Incidence of Bacteremia and Serious Bacterial Infections in Hyperpyrexic Infants Offered Universal Pneumococcal Conjugate Vaccine 13 and Haemophilus influenzae B Immunization.

BACKGROUND: High fevers, especially in young children, often alarm clinicians and prompt extensive evaluation based on perceptions of increased risk of serious bacterial infection (SBI), and even brain damage or seizure disorders. OBJECTIVE: The aim of this study was to determine the prevalence of SBI in infants aged 3-36 months with fever ≥40.5°C in a population of infants offered universal pneumococcal conjugate vaccine 13 and Haemophilus influenzae B immunization. METHODS: This study is a retrospective review of all infants aged 3-36 months with temperature ≥40.5°C presenting to a tertiary care pediatric emergency department over a 30-month period in an era of universal pneumococcal conjugate 13 and H. influenzae B immunization. RESULTS: SBI was recorded in 54 (21.8%) of 247 study infants, most commonly pneumonia 30 patients (12.1%) and urinary tract infection 16 patients (6.5%). Two patients had positive blood cultures, yielding a bacteremia rate of 0.8%. Patients with SBI had a significantly higher WBC count (P < 0.0001) and C-reactive protein levels (P < 0.0001), and were significantly more likely to be hospitalized (P < 0.0001). DISCUSSION: Although SBI was common (21.8%) in our cohort of hyperpyrexic infants universally offered vaccination with pneumococcal conjugate 13 and H. influenzae B vaccines, bacteremia was a rare finding (0.8%).

Inhibition of tau amyloid formation and disruption of its preformed fibrils by Naphthoquinone-Dopamine hybrid.

Misfolding and aggregation of tau protein, into pathological amyloids, are hallmarks of a group of neurodegenerative diseases collectively termed tauopathies and their modulation may be therapeutically valuable. Herein, we describe the synthesis and characterization of a dopamine-based hybrid molecule, naphthoquinone-dopamine (NQDA). Using thioflavin S assay, CD, transmission electron microscopy, dynamic light scattering, Congo Red birefringence, and large unilamellar vesicle leakage assays, we demonstrated its efficacy in inhibiting the in vitro aggregation of key tau-derived amyloidogenic fragments, PHF6 (VQIVYK) and PHF6* (VQIINK), prime drivers of aggregation of full-length tau in disease pathology. Isothermal titration calorimetry analysis revealed that the interaction between NQDA and PHF6 is spontaneous and has significant binding efficiency driven by both entropic and enthalpic processes. Furthermore, NQDA efficiently disassembled preformed fibrils of PHF6 and PHF6* into nontoxic species. Molecular dynamic simulations supported the in vitro results and provided a plausible mode of binding of NQDA with PHF6 fibril. NQDA was also capable of inhibiting the aggregation of full-length tau protein and disrupting its preformed fibrils in vitro in a dose-dependent manner. In a comparative study, the IC50 value (50% inhibition of fibril formation) of NQDA in inhibiting the aggregation of PHF6 (25 µm) was ~ 17 µm, which is lower than for other bona fide amyloid inhibitors, naphthoquinone-tryptophan, rosmarinic acid, epigallocatechin gallate, ~ 21, ~ 77, or ~ 19 µm, respectively. Comparable superiority of NQDA was observed for inhibition of PHF6*. These findings suggest that NQDA can be a useful scaffold for designing new therapeutics for Alzheimer's disease and other tauopathies.

Naphthoquinone-Dopamine Hybrids Inhibit α-Synuclein Aggregation, Disrupt Preformed Fibrils, and Attenuate Aggregate-Induced Toxicity.

Accumulation and aggregation of the intrinsically disordered protein α-synuclein (α-Syn) into amyloid fibrils are hallmarks of a series of heterogeneous neurodegenerative disorders, known as synucleinopathies and most notably Parkinson's disease (PD). The crucial role of α-Syn aggregation in PD makes it an attractive target for the development of disease-modifying therapeutics that would inhibit α-Syn aggregation or disrupt its preformed fibrillar assemblies. To this end, we have designed and synthesized two naphthoquinone-dopamine-based hybrid small molecules, NQDA and Cl-NQDA, and demonstrated their ability to inhibit in vitro amyloid formation by α-Syn using ThT assay, CD, TEM, and Congo red birefringence. Moreover, these hybrid molecules efficiently disassembled preformed fibrils of α-Syn into nontoxic species, as evident from LUV leakage assay. NQDA and Cl-NQDA were found to have low cytotoxicity and they attenuated the toxicity induced by α-Syn towards SH-SY5Y neuroblastoma cells. NQDA was found to efficiently cross an in vitro human blood-brain barrier model. These naphthoquinone-dopamine based derivatives can be an attractive scaffold for therapeutic design towards PD.