiological findings.

FilmArray® Meningitis/Encephalitis panel (FAME-p) is used to diagnose central nervous system (CNS) infections. In this study, we investigated performance of FAME-p compared to comparator assays (CA), and for the first time, clinical diagnosis at discharge (CDD). 1000 consecutive patients with a cerebrospinal fluid (CSF) sample analyzed with FAME-p were identified.

Protease Activated Probes for Real-Time Ratiometric Imaging of Solid Tumors.

Surgery is the preferred treatment option for most solid tumors. However, inaccurate detection of cancer borders leads to either incomplete removal of malignant cells or excess excision of healthy tissue. While fluorescent contrast agents and imaging systems improve tumor visualization, they can suffer from low signal-to-background and are prone to technical artifacts.

Heparin-binding protein as a marker of ventriculostomy related infection and central nervous system inflammation in neuro-intensive care.

Objective: Diagnosis of ventriculostomy related infections (VRI) in the neuro-intensive care unit remains challenging and current biomarkers lack adequate precision. The aim of this study was to explore the potential of Heparin-binding protein (HBP) in cerebrospinal fluid (CSF) as a diagnostic biomarker of VRI.

Methods: All patients treated with an external ventricular drain (EVD) between January 2009 and March 2010 at Skåne university hospital in Lund, Sweden, were consecutively included.

Mycoplasma pneumonia with severe cold agglutinin hemolysis, thrombocytosis, leukemoid reaction and acute renal failure.

is a common cause of community acquired pneumonia and although most cases are mild, complications sometimes occur. Cold agglutinin hemolysis is a known complication of infection, and usually presents as a mild and transient hemolysis. Here we present a case of infection with in a 64-year-old male that caused life threatening hemolysis that required multiple blood transfusions.

The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection.

Lysosomes are key degradative compartments of the cell. Transport to lysosomes relies on GlcNAc-1-phosphotransferase-mediated tagging of soluble enzymes with mannose 6-phosphate (M6P). GlcNAc-1-phosphotransferase deficiency leads to the severe lysosomal storage disorder mucolipidosis II (MLII).

A synthetic covalent ligand of the C/EBPβ transactivation domain inhibits acute myeloid leukemia cells.

C/EBPβ has recently emerged as a pro-leukemogenic transcription factor that cooperates with oncoprotein MYB to maintain proliferation and differentiation block of AML cells, making C/EBPβ an interesting drug target for AML. Here we have studied the inhibitory potential and biological effects of a synthetic analog of the natural product helenalin, a known inhibitor of C/EBPβ. The synthetic compound inhibits C/EBPβ by covalent binding to cysteine residues in the transactivation domain, thereby causing up-regulation of differentiation-associated genes, cell death and reduced self-renewal potential of AML cells.

Challenges for Targeting SARS-CoV-2 Proteases as a Therapeutic Strategy for COVID-19.

Two proteases produced by the SARS-CoV-2 virus, the main protease and papain-like protease, are essential for viral replication and have become the focus of drug development programs for treatment of COVID-19. We screened a highly focused library of compounds containing covalent warheads designed to target cysteine proteases to identify new lead scaffolds for both M and PL proteases. These efforts identified a small number of hits for the M protease and no viable hits for the PL protease.

Synthesis of Guaianolide Analogues with a Tunable α-Methylene-γ-lactam Electrophile and Correlating Bioactivity with Thiol Reactivity.

α-Methylene-γ-lactones are present in ∼3% of known natural products, and compounds comprising this motif display a range of biological activities. However, this reactive lactone limits informed structure-activity relationships for these bioactive molecules. Herein, we describe chemically tuning the electrophilicity of the α-methylene-γ-lactone by replacement with an α-methylene-γ-lactam.

AND-gate contrast agents for enhanced fluorescence-guided surgery.

Surgical resection of tumours requires precisely locating and defining the margins between lesions and normal tissue. However, this is made difficult by irregular margin borders. Although molecularly targeted optical contrast agents can be used to define tumour margins during surgery in real time, the selectivity of the contrast agents is often limited by the target being expressed in both healthy and tumour tissues.

Methods for analysis of near-infrared (NIR) quenched-fluorescent contrast agents in mouse models of cancer.

Optical contrast agents containing near-infrared (NIR) fluorophores are useful for visualizing biological landmarks, enzyme activities and biological processes in live animals and humans. Activatable (smart) quenched-fluorescent probes are sensors that become fluorescent after processing by an enzyme or in response to a physiological change (i.e.

Cost-Effectiveness Analysis of Patiromer in Combination with Renin-Angiotensin-Aldosterone System Inhibitors for Chronic Kidney Disease in Sweden.

Objectives: Patients with chronic kidney disease (CKD) are commonly treated with renin-angiotensin-aldosterone system inhibitors (RAASi) in order to delay progression of renal disease. However, research has shown that RAASi in CKD patients increases hyperkalaemia (HK) prevalence, which leads to RAASi discontinuation or dose reduction with the loss of benefits on the kidney. Patiromer is a novel therapy for HK treatment and may enable patients to remain on their RAASi regimen.

Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor.

As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-ε-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging.

SN-38 Conjugated Gold Nanoparticles Activated by Ewing Sarcoma Specific mRNAs Exhibit In Vitro and In Vivo Efficacy.

The limited delivery of chemotherapy agents to cancer cells and the nonspecific action of these agents are significant challenges in oncology. We have previously developed a customizable drug delivery and activation system in which a nucleic acid functionalized gold nanoparticle (Au-NP) delivers a drug that is selectively activated within a cancer cell by the presence of an mRNA unique to the cancer cell. The amount of drug released from sequestration to the Au-NP is determined by both the presence and the abundance of the cancer cell specific mRNA in a cell.

Helenalin Analogues Targeting NF-κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles.

Helenalin is a pseudoguaianolide natural product that targets Cys38 within the DNA binding domain of NF-κB transcription factor p65 (RelA). Helenalin contains two Michael acceptors that covalently modify cysteines: a α-methylene-γ-butyrolactone and a cyclopentenone. We recently reported two simplified helenalin analogues that mimic the biological activity of helenalin and contain both electrophilic moieties.

Appropriateness criteria for treatment of osteoporotic vertebral compression fractures.

The purpose of this study was to review and summarise the literature on appropriateness criteria for treatment of osteoporotic vertebral compression fractures (OVCF), with appropriateness defined as a treatment where the expected benefits outweigh the expected harms, confirmed by available evidence and expert opinion. A comprehensive search of peer-reviewed publications (PubMed, EMBASE) and grey literature was performed. To be included for analysis, documents had to be a review article (e.

Targeting NF-κB p65 with a Helenalin Inspired Bis-electrophile.

The canonical NF-κB signaling pathway is a mediator of the cellular inflammatory response and a target for developing therapeutics for multiple human diseases. The furthest downstream proteins in the pathway, the p50/p65 transcription factor heterodimer, have been recalcitrant toward small molecule inhibition despite the substantial number of compounds known to inhibit upstream proteins in the activation pathway. Given the roles of many of these upstream proteins in multiple biochemical pathways, targeting the p50/p65 heterodimer offers an opportunity for enhanced on-target specificity.

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions.

Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogues possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics.

Ventriculostomy-related infections in subarachnoid hemorrhage patients-a retrospective study of incidence, etiology, and antimicrobial therapy.

Background: This study was performed to investigate the incidence and etiology of ventriculostomy-related infections (VRIs) in patients with subarachnoid hemorrhage (SAH) and to assess adherence to local clinical guidelines regarding empirical antimicrobial therapy and diagnostic routines.

Methods: A total of 191 consecutive SAH patients treated in the neuro-intensive care unit of Uppsala University Hospital between 2010 and 2013 were included retrospectively. Information regarding cerebrospinal fluid samples, bacterial cultures, ventriculostomy treatment, patient characteristics, and antibiotic treatment were collected from electronic patient records.

Alkyne Ligation Handles: Propargylation of Hydroxyl, Sulfhydryl, Amino, and Carboxyl Groups via the Nicholas Reaction.

The Nicholas reaction has been applied to the installation of alkyne ligation handles. Acid-promoted propargylation of hydroxyl, sulfhydryl, amino, and carboxyl groups using dicobalt hexacarbonyl-stabilized propargylium ions is reported. This method is useful for introduction of propargyl groups into base-sensitive molecules, thereby expanding the toolbox of methods for the incorporation of alkynes for bio-orthogonal reactions.