Lending a Hand Instead of Breaking the Bank: The Imperative Need to Resolve the Circuit Split for Determining Undue Hardship for Section 523(A)(8) Student Loan Discharges

The Bankruptcy Code permits petitioners to discharge their student debts if they are able to demonstrate that their loans impose an undue hardship. Somewhat frustratingly, the Code does not define what exactly constitutes undue hardship in the context of student loan discharges. Moreover, neither Congress nor the Supreme Court has broken its silence to offer guidance on the issue. As a result, the rest of the federal judiciary has been once again, left to its own devices. Over the past few decades, the Brunner and totality-of-the-circumstances tests have emerged as the standards that federal circuits choose between to assess whether student loan repayment would cause the petitioner undue hardship. Although an overwhelming majority of circuits has endorsed the Brunner formulation, the test is considered by many to set an impossibly high burden for petitioners to surmount. This Note argues that the circuit split for determining undue hardship is purely illusory. The plain wording of both the Brunner and totality-of-the-circumstances formulations indicates that there is no real difference in the substantive inquiry conducted by each test. Rather, the divergence stems from a history of a retributive dicta being wrongly imputed to the Brunner standard. This Note argues that if the Brunner Standard is properly applied, the notion of a circuit split will be dispelled. Furthermore, this Note also encourages Congress to assist the judiciary by providing guidance on how it defines undue hardship

Lending a Hand Instead of Breaking the Bank: The Imperative Need to Resolve the Circuit Split for Determining Undue Hardship for Section 523(A)(8) Student Loan Discharges

The Bankruptcy Code permits petitioners to discharge their student debts if they are able to demonstrate that their loans impose an undue hardship. Somewhat frustratingly, the Code does not define what exactly constitutes undue hardship in the context of student loan discharges. Moreover, neither Congress nor the Supreme Court has broken its silence to offer guidance on the issue. As a result, the rest of the federal judiciary has been once again, left to its own devices. Over the past few decades, the Brunner and totality-of-the-circumstances tests have emerged as the standards that federal circuits choose between to assess whether student loan repayment would cause the petitioner undue hardship. Although an overwhelming majority of circuits has endorsed the Brunner formulation, the test is considered by many to set an impossibly high burden for petitioners to surmount. This Note argues that the circuit split for determining undue hardship is purely illusory. The plain wording of both the Brunner and totality-of-the-circumstances formulations indicates that there is no real difference in the substantive inquiry conducted by each test. Rather, the divergence stems from a history of a retributive dicta being wrongly imputed to the Brunner standard. This Note argues that if the Brunner Standard is properly applied, the notion of a circuit split will be dispelled. Furthermore, this Note also encourages Congress to assist the judiciary by providing guidance on how it defines undue hardship

The blood-brain barrier: physiology and strategies for drug delivery

The blood-brain barrier (BBB) is a dynamic structure that functions as a gatekeeper, reflecting the unique requirements of the brain. In this review, following a brief historical overview of how the concepts of the BBB and the neurovascular unit (NVU) developed, we describe its physiology and architecture, which pose a particular challenge to therapeutic intervention. We then discuss how the restrictive nature of this barrier can be overcome for the delivery of therapeutic agents. Alterations to drug formulation offer one option, in part by utilizing distinct transport modes; another is invasive or non-invasive strategies to bypass the BBB. An emerging non-invasive technology for targeted drug delivery is focused ultrasound that allows for the safe and reversible disruption of the BBB. We discuss the underlying mechanisms and provide an outlook, emphasizing the need for more research into the NVU and investment in innovative technologies to overcome the BBB for drug delivery

Repeated ultrasound treatment of tau transgenic mice clears neuronal tau by autophagy and improves behavioral functions

Intracellular deposits of pathological tau are the hallmark of a broad spectrum of neurodegenerative disorders collectively known as tauopathies, with Alzheimer's disease, a secondary tauopathy, being further characterized by extracellular amyloid plaques. A major obstacle in developing effective treatments for tauopathies is the presence of the blood-brain barrier, which restricts the access of therapeutic agents to the brain. An emerging technology to overcome this limitation is the application of low-intensity ultrasound which, together with intravenously injected microbubbles, transiently opens the blood-brain barrier, thereby facilitating the delivery of therapeutic agents into the brain. Interestingly, even in the absence of therapeutic agents, ultrasound has previously been shown to reduce amyloid plaques and improve cognitive functions in amyloid-depositing mice through microglial clearance. Ultrasound has also been shown to facilitate the delivery of antibody fragments against pathological tau in P301L tau transgenic mice; however, the effect of ultrasound alone has not been thoroughly investigated in a tauopathy mouse model.Methods: Here, we performed repeated scanning ultrasound treatments over a period of 15 weeks in K3691 tau transgenic mice with an early-onset tau-related motor and memory phenotype. We used immunohistochemical and biochemical methods to analyze the effect of ultrasound on the mice and determine the underlying mechanism of action, together with an analysis of their motor and memory functions following repeated ultrasound treatments.Results: Repeated ultrasound treatments significantly reduced tau pathology in the absence of histological damage. Associated impaired motor functions showed improvement towards the end of the treatment regime, with memory functions showing a trend towards improvement. In assessing potential clearance mechanisms, we ruled out a role for ubiquitination of tau, a prerequisite for proteasomal clearance. However, the treatment regime induced the autophagy pathway in neurons as reflected by an increase in the autophagosome membrane marker LC3II and a reduction in the autophagic flux marker p62, along with a decrease of mTOR activity and an increase in beclin 1 levels. Moreover, there was a significant increase in the interaction of tau and p62 in the ultrasound-treated mice, suggesting removal of tau by autophagosomes.Conclusions: Our findings indicate that a neuronal protein aggregate clearance mechanism induced by ultrasound-mediated blood-brain barrier opening operates for tau, further supporting the potential of low-intensity ultrasound to treat neurodegenerative disorders

Effect of amyloids on the vesicular machinery: Implications for somatic neurotransmission

Certain neurodegenerative diseases are thought to be initiated by the aggregation of amyloidogenic proteins. However, the mechanism underlying toxicity remains obscure. Most of the suggested mechanisms are generic in nature and do not directly explain the neuron-type specific lesions observed in many of these diseases. Some recent reports suggest that the toxic aggregates impair the synaptic vesicular machinery. This may lead to an understanding of the neuron-type specificity observed in these diseases. A disruption of the vesicular machinery can also be deleterious for extra-synaptic, especially somatic, neurotransmission (common in serotonergic and dopaminergic systems which are specifically affected in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively), though this relationship has remained unexplored. In this review, we discuss amyloid-induced damage to the neurotransmitter vesicular machinery, with an eye on the possible implications for somatic exocytosis. We argue that the larger size of the system, and the availability of multi-photon microscopy techniques for directly visualizing monoamines, make the somatic exocytosis machinery a more tractable model for understanding the effect of amyloids on all types of vesicular neurotransmission. Indeed, exploring this neglected connection may not just be important, it may be a more fruitful route for understanding AD and PD

Role for caveolin-mediated transcytosis in facilitating transport of large cargoes into the brain via ultrasound

The blood-brain barrier (BBB) is a dynamic diffusional barrier regulating the molecular and chemical flux between the blood and brain, thereby preserving cerebral homeostasis. Endothelial cells form the core anatomical component of the BBB based on properties such as specialized junctional complexes between cells, which restricts paracellular transport, and extremely low levels of vesicular transport, restricting transcytosis. In performing its protective function, the BBB also constrains the entry of therapeutics into the brain, hampering the treatment of various neurological disorders. Focused ultrasound is a novel therapeutic modality that has shown efficacy in transiently and non-invasively opening the BBB for the targeted delivery of therapeutics to the brain. Although the ability of ultrasound to disrupt the junctional assembly of endothelial cells has been partially investigated, its effect on the transcellular mode of transport has been largely neglected. In this study, we found that ultrasound induces a pronounced increase in the levels of the vesicle-forming protein caveolin-1. In order to investigate the role of vesicle-mediated transcytoplasmic transport, we compared the leakage of various cargo sizes between a mouse model that lacks caveolin-1 and wild-type mice following sonication of the hippocampus. The absence of caveolin-1 did not lead to overt abnormalities in the cerebral vasculature in the mice. We found that caveolin-1 has a critical role specifically in the transport of large (500\ua0kDa), but not smaller (3 and 70\ua0kDa) cargoes. Our findings indicate differential effects of therapeutic ultrasound on cellular transport mechanisms, with implications for therapeutic interventions

Altered Brain Endothelial Cell Phenotype from a Familial Alzheimer Mutation and Its Potential Implications for Amyloid Clearance and Drug Delivery

The blood-brain barrier (BBB) presents a barrier for circulating factors, but simultaneously challenges drug delivery. How the BBB is altered in Alzheimer disease (AD) is not fully understood. To facilitate this analysis, we derived brain endothelial cells (iBECs) from human induced pluripotent stem cells (hiPSCs) of several patients carrying the familial AD PSEN1 mutation. We demonstrate that, compared with isogenic PSEN1 corrected and control iBECs, AD-iBECs exhibit altered tight and adherens junction protein expression as well as efflux properties. Furthermore, by applying focused ultrasound (FUS) that transiently opens the BBB and achieves multiple therapeutic effects in AD mouse models, we found an altered permeability to 3-5 kDa dextran as a model cargo and the amyloid-beta (A beta) peptide in AD-iBECs compared with control iBECs. This presents human-derived in vitro models of the BBB as a valuable tool to understand its role and properties in a disease context, with possible implications for drug delivery.Peer reviewe

Multimodal analysis of aged wild-type mice exposed to repeated scanning ultrasound treatments demonstrates long-term safety

The blood-brain barrier presents a major challenge for the delivery of therapeutic agents to the brain; however, it can be transiently opened by combining low intensity ultrasound with microbubble infusion. Studies evaluating this technology have largely been performed in rodents, including models of neurological conditions. However, despite promising outcomes in terms of drug delivery and the amelioration of neurological impairments, the potential for long-term adverse effects presents a major concern in the context of clinical applications.Methods: To fill this gap, we repeatedly treated 12-month-old wild-type mice with ultrasound, followed by a multimodal analysis for up to 18 months of age.Results: We found that spatial memory in these aged mice was not adversely affected as assessed in the active place avoidance test. Sholl analysis of Golgi impregnations in the dentate gyrus of the hippocampus did not reveal any changes to the neuronal cytoarchitecture. Long-term potentiation, a cellular correlate of memory, was still achievable, magnetic resonance spectroscopy revealed no major changes in metabolites, and diffusion tensor imaging revealed normal microstructure and tissue integrity in the hippocampus. More specifically, all measures of diffusion appeared to support a neuroprotective effect of ultrasound treatment on the brain.Conclusion: This multimodal analysis indicates that therapeutic ultrasound for blood-brain barrier opening is safe and potentially protective in the long-term, underscoring its validity as a potential treatment modality for diseases of the brain