Self-Assembling Peptide-Based High-Relaxivity Targeted MRI Contrast Agents.

Concentration-dependent increases in relaxivity (r1) were found to be induced by self-assembly when Fmoc is adjacent to tryptophan in peptide-based MRI contrast agents featuring Gd-DOTA.  A series of di- and tri-peptides were synthesized to test the effect of ionic strength, N-terminal substituent, peptide length, net charge, and relative location of Fmoc and tryptophan on r1 and critical aggregation concentration (CAC) at 1.0 Tesla. Compared to nominal r1 values of 3.5-7.4 mM-1s-1 per Gd(III), r1 values increased dramatically to 13.2-16.9 mM-1s-1 per Gd(III) upon self-assembly, with CACs between 0.22 and 2.59 mM when tested in H2O or PBS. When tested in fetal bovine serum (FBS), the compounds maintained high r1 values of 11.2-13.0 mM-1s-1, but had dramatically lower CAC values below 25 µM. These findings guided the synthesis of two targeted, high-relaxivity MRI contrast agents that contained PSMA-binding ligand, DCL. Their r1 values in H2O or PBS increased from 5.9-7.4 mM-1s-1 to 13.5-14.8 mM-1s-1 with CAC values of 1.65-2.70 mM. In FBS, their r1 values were found to be 11.2-11.9 mM-1s-1, with CAC values below 25 µM. By the conjugation of targeting agents in the last step of synthesis, a broadly applicable route to targeted, high-relaxivity MRI contrast agents is offered.

Isolated cryptococcal osteomyelitis in the setting of immune reconstitution inflammatory syndrome.

Cryptococcal infections, though rare, must be considered in all immunocompromised patients. Patients with HIV/AIDS on antiretrovirals may have a treatment course complicated by immune reconstitution inflammatory syndrome. Here we present a case of a 38-year-old woman with HIV/AIDS with knee pain who only began to experience severe pain after induction of antiretroviral therapy. She was found to have cryptococcal osteomyelitis without dissemination to the central nervous system, an unusual presentation for immunocompromised patients. She was treated with oral fluconazole with a resolution of symptoms. This case report suggests conservative management of isolated cryptococcal infection with fluconazole, regardless of immune status.

Conservative treatment of isolated cryptococcus infection in a patient with a weakened immune system Cryptococcus neoformans is a fungus found in the soil which care rarely infect humans, especially those who have a weakened immune system, like those with HIV infection. The treatment of HIV in people with 'secondary infections', like cryptococcal infections, may cause patients to get worse before they get better as the immune system starts to function and attack the secondary infection. In this case report, we look at a patient who had untreated HIV who only began to develop symptoms of a secondary cryptococcal infection once treatment for HIV was started. However, because the cryptococcal infection was only in her bone and not throughout her body and nervous system, we were able to treat her with a conservative, oral regimen. In patients with severe cryptococcal infection or with infection of their nervous system, they often need to be treated with medications that can cause a lot of unwanted side effects. The key takeaway from this article is that conservative treatment of Cryptococcus may be effective, even in people with weakened immune systems, as long as the cryptococcal infection is isolated.

A Case Series of Eustachian Valve Endocarditis: An Under-Diagnosed and Rare Entity.

BACKGROUND The eustachian valve is rarely involved in bacterial endocarditis. Patients who present with bacteremia and evidence of organic septic emboli should raise the suspicion of endocarditis as a possible differential diagnosis. This case series describes 2 unique cases of eustachian valve endocarditis (EVE) in patients who had a history of intravenous drug use; although 63% of EVE is caused by Staphylococcus aureus, the causative agent in our first case was methicillin-resistant Staphylococcus epidermidis (MRSE), which is only the third reported case of EVE caused by Staphylococcus epidermidis. Of note, the previous 2 cases of MRSE EVE were also found to be associated with cardiovascular hardware. CASE REPORT The first case of the series describes EVE by MRSE with an endovascular graft acting as the nidus of infection. Second case of EVE was caused by methicillin-sensitive Staphylococcus epidermidis (MSSA), the source of bacteremia being a rectovesicular abscess. Although initial transthoracic echoes were negative in both cases, subsequent transesophageal echoes were able to detect vegetations on the eustachian valves. Treatment included 4-6 weeks of culture-directed antibiotic therapy for both of our cases. CONCLUSIONS EVE may be an under-diagnosed sequelae of staphylococcal bacteremia, especially in the intravenous drug abuse population, further reinforcing the importance of systemically visualizing all cardiac valves, including the eustachian valves, while performing echocardiography.

Modular Synthesis of Peptide-Based Single- and Multimodal Targeted Molecular Imaging Agents.

A practical, modular synthesis of targeted molecular imaging agents (TMIAs) containing near-infrared dyes for optical molecular imaging (OMI) or chelated metals for magnetic resonance imaging (MRI) and single-photon emission correlation tomography (SPECT) or positron emission tomography (PET) has been developed. In the method, imaging modules are formed early in the synthesis by attaching imaging agents to the side chain of protected lysines. These modules may be assembled to provide a given set of single- or dual-modal imaging agents, which may be conjugated in the last steps of the synthesis under mild conditions to linkers and targeting groups. A key discovery was the ability of a metal such as gadolinium, useful in MRI, to serve as a protecting group for the chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). It was further discovered that two lanthanide metals, La and Ce, can double as protecting groups and placeholder metals, which may be transmetalated under mild conditions by metals used for PET in the final step. The modular method enabled the synthesis of discrete targeted probes with two of the same or different dyes, two same or different metals, or mixtures of dyes and metals. The approach was exemplified by the synthesis of single- or dual-modal imaging modules for MRI-OMI, PET-OMI, and PET-MRI, followed by conjugation to the integrin-seeking peptide, c(RGDyK). For Gd modules, their efficacy for MRI was verified by measuring the NMR spin-lattice relaxivity. To validate functional imaging of TMIAs, dual-modal agents containing Cy5.5 were shown to target A549 cancer cells by confocal fluorescence microscopy.

Adjunctive ceftaroline in combination with daptomycin or vancomycin for complicated methicillin-resistant Staphylococcus aureus bacteremia after monotherapy failure.

BACKGROUND: Methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) may fail to improve with standard monotherapy, particularly in patients with multifocal infection, incomplete source control, or persistent bacteremia. Synergy observed in vitro between ceftaroline (CPT) and daptomycin (DAP) or vancomycin (VAN) may translate into clinical benefit. Here, we describe our experience with DAP/CPT and VAN/CPT for complicated MRSA-B after monotherapy failure. METHODS: Single-center, retrospective review of consecutive patients treated with DAP/CPT or VAN/CPT for MRSA-B after monotherapy failure from 1 January 2016 to 30 November 2018. RESULTS: We identified 11 instances of combination therapy in 10 patients (DAP/CPT = 6, VAN/CPT = 5) with 1 patient receiving VAN/CPT followed by DAP/CPT. Rates of multifocal infection, incomplete source control, persistent bacteremia, and infective endocarditis were high (100%, 80%, 60%, and 60%, respectively). Combination therapy was initiated most commonly for persistent bacteremia (60%). When patients were persistently bacteremic, median preceding duration was 13 days and median time to clearance was 3 days. Total microbiologic cure rate was 100%. There were zero instances of bacteremia relapse at 30 days (30D) or 60 days (60D). All-cause 30D and 60D mortality rates were 11.1% and 33.3%, respectively. CONCLUSIONS: Combination therapy demonstrated success in diverse cases of refractory MRSA-B, including instances of persistent bacteremia paired with incomplete source control. Optimal timing and therapeutic cadence for combination therapy remain unclear. Our findings suggest that DAP/CPT and VAN/CPT can be considered for complicated MRSA bacteremia when other treatment options fail or are unavailable. We propose persistent bacteremia with incomplete source control to be a clinical niche particularly worthy of further investigation.

Modular Synthesis of DOTA-Metal-Based PSMA-Targeted Imaging Agents for MRI and PET of Prostate Cancer.

A practical, convergent synthesis of prostate-specific membrane antigen (PSMA) targeted imaging agents for MRI, PET, and SPECT of prostate cancer has been developed. In this approach, metals chelated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) were placed on the side chains of lysine early in the synthesis to form imaging modules. These are coupled to targeting modules, in this case consisting of the PSMA-binding urea DCL, bonded to an activated linker. The modular approach to targeted molecular imaging agents (TMIAs) offers distinct advantages. By chelating the MRI contrast metal Gd early, it doubles as a protecting group for DOTA. Standard coupling and deprotection steps may be utilized to assemble the modules into peptides, and the need for tri-tert-butyl protection of DOTA requiring removal by strong acid is averted. This enables mild conjugation of the imaging module to a wide variety of targeting agents in the final step. It was further discovered that two labile metals, La3+ or Ce3+ , can be used as placeholders in DOTA during the synthesis, then transmetalated in mild acid by Cu2+ , Ga3+ , In3+ , and Y3+ , metals used in PET/SPECT. This enables the efficient synthesis of nonradioactive analogues of targeted molecular imaging agents that may be transported or stored until needed. A simple and mild two-step transmetalation, involving de-metalation in dilute acid, followed by rapid chelation of the radioactive metal, may be conveniently performed later at the clinic to provide the TMIAs for PET or SPECT.

Recognition of Stroke Warning Signs and Risk Factors Among Rural Population in Central Pennsylvania.

BACKGROUND: Recognition of stroke warning signs and risk factors reduces prehospital delay and increases stroke survival. The goal of this study was to evaluate the public knowledge of stroke warning signs and risk factors in a rural area in Central Pennsylvania. MATERIALS AND METHODS: In this study, the 2016 Sullivan County Health Fair attendees in central Pennsylvania answered a structured close-ended multiple choice questionnaire about stroke warning signs and risk factors. Further questions were asked about their reaction to acute stroke, the source of their stroke knowledge, and if they had personally known a stroke victim. RESULTS: Out of 163 respondents, 85.3% selected ≥3 (out of 4) correct stroke warning signs and 71.8% of respondents selected ≥3 (out of 5) correct stroke risk factors. Regarding the wrong stroke warning signs, 34.4% mentioned neck pain followed by chest pain (33.1%). Identification of ≥1 (out of 3) wrong stroke warning signs were significantly lower among the respondents of postgraduate level education in comparison with other literacy groups. 95.7% of respondents chose "call 911 immediately" in response to an acute stroke. A relative with a history of stroke was the most cited source of information. Multivariate analysis found that a high level of education increases odds of recognition of ≥3 correct stroke risk factors (0.21; 95% confidence interval, 0.09-0.61). Knowing anyone with stroke was associated with an awareness of the life-threatening nature of stroke (r = 0.21, P < 0.01). CONCLUSION: Respondents' recognition of stroke warning signs was favorable. About 85% of respondents recognized at least three stroke warning signs with no significant age and literacy effect. Our results provide evidence that the subjects most at risk of stroke are those with the least awareness of stroke risk factors.

An electron paramagnetic resonance mobile universal surface explorer.

Many samples cannot be studied by electron paramagnetic resonance (EPR) spectroscopy because they are too large to fit into the spectrometer and too precious to be destructively sampled for study. An EPR mobile universal surface explorer (MOUSE), also known as a unilateral EPR spectrometer, was constructed for studying this class of sample. The EPR MOUSE can nondestructively record a low frequency EPR (LFEPR) spectrum of a small region of any size object by placing the MOUSE against the object. The capabilities of the EPR MOUSE are demonstrated on paramagnetic paint pigments on canvas, magnetic ink on paper, and a ceramic candlestick. The mobile nature of the MOUSE will allow the spectrometer to be brought to the sample, thus opening new applications of EPR spectroscopy.

Low Frequency EPR and EMR Point Spectroscopy and Imaging of a Surface.

Low frequency electron paramagnetic resonance (LFEPR) spectrometers operating between 100 and 500 MHz typically have large-volume magnets that accommodate large samples. LFEPR spectroscopy with a 2.9 mm diameter surface coil was used to record point spectra and image the spatial distribution of the spin probe 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and electrophotographic toner in printed letters on a flat surface. The location of the surface coil was fixed on the desired location when a spectrum was recorded. The magnetic field of the spectrometer was fixed on the location of the signal and the sample was scanned under the surface coil in parallel trajectories to produce an image of the signal in the letters "LFEPR". We speculate on the utility of this technique to study flat objects such as paintings and illuminated manuscripts with cultural heritage significance.

A method of switching the signal in an MRI phantom based on trace ion currents.

A method for electrically changing the hydrogen nuclear magnetic resonance (NMR) signal intensity in a magnetic resonance imaging (MRI) phantom is presented. The method is based on creating local magnetic field inhomogeneities from impurity ion currents in a polar hydrocarbon. The effect is demonstrated using the propylene carbonate on an NMR spectrometer and an MRI scanner. This effect is largest when the electric field is applied perpendicular to the static magnetic field in magnetic resonance, and is linear with applied voltage. The applicability of a switchable signal in an MRI phantom is demonstrated with a spin-echo, echo planar imaging sequence where the MRI signal is changed between blocks of 10 images in a series of 200 images. This technique may find applications in inter and intra platform fMRI quality control.

An MRI digital brain phantom for validation of segmentation methods.

Knowledge of the exact spatial distribution of brain tissues in images acquired by magnetic resonance imaging (MRI) is necessary to measure and compare the performance of segmentation algorithms. Currently available physical phantoms do not satisfy this requirement. State-of-the-art digital brain phantoms also fall short because they do not handle separately anatomical structures (e.g. basal ganglia) and provide relatively rough simulations of tissue fine structure and inhomogeneity. We present a software procedure for the construction of a realistic MRI digital brain phantom. The phantom consists of hydrogen nuclear magnetic resonance spin-lattice relaxation rate (R1), spin-spin relaxation rate (R2), and proton density (PD) values for a 24 × 19 × 15.5 cm volume of a "normal" head. The phantom includes 17 normal tissues, each characterized by both mean value and variations in R1, R2, and PD. In addition, an optional tissue class for multiple sclerosis (MS) lesions is simulated. The phantom was used to create realistic magnetic resonance (MR) images of the brain using simulated conventional spin-echo (CSE) and fast field-echo (FFE) sequences. Results of mono-parametric segmentation of simulations of sequences with different noise and slice thickness are presented as an example of possible applications of the phantom. The phantom data and simulated images are available online at http://lab.ibb.cnr.it/.

A volume resolution phantom for MRI.

Multisite quantitative magnetic resonance imaging (qMRI) of volume requires a small isotropic point spread-function (PSF) that is spatially, temporarily, and platform invariant. A phantom which will allow rapid assessment of this metric throughout the imaged volume without repositioning will assist certification of imaging sites for use in qMRI studies based on volume. This paper presents a phantom design for this purpose with a three-dimensional repeating pattern throughout its 800-cm(3) volume. The image of the pattern from the phantom contains a series of positive signal points and lines which can be used to measure the PSF, gradient linearity, gradient orthogonality, and B(0) homogeneity at multiple locations throughout its volume. The phantom is readily constructed, can be filled with any nuclear magnetic resonance signal-bearing liquid, and the design is scalable to cover larger volumes.

Unilateral MRI using a rastered projection.

Unilateral magnetic resonance techniques, where magnet and radio frequency (RF) coil are placed on one side of the sample, can provide valuable information about a sample which otherwise cannot be accommodated in conventional high spectral resolution magnetic resonance systems. A unilateral magnetic resonance imaging approach utilizing the stray field from a disc magnet and a butterfly geometry RF coil is described. The coil excites spins in a volume centered around an arc through the sample. Translating the RF coil relative to the magnet and recording the signal at each translational location creates a projection of the signal in a tomographic slice through the sample. Rotating the RF coil relative to the sample and repeating the translation creates projections through the sample at different angles. Backprojecting this information yields an image. A proof of concept device operating on this principle at 12.4 MHz was constructed and characterized. Projections through three phantoms are presented with a 1.2-4 cm field of view, thickness of 102 microm, and at a distance of 3mm from the RF coil and 14 mm from the magnet. The edge spread function (ESF) was measured resulting in a 4mm full width at half maximum (FWHM) line spread function (LSF) estimation using a Gaussian model. An example of one reconstructed image is presented.