Faculty Bibliography

Age-associated deposition of amyloid-β in cerebral blood vessels, a condition referred to as cerebral amyloid angiopathy, can contribute to stroke and dementia. This research aimed to design new radioactive technetium-99 m complexes that bind to amyloid-β plaques that have the potential to assist in diagnosis of cerebral amyloid angiopathy using single-photon-emitted computed tomography (SPECT) imaging. Six new pyridylthiosemicarbazide ligands containing either benzofuran or styrylpyridyl functional groups that are known to selectively bind to amyloid plaques were prepared. Non-radioactive isotopes of technetium are not available so rhenium was used as a surrogate for exploratory chemistry. The new ligands were used to prepare well-defined [Re-oxo]³⁺ complexes where two pyridylthiosemicarbazide ligands were coordinated to a single metal ion to give bivalent complexes with two amyloid-β targeting functional groups. The interaction of the [Re-oxo]³⁺ complexes with synthetic amyloid-β_1-42 and with amyloid plaques in human brain tissue was investigated. Two ligands were selected to develop methods to prepare their [^99mTc-oxo]³⁺ complexes at the tracer level. These technetium-99 m complexes are likely to be isostructural to their rhenium-oxo analogues.

Clostridium difficile is an important cause of health care associated infections. The epidemiology of C. difficile infection (CDI) in children has changed over the past few decades. There is now a higher incidence in hospitalized children, and there has been an emergence of community-onset infection. A hypervirulent strain, North American pulse type 1, has also developed. Neonates and young infants have high rates of colonization but rarely have symptoms. The well-known risk factor for CDI in children age 2 years or older is antibiotic use. Inflammatory bowel disease and cancer are associated with increased incidence and severity of CDI. Nucleic acid amplification tests are now widely used for diagnosis given their rapid turnover and higher sensitivity and specificity. The treatment for an initial episode and first recurrence is oral metronidazole. Oral vancomycin is reserved for second recurrence or severe cases. A new treatment option, fecal bowel transplant, has been reported to be safe and effective in adults, and studies are now being conducted in children. [Pediatr Ann. 2018;47(9):e359-e365.].

Infection-related glomerulonephritis results from glomerular immune complex deposition due to a variety of potential pathogens. Poststreptococcal glomerulonephritis is the best known example. We present a case of acute infection-related glomerulonephritis associated with disseminated gonococcal infection in a sexually active 13-year-old girl, the first report of such an association in the absence of endocarditis. The patient presented with features of acute disseminated gonococcal infection including fever, hypotension, tenosynovitis, polyarthralgias and petechiae. She developed hypocomplementemic glomerulonephritis synchronous with the acute infection. The renal biopsy revealed a diffuse endocapillary proliferative and exudative glomerulonephritis with subepithelial electron-dense humps and granular glomerular capillary wall staining for C3 and IgG, typical of acute postinfectious glomerulonephritis. After treatment and resolution of the gonococcal infection, the serum creatinine, complement levels and urine sediment normalised. The only residual renal damage 16 months later was low-grade proteinuria.

Bis(thiosemicarbazonato)copper(II) complexes are of interest as potential therapeutics for cancer and neurodegenerative diseases as well as imaging agents for positron emission tomography (PET). The cellular uptake of six bis(thiosemcarbazonato)copper(II)complexes derived from glyoxal, with different functional groups Cu(gtsx) where x = different functional groups, was investigated in SKOV-3, HEK293, and HEK293 P-gp cell lines. Treatment of the cells with the copper complexes increased intracellular copper and increased levels of p-ERK due to activation of the Ras-Raf-MEK-ERK pathway. Treatment of SKOV-3 cells with low concentrations (μM) of two of the copper complexes led to trafficking of the endogenous copper transporter ATP7A from the Golgi network to the cell membrane. Experiments in HEK293 and HEK293-P-gp cells suggest that Cu(gtsm) and Cu(gtse) are substrates for the P-gp efflux protein but the complex with a pyrrolidine functional group, Cu(gtspyr), is not. A PET experiment in mice showed that [⁶⁴Cu]Cu(gtspyr) has reasonable brain uptake but high liver uptake.

OBJECTIVE:Antimicrobial stewardship programs (ASPs) ensure appropriate antibiotic use, reduce health care costs, and minimize antibiotic resistance. National asthma guidelines do not recommend antibiotics during an exacerbation unless the child has an infection or comorbidities. The American Academy of Pediatrics (AAP) established a benchmark for unjustified antibiotic use at 6.6%.9 A retrospective study at our institution showed that 7.8% of antibiotics were prescribed without justification in children admitted for asthma. The purpose of this study was to reduce unjustified antibiotic use at our institution by 25% in children through an ASP directed toward asthma. METHODS:The study period lasted from November 2015 to March 2016. Children 6 months to 17 years of age, admitted for an asthma exacerbation, were included while those with comorbidities were excluded. A multidisciplinary team from pediatric pharmacotherapy, pulmonology, emergency department (ED), infectious diseases, and quality improvement was formed to focus on process improvement. Interventions were executed in a series of Plan-Do-Study-Act cycles. In cycle 1, our asthma guidelines on appropriate antibiotic use were disseminated to pediatric house staff and posted in pediatric units. Cycle 2 encompassed presenting the ASP and guidelines to the pediatric ED staff. Cycle 3 consisted of a journal club with the pulmonary division to discuss the role of azithromycin in an asthma exacerbation. RESULTS:In cycle 1, twenty-four patients were reviewed in November 2015. Antibiotics were prescribed in 8/24 (33%) children, with an unjustified rate of 2/24 (8.3%). In cycle 2, twenty-three patients were reviewed in December and January with 8/23 (35%) prescribed antibiotics and an unjustified rate of 2/23 (8.7%). For cycle 3, in February and March 2016, twenty-one children were reviewed. Antibiotics were prescribed in 6/21 (27%) children and all were justified. In total, 68 patients were included in our study and had an unjustified antibiotic prescribing rate of 4/68 (5.9%), a reduction of 25%. CONCLUSION/CONCLUSIONS:Our ASP surpassed the benchmark set by AAP guidelines, by reducing the percentage of unjustified antibiotics in children with asthma to 5.9%.

A short, monodisperse oligoethylene glycol-containing photocleavable lysine tag was developed to facilitate the efficient purification of hydrophobic and fibril-forming peptides. This new tag was used to prepare a modified Aβ₄₂ peptide with increased solubility and decreased propensity to aggregate in aqueous media. The solubilising tag was readily removed by irradiation with UV light and permitted the preparation and isolation of Aβ₄₂ in high purity and yield.

A new palladium mediated "one pot" synthesis of thioamides from aromatic carboxylic acids (ArCO₂H + RNCS → ArC(S)NHR + CO₂) was discovered by gas-phase experiments and theoretical studies. Palladium-mediated decarboxylation of aromatic carboxylic acids followed by addition of substituted isothiocyanates leads to the corresponding thioamide derivatives.