Patients who undergo hepatic arterial chemotherapy are not at an increased risk of developing hepatic arterial thrombosis or other hepatic arterial complications after orthotopic liver transplantation.

Time-homogeneous Markov models are widely used tools for analyzing longitudinal data about the progression of a chronic disease over time. There are advantages to modeling the true disease progression as a discrete time stationary Markov chain. However, one limitation of this method is its inability to handle uneven follow-up assessments or skipped visits. A continuous time version of a homogeneous Markov process multi-state model could be an alternative approach. In this article, we conduct comparisons of these two methods for unevenly spaced observations. Simulations compare the performance of the two methods and two applications illustrate the results.

BACKGROUND-Subjective memory complaints are common in aged persons, indicating an increased, but incompletely understood, risk for dementia. Objective-To compare cognitive trajectories and autopsy results of individuals with subjective complaints after stratifying by whether a subsequent clinical dementia occurred. DESIGN-Observational study. SETTING-University of Kentucky cohort with yearly longitudinal assessments and eventual autopsies. PARTICIPANTS-Among 516 patients who were cognitively intact and depression-free at enrollment, 296 declared a memory complaint during follow-up. Among those who came to autopsy, 118 died but never developed dementia, while 36 died following dementia diagnosis. MEASUREMENTS-Cognitive domain trajectories were compared using linear mixed models adjusted for age, gender, years of education and APOE status. Neuropathological findings were compared cross-sectionally after adjustment for age at death.

Beta-amyloid (Aβ) immunotherapy is a promising intervention to slow Alzheimer’s disease (AD). Aging dogs naturally accumulate Aβ and show cognitive decline. An active vaccine against fibrillar Aβ 1–42 (VAC) in aged beagles resulted in maintenance but not improvement of cognition along with reduced brain Aβ. Behavioral enrichment (ENR) led to cognitive benefits but no reduction in Aβ. We hypothesized cognitive outcomes could be improved by combining VAC with ENR in aged dogs. Aged dogs (11–12 years) were placed into 4 groups: (1) control/control (C/C); (2) control/VAC (C/V); (3) ENR/control (E/C); (4) ENR and VAC (E/V) and treated for 20 months. VAC decreased brain Aβ, pyroglutamate Aβ, increased CSF Aβ42 and BDNF RNA levels but also increased microhemorrhages. ENR reduced brain Aβ and prevented microhemorrhages. The combination treatment resulted in a significant maintenance of learning over time, reduced Aβ and increased BDNF mRNA despite increased microhemorrhages, however there were no benefits to memory. These results suggest that the combination of immunotherapy with behavioral enrichment leads to cognitive maintenance associated with reduced neuropathology that may benefit people with AD.

Maintenance of cellular homeostasis is regulated by the molecular chaperones. Under pathogenic conditions, aberrant proteins are triaged by the chaperone network. These aberrant proteins, known as “clients,” have major roles in the pathogenesis of numerous neurological disorders, including tau in Alzheimer’s disease, α-synuclein and LRRK2 in Parkinson’s disease, SOD-1, TDP-43 and FUS in amyotrophic lateral sclerosis, and polyQ-expanded proteins such as huntingtin in Huntington’s disease. Recent work has demonstrated that the use of chemical compounds which inhibit the activity of molecular chaperones subsequently alter the fate of aberrant clients. Inhibition of Hsp90 and Hsc70, two major molecular chaperones, has led to a greater understanding of how chaperone triage decisions are made and how perturbing the chaperone system can promote clearance of these pathogenic clients. Described here are major pathways and components of several prominent neurological disorders. Also discussed is how treatment with chaperone inhibitors, predominately Hsp90 inhibitors which are selective for a diseased state, can relieve the burden of aberrant client signaling in these neurological disorders.