RESUMO
BACKGROUND: Oculocutaneous albinism (OCA) results in reduced melanin synthesis, skin hypopigmentation, increased risk of UV-induced malignancy, and developmental eye abnormalities affecting vision. No treatments exist. We have shown that oral nitisinone increases ocular and fur pigmentation in a mouse model of one form of albinism, OCA-1B, due to hypomorphic mutations in the Tyrosinase gene. METHODS: In this open-label pilot study, 5 adult patients with OCA-1B established baseline measurements of iris, skin, and hair pigmentation and were treated over 12 months with 2 mg/d oral nitisinone. Changes in pigmentation and visual function were evaluated at 3-month intervals. RESULTS: The mean change in iris transillumination, a marker of melanin, from baseline was 1.0 ± 1.54 points, representing no change. The method of iris transillumination grading showed a high intergrader reliability (intraclass correlation coefficient ≥ 0.88 at each visit). The number of letters read (visual acuity) improved significantly at month 12 for both eyes (right eye, OD, mean 4.2 [95% CI, 0.3, 8.1], P = 0.04) and left eye (OS, 5 [1.0, 9.1], P = 0.003). Skin pigmentation on the inner bicep increased (M index increase = 1.72 [0.03, 3.41], P = 0.047). Finally, hair pigmentation increased by both reflectometry (M index [17.3 {4.4, 30.2}, P = 0.01]) and biochemically. CONCLUSION: Nitisinone did not result in an increase in iris melanin content but may increase hair and skin pigmentation in patients with OCA-1B. The iris transillumination grading scale used in this study proved robust, with potential for use in future clinical trials. CLINICALTRIALS: gov NCT01838655. FUNDING: Intramural program of the National Eye Institute.
RESUMO
Small magnetic nanoparticles that have surfaces decorated with stimuli-responsive polymers can be reversibly aggregated via a stimulus, such as temperature, to enable efficient and rapid biomarker separation. To fully realize the potential of these particles, the synthesis needs to be highly reproducible and scalable to large quantity. We have developed a new synthesis for temperature-responsive magnetic nanoparticles via an in situ co-precipitation process of Fe2+/Fe3+ salts at room temperature with poly(acrylic acid)- block-poly( N-isopropylacrylamide) diblock co-polymer template, synthesized via the reversible addition-fragmentation chain-transfer polymerization method. These particles were 56% polymer by weight with a 6.5:1 Fe/COOH ratio and demonstrated remarkable stability over a 2 month period. The hydrodynamic diameter remained constant at â¼28 nm with a consistent transition temperature of 34 °C, and the magnetic particle separation efficiency at 40 °C was ≥95% over the 2 month span. These properties were maintained for all large-scale synthesis batches. To demonstrate the practical utility of the stimuli-responsive magnetic nanoparticles, the particles were incorporated into a temperature-responsive binary reagent system and efficiently separated a model protein biomarker (mouse IgG) as well as purified extracellular vesicles derived from a human biofluid, seminal plasma. The ease of using these particles will prove beneficial for various biomedical applications.