Monilethrix is a rare genodermatosis characterized by a hair shaft dysplasia responsible for hypotrichosis. We report the case of a child with monilethrix with no associated cases in the family. Trichoscopy facilitated the diagnosis. A 2-year-old boy presented with diffuse alopecia and persistent fragile hair for several months. Clinical examination revealed alopecia with hairs broken several millimeters from the scalp. Trichoscopy revealed zones of dystrophic constriction of the hair shaft, separated at regular intervals by elliptical nodes of normal thickness, giving a “necklace” appearance. The diagnosis of monilethrix was made on the basis of these specific features. The diagnosis of monilethrix was more difficult to establish in our patient owing to the absence of any familial cases.

BACKGROUND. Corneocytes of the nail plate, like those of the stratum corneum, generate cornified envelopes (CEs) of cross-linked protein that can be visualized readily after removal of non-cross-linked protein by detergent extraction. Defective CE formation occurs in epidermal scale and hair in transglutaminase 1 (TGM1)-negative lamellar ichthyosis (LI) and has been proposed as a diagnostic aid for this syndrome. OBJECTIVES. (i) To ascertain whether TGM1 is important for CE formation in nail; (ii) to characterize CE abnormalities occurring in LI that may be distinguished from other types of inherited ichthyosis when nail samples are subjected to detergent extraction; and (iii) to evaluate the utility of nails as a diagnostic aid for LI. METHODS. Nail samples were provided by nine patients previously classified as having TGM1-negative LI, four with other types of ichthyotic conditions and six normal controls. Samples were extracted extensively in sodium dodecyl sulphate under reducing conditions and examined by light and electron microscopy. RESULTS. After extraction, defective CE cross-linking was visualized in epidermal corneocytes from seven of nine patients exhibiting TGM1-negative LI, whereas nail samples from patients with the other syndromes were normal. The defects in CE structure resembled those recently reported for LI scale, although in some cases residual CE and CE-associated structures were present. CONCLUSIONS. Despite the paucity of clinical nail symptoms in LI, TGM1 activity is important for generation of normal CE in nail plate, consistent with its importance in protein cross-linking in interfollicular epidermis and hair. Lack of this activity leads to a strikingly aberrant appearance of CE in LI nail after detergent extraction that is evident ultrastructurally in a large majority of cases. Nail envelopes therefore could provide a useful diagnostic tool in distinguishing LI from other ichthyoses with overlapping clinical features.

Background

Methods and results

Conclusions

Abstract of the Dissertation

Rational Design, Synthesis and Evaluation of Benzothiazole Amphiphiles with Applications in Neurodegenerative Diseases

by

Jessica Lynn Cifelli

Doctor of Philosophy in Chemistry

University of California, San Diego, 2016

Professor Jerry Yang, Chair

Neurodegenerative diseases (NDDs), or disorders with progressive neuronal or nervous system dysfunction, affect millions of people worldwide each year. With a steadily increasing aging population, the amount of people affected is projected to exponentially increase unless there are significant advances made in research. As such, this dissertation will explore small molecule therapeutics that can potentially alleviate common pathological features of NDDs, with a focus on Alzheimer’s disease (AD). First, this dissertation will describe the rational design strategy towards improving the biocompatibility, of a class of amyloid-binding benzothiazoles particularly, with focus on decreasing toxicity. Here, novel benzothiazole amphiphiles or BAMs were designed, synthesized and evaluated to have a decreased toxicity over the parent compound when observed in various cell lines. In the subsequent chapters, these improved derivatives were further evaluated and modified for use in NDDs diagnostics or therapeutics. Specifically, BAMs capability to protect cells against the pathological hallmark of AD, β-amyloid (Aβ), its related toxicity and oxidative stress, was examined. Next, charged derivatives of BAM1-EG6 were synthesized for use in improving the binding to several NDD associated amyloids, including Aβ and α-synuclein (αS). This non-covalent strategy has potential future applications to differentiate between amyloids for diagnostics, or in therapeutics if metal chelation was utilized instead of charge-charge interactions.

The last two chapters of this dissertation, analyzes the ability of BAMs to increase dendritic spine density. Since decreased synaptic density and function is associated with many NDDs, particularly as one of the initial pathologies, small molecules that could alleviate or even reverse these effects would be quite valuable. Here, the BAMs spinogenic properties were evaluated in both primary hippocampal neurons as well as human induced pluripotent stem cell (hiPSC)-derived neurons. Importantly, the ability of BAMs to counteract Aβ-induced dendritic spine loss was also examined in primary culture. Lastly, the possibility of these effects translating into humans was evaluated utilizing hiPSC-derived neurons. Collectively, this dissertation presents on small molecules with a dual-modality (i.e amyloid binding capabilities and spinogenic activity), which may find use as part of a therapeutic regiment for AD and other NDDs.