Case report presenting the diagnostic challenges in a patient with recurrent acquired angioedema, antiphospholipid antibodies and undetectable C2 levels.

Background: Angioedema secondary to acquired C1 inhibitor deficiency (AAE) is a rare disease. It usually is associated with lymphoproliferative disorders. We present a case of AAE in a patient with antiphospholipid syndrome (APS), a non-Hodgkin lymphoproliferative disorder (NHL) with undetectable levels of C2, C4, and an undetectable CH50.

Reproducibility of 2D GluCEST in healthy human volunteers at 7 T.

Purpose: To investigate the reproducibility of gray and white matter glutamate contrast of a brain slice among a small group of healthy volunteers by using the 2D single-slice glutamate CEST (GluCEST) imaging technique.

Methods: Six healthy volunteers were scanned multiple times for within-day and between-day reproducibility. One more volunteer was scanned for within-day reproducibility at 7T MRI.

A novel application of the Staudinger ligation to access neutral cyclic di-nucleotide analog precursors a divergent method.

Our efforts to develop a scalable and divergent synthesis of cyclic di-nucleotide analog precursors have resulted in (1) an orthogonally protected di-amino carbohydrate as well as (2) the novel application of the Staudinger ligation to provide medium-sized macrocycles featuring carbamate or urea linkages.

Longitudinal imaging reveals subhippocampal dynamics in glutamate levels associated with histopathologic events in a mouse model of tauopathy and healthy mice.

Tauopathies are neurodegenerative disorders characterized by abnormal intracellular aggregates of tau protein, and include Alzheimer's disease, corticobasal degeneration, frontotemporal dementia, and traumatic brain injury. Glutamate metabolism is altered in neurodegenerative disorders manifesting in higher or lower concentrations of glutamate, its transporters or receptors. Previously, glutamate chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) demonstrated that glutamate levels are reduced in regions of synapse loss in the hippocampus of a mouse model of late-stage tauopathy.

Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders.

Systemic mitochondrial energy deficiency is implicated in the pathophysiology of many age-related human diseases. Currently available tools to estimate mitochondrial oxidative phosphorylation (OXPHOS) capacity in skeletal muscle in vivo lack high anatomic resolution. Muscle groups vary with respect to their contractile and metabolic properties.

Localized, gradient-reversed ultrafast z-spectroscopy in vivo at 7T.

Purpose: To collect ultrafast z-spectra in vivo in situations where voxel homogeneity cannot be assured.

Theory: Saturating in the presence of a gradient encodes the frequency offset spatially across a voxel. This encoding can be resolved by applying a similar gradient during readout.

Lactate Chemical Exchange Saturation Transfer (LATEST) Imaging in vivo A Biomarker for LDH Activity.

Non-invasive imaging of lactate is of enormous significance in cancer and metabolic disorders where glycolysis dominates. Here, for the first time, we describe a chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) method (LATEST), based on the exchange between lactate hydroxyl proton and bulk water protons to image lactate with high spatial resolution. We demonstrate the feasibility of imaging lactate with LATEST in lactate phantoms under physiological conditions, in a mouse model of lymphoma tumors, and in skeletal muscle of healthy human subjects pre- and post-exercise.

Desmethyl macrolides: synthesis and evaluation of 4-desmethyl telithromycin.

Novel sources of antibiotics are needed to address the serious threat of bacterial resistance. Accordingly, we have launched a structure-based drug design program featuring a desmethylation strategy wherein methyl groups have been replaced with hydrogens. Herein we report the total synthesis, molecular modeling, and biological evaluation of 4-desmethyl telithromycin (6), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (2) and our final analogue in this series.

In vivo magnetic resonance imaging of tumor protease activity.

Increased expression of cathepsins has diagnostic as well as prognostic value in several types of cancer. Here, we demonstrate a novel magnetic resonance imaging (MRI) method, which uses poly-L-glutamate (PLG) as an MRI probe to map cathepsin expression in vivo, in a rat brain tumor model. This noninvasive, high-resolution and non-radioactive method exploits the differences in the CEST signals of PLG in the native form and cathepsin mediated cleaved form.

In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy.

Glutamate is the primary excitatory neurotransmitter in the brain, and is implicated in neurodegenerative diseases such as Alzheimer's disease (AD) and several other tauopathies. The current method for measuring glutamate in vivo is proton magnetic resonance spectroscopy ((1)H MRS), although it has poor spatial resolution and weak sensitivity to glutamate changes. In this study, we sought to measure the effect of tau pathology on glutamate levels throughout the brain of a mouse model of tauopathy using a novel magnetic resonance imaging (MRI) technique.

In vivo chemical exchange saturation transfer imaging of creatine (CrCEST) in skeletal muscle at 3T.

Purpose: To characterize the chemical exchange saturation transfer (CEST)-based technique to measure free creatine (Cr), a key component of muscle energy metabolism, distribution in skeletal muscle with high spatial resolution before and after exercise at 3T.

Materials And Methods: CrCEST saturation parameters were empirically optimized for 3T. CEST, T2 , magnetization transfer ratio (MTR), and (31) P magnetic resonance spectroscopy (MRS) acquisitions of the lower leg were performed before and after mild plantar flexion exercise on a 3T whole-body MR scanner on six healthy volunteers.

Glutaminase catalyzes reaction of glutamate to GABA.

Here, for the first time, we report an NMR spectroscopy study of l-Glutamine (Gln) conversion by Glutaminase (Glnase), which shows that the reaction involves two distinct steps. In the first step, Glnase rapidly hydrolyzes Gln to Glutamate (Glu) (∼16.87 μmol of Gln/min/mg of Glnase) and in the second step, Glu generated in the first step is decarboxylated into gamma-amino butyric acid (GABA) with a much slower rate (∼0.

Desmethyl Macrolides: Synthesis and Evaluation of 4,8,10-Tridesmethyl Cethromycin.

Antibiotic-resistant bacteria are emerging at an alarming rate in both hospital and community settings. Motivated by this issue, we have prepared desmethyl (i.e.

A technique for in vivo mapping of myocardial creatine kinase metabolism.

ATP derived from the conversion of phosphocreatine to creatine by creatine kinase provides an essential chemical energy source that governs myocardial contraction. Here, we demonstrate that the exchange of amine protons from creatine with protons in bulk water can be exploited to image creatine through chemical exchange saturation transfer (CrEST) in myocardial tissue. We show that CrEST provides about two orders of magnitude higher sensitivity compared to (1)H magnetic resonance spectroscopy.

Desmethyl Macrolides: Synthesis and Evaluation of 4,8-Didesmethyl Telithromycin.

There is an urgent need for novel sources of antibiotics to address the incessant and inevitable onset of bacterial resistance. To this end, we have initiated a structure-based drug design program that features a desmethylation strategy (i.e.

Imaging of glutamate in the spinal cord using GluCEST.

Glutamate (Glu) is the most abundant excitatory neurotransmitter in the brain and spinal cord. The concentration of Glu is altered in a range of neurologic disorders that affect the spinal cord including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and spinal cord injury. Currently available magnetic resonance spectroscopy (MRS) methods for measuring Glu are limited to low spatial resolution, which makes it difficult to measure differences in gray and white matter glutamate.

Method for high-resolution imaging of creatine in vivo using chemical exchange saturation transfer.

Purpose: To develop a chemical exchange saturation transfer (CEST)-based technique to measure free creatine (Cr) and to validate the technique by measuring the distribution of Cr in muscle with high spatial resolution before and after exercise.

Methods: Phantom studies were performed to determine contributions from other Cr kinase metabolites to the CEST effect from Cr (CrCEST). CEST, T2 , magnetization transfer ratio and (31) P magnetic resonance spectroscopy acquisitions of the lower leg were performed before and after plantar flexion exercise on a 7T whole-body magnetic resonance scanner on healthy volunteers.

Development of the Pediatric Quality of Life Inventory™ Eosinophilic Esophagitis module items: qualitative methods.

Background: Currently there is no disease-specific outcome measure to assess the health-related quality of life (HRQOL) of pediatric patients with Eosinophilic Esophagitis (EoE). Therefore, the objective of this qualitative study was to further develop and finalize the items and support the content validity for the new Pediatric Quality of Life Inventory™ (PedsQL™) Eosinophilic Esophagitis Module.

Methods: Multiphase qualitative methodology was utilized in the development of the PedsQL™ EoE Module conceptual model.

Desmethyl Macrolides: Synthesis and Evaluation of 4,10-Didesmethyl Telithromycin.

Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling and biological evaluation of 4,10-didesmethyl telithromycin (4), a novel desmethyl analogue of the 3rd-generation drug telithromycin (2). Telithromycin is an FDA-approved ketolide antibiotic derived from erythromycin (1).

Synthesis of 5-fluoro- and 5-hydroxymethanoprolines via lithiation of N-BOC-methanopyrrolidines. Constrained Cγ-exo and Cγ-endo Flp and Hyp conformer mimics.

Proline derivatives with a C(γ)-exo pucker typically display a high amide bond trans/cis (K(T/C)) ratio. This pucker enhances n→π* overlap of the amide oxygen and ester carbonyl carbon, which favors a trans amide bond. If there were no difference in n→π* interaction between the ring puckers, then the correlation between ring pucker and K(T/C) might be broken.

Development of a validated patient-reported symptom metric for pediatric eosinophilic esophagitis: qualitative methods.

Background: Previous attempts to measure symptoms in pediatric Eosinophilic Esophagitis (EoE) have not fully included patients and parents in the item development process. We sought to identify and validate key patient self-reported and parent proxy-reported outcomes (PROs) specific to EoE.

Methods: We developed methodology for focus and cognitive interviews based on the Food and Drug Administration (FDA) guidelines for PROs, the validated generic PedsQL™ guidelines, and the consolidated criteria for reporting qualitative research (COREQ).

Total synthesis of (-)-4,8,10-tridesmethyl telithromycin.

Novel sources of antibiotics are required to address the serious problem of antibiotic resistance. Telithromycin (2) is a third-generation macrolide antibiotic prepared from erythromycin (1) and used clinically since 2004. Herein we report the details of our efforts that ultimately led to the total synthesis of (-)-4,8,10-tridesmethyl telithromycin (3) wherein methyl groups have been replaced with hydrogens.

Quality of life in paediatric eosinophilic oesophagitis: what is important to patients?

Background And Aims: Current research outcomes in paediatric eosinophilic oesophagitis (EoE) are directed towards histological improvement with no attention to health-related quality of life (HRQOL). The primary objective of this study was to identify key patient-reported and parent proxy outcome elements of EoE disease-specific HRQOL.

Methods: The research team comprised clinical allergists and gastroenterologists with expertise in paediatric EoE as well as two PhD psychologists with extensive experience in qualitative research.

Long-term outcomes in pediatric-onset esophageal eosinophilia.

Background: Pediatric eosinophilic esophagitis (EoE) is a newly recognized antigen-induced form of chronic esophagitis (CE).

Objective: Characterization of long-term clinical outcomes in patients with pediatric EoE is needed.

Methods: From histologic review of 3817 pediatric esophageal biopsy specimens from 1982-1999, we conducted a nested case-control study of patients with retrospectively identified histologic eosinophilic esophagitis (rEoE) and CE, as well as an age-matched control cohort.