Presenilin 1 (PS1) is the catalytic core of γ-secretase, which cleaves type-1 transmembrane proteins including the amyloid precursor protein (APP). PS1 also has γ-secretase independent functions and dominant PS1 missense mutations are the most common cause of familial Alzheimer’s disease (FAD). Whether PS1 FAD mutations are gain or loss-of-function remains controversial, primarily because most studies have relied on overexpression in mouse and/or non-neuronal systems. We used isogenic euploid human iPSC lines to generate and study an allelic series of PS1 mutations including heterozygous null mutations and homozygous and heterozygous FAD PS1 mutations. Rigorous analysis of this allelic series in differentiated, purified neurons allowed us to resolve this controversy and to conclude that FAD PS1 mutations, expressed at normal levels in the appropriate cell-type, impair γ-secretase activity, but do not disrupt γ-secretase independent functions of PS1. Thus, FAD PS1 mutations do not act as simple loss of PS1 function, but instead dominantly gain an activity toxic to some, but not all PS1 functions.

Canine biological specimens are often part of the physical evidence from crime scenes. Until now, there have been no validated canine-specific forensic reagent kits available. A multiplex genotyping system, comprising 18 short tandem repeats (STRs) and a sex-linked zinc finger locus for gender determination, was developed for generating population genetic data assessing the weight of canine forensic DNA profiles. Allele frequencies were estimated for 236 pedigreed and 431 mixed breed dogs residing in the U.S. Average random match probability is 1 in 2 x 10(33) using the regional database and 1 in 4 x 10(39) using the breed dataset. Each pedigreed population was genetically distinct and could be differentiated from the mixed breed dog population but genetic variation was not significantly correlated with geographic transition. Results herein support the use of the allele frequency data with the canine STR multiplex for conveying the significance of identity testing for forensic casework, parentage testing, and breed assignments.

Fat embolism syndrome (FES) typically occurs following orthopedic trauma and may present with altered mental status and even coma. Nonconvulsive status epilepticus is an electroclinical state associated with an altered level of consciousness but lacking convulsive motor activity and has been reported in fat embolism. The diagnosis is clinical and is treated with supportive care, antiepileptic therapy, and sedation. A 56-year-old male presented with altered mental status following internal fixation for an acute right femur fracture due to a motor vehicle accident 24 hours earlier. Continued neuromonitoring revealed nonconvulsive status epilepticus. Magnetic resonance imaging of the brain showed multiple bilateral acute cerebral infarcts with a specific pattern favoring the diagnosis of fat embolism syndrome. He was found to have a significant right to left intracardiac shunt on a transesophageal echocardiogram. He improved substantially over time with supportive therapy, was successfully extubated on day 6, and discharged to inpatient rehabilitation on postoperative day 15. Fat embolisms can result in a wide range of neurologic manifestations. Nonrefractory nonconvulsive status epilepticus that responds to antiepileptic drugs, sedation, and supportive therapy can have a favorable outcome. A high index of suspicion and early recognition reduces the chances of unnecessary interventions and may improve survival.

Renal artery stenosis (RAS) typically involves varying degrees of calcification, and treatment can be fraught with risk and suboptimal results. Intravascular lithotripsy (IVL) uses shockwaves to fragment calcium to facilitate angioplasty. We present a case of severe bilateral RAS successfully treated with IVL and stenting after conventional methods had failed. ( Level of Difficulty: Intermediate. )