Acute limb ischemia secondary to bullet embolism following a cardiac gunshot wound in a pediatric patient.

Bullet embolism following a gunshot wound to the heart is a very unusual cause of acute limb ischemia. We report the case of a 3-year-old boy who sustained a penetrating cardiac trauma secondary to an accidental self-inflicted gunshot wound with a BB (ball bearing) gun. The BB pellet entered the left ventricle and embolized into the peripheral circulation, lodging at the bifurcation of the left common femoral artery. This resulted in acute left lower extremity ischemia. The patient was successfully treated by open common femoral artery exploration and foreign body removal.

Three-dimensional Analysis of Facial Asymmetry in Unilateral Lambdoid Craniosynostosis.

OBJECTIVE: Unilateral lambdoid synostosis (ULS) is characterized by occipital flattening, mastoid bulging, and contralateral parietal bossing. Anterior craniofacial features are less well-defined. This study utilizes volumetric, craniometric, and composite heat maps of three-dimensional (3D) rendered CT scans to analyze anterior craniofacial asymmetry in ULS and compared to controls. DESIGN: A retrospective review of three-dimensional CT scans. SETTING: Tertiary care pediatric institution. PATIENTS, PARTICIPANTS: 30 ULS and 30 control patients. MAIN OUTCOME MEASURE(S): Volumetric and craniometric analysis of the anterior fossa, orbits, zygomas, maxilla, and mandible was performed. RESULTS: The anterior fossa volume was greater bilaterally (0.047, 0.038), and the fossa angle was more anterior contralaterally (<0.001) and more anterior bilaterally than controls (0.038, 0.033). The orbits had greater height and lesser depth bilaterally compared to controls (0.006, 0.009; < 0.001, < 0.001). Zygoma length was significantly greater on the contralateral side than controls (0.048; < 0.001). Nasal contralateral deviation of 3.57 ± 1.97°. The maxillary length was longer on the contralateral side (0.045). The mandibular angle was more anterior on the ipsilateral side and posterior on the contralateral side (<0.001) compared to controls (0.042, < 0.001). Chin had a contralateral deviation of 1.04 ± 3.74°. CONCLUSIONS: ULS has significant asymmetry in the anterior craniofacial skeleton. There is a bilateral expansion of the anterior cranial fossa with greater frontal bossing on the contralateral side. Increased orbital height and decreased depth. Contralateral zygomatic and mandibular body lengthening with posterior mandibular deviation. These features may provide more effective diagnosis and potential clinical management strategies.

Mitochondrial clearance and maturation of autophagosomes are compromised in LRRK2 G2019S familial Parkinson's disease patient fibroblasts.

This study utilized human fibroblasts as a preclinical discovery and diagnostic platform for identification of cell biological signatures specific for the LRRK2 G2019S mutation producing Parkinson's disease (PD). Using live cell imaging with a pH-sensitive Rosella biosensor probe reflecting lysosomal breakdown of mitochondria, mitophagy rates were found to be decreased in fibroblasts carrying the LRRK2 G2019S mutation compared to cells isolated from healthy subject (HS) controls. The mutant LRRK2 increased kinase activity was reduced by pharmacological inhibition and targeted antisense oligonucleotide treatment, which normalized mitophagy rates in the G2019S cells and also increased mitophagy levels in HS cells. Detailed mechanistic analysis showed a reduction of mature autophagosomes in LRRK2 G2019S fibroblasts, which was rescued by LRRK2 specific kinase inhibition. These findings demonstrate an important role for LRRK2 protein in regulation of mitochondrial clearance by the lysosomes, which is hampered in PD with the G2019S mutation. The current results are relevant for cell phenotypic diagnostic approaches and potentially for stratification of PD patients for targeted therapy.

Neurite Collapse and Altered ER Ca2+ Control in Human Parkinson Disease Patient iPSC-Derived Neurons with LRRK2 G2019S Mutation.

The Parkinson disease (PD) genetic LRRK2 gain-of-function mutations may relate to the ER pathological changes seen in PD patients at postmortem. Human induced pluripotent stem cell (iPSC)-derived neurons with the PD pathogenic LRRK2 G2019S mutation exhibited neurite collapse when challenged with the ER Ca2+ influx sarco/ER Ca2+-ATPase inhibitor thapsigargin (THP). Baseline ER Ca2+ levels measured with the ER Ca2+ indicator CEPIA-ER were lower in LRRK2 G2019S human neurons, including in differentiated midbrain dopamine neurons in vitro. After THP challenge, PD patient-derived neurons displayed increased Ca2+ influx and decreased intracellular Ca2+ buffering upon membrane depolarization. These effects were reversed following LRRK2 mutation correction by antisense oligonucleotides and gene editing. Gene expression analysis in LRRK2 G2019S neurons identified modified levels of key store-operated Ca2+ entry regulators, with no alterations in ER Ca2+ efflux. These results demonstrate PD gene mutation LRRK2 G2019S ER calcium-dependent pathogenic effects in human neurons.

The glycoprotein GPNMB is selectively elevated in the substantia nigra of Parkinson's disease patients and increases after lysosomal stress.

GPNMB is a glycoprotein observed upon tissue damage and inflammation and is associated with astrocytes, microglia, and macrophages. Gene variations in GPNMB are linked with Parkinson's disease (PD) risk, and changes in protein levels of GPNMB have been found in lysosomal storage disorders, including Gaucher's disease with glucocerebrosidase (GCase) deficiency. In the current study, GPNMB increases were seen in the substantia nigra (SN) of PD patients compared to age-matched controls. Such PD patients have a decrease in GCase activity and corresponding elevation of glycosphingolipids in the SN (Rocha et al., 2015a). Interestingly, transgenic mice modelling synucleinopathy did not show GPNMB elevations or altered GCase activity levels compared to wild-type mice. However, upon CBE-induced GCase lysosomal dysfunction with elevated glycosphingolipids in wild-type mice, there were similar changes in GPNMB levels in the brain as seen in PD patient brains. These results indicate that GPNMB levels do not depend on alpha-synuclein load per se but relate directly to the lipidopathy changes induced by CBE-mediated GCase inhibition. The experimental modelling of elevating glycolipids resulted in GPNMB elevations with glial activation in several brain regions in mice. This is the first demonstration of region-specific elevations of GPNMB protein in Parkinson's disease. The presence of GPNMB in PD patient substantia nigra, the induction of GPNMB after experimental glycosphingolipid increases, but not with pure alpha-synucleinopathy, point towards the potential for primary lipid-induced degeneration in PD.

Hereditary multiple exostoses as a novel cause of bilateral popliteal artery aneurysms in the elderly.

Hereditary multiple exostoses (HME) is a genetic condition characterized by the development of multiple osteochondromas during childhood and adolescence. On rare occasions, these bony tumors can be associated with vascular injury, most commonly involving the popliteal artery. Such patients typically present with vascular complications in adolescence and young adulthood. We report an autopsy study of an elderly man who presented with bilateral popliteal artery pseudoaneurysms in the setting of HME at age 81. This is the oldest patient presenting with a vascular complication due to HME reported to date, as well as the only known case of bilateral popliteal pseudoaneurysms caused by HME. This is also the only autopsy study of this vascular complication so far reported. Our case illustrates that vascular complications from HME can occur even in the elderly, and may show bilateral involvement.