Loss of LRP1 in Adult Neural Stem Cells Impairs Migration to Ischemic Lesions.

After ischemia, cells in the brain parenchyma upregulate stromal derived factor 1 (SDF1), driving chemokine receptor CXCR4-mediated migration of adult neural stem cells to the ischemic injury. We discovered a novel regulator of CXCR4 in neural stem cells, low-density lipoprotein receptor related protein 1 (LRP1). We used Nestin-driven knockout of LRP1 and induction of td-tomato in neural stem cells of adult mice. We observed reduced localization of td-tomato positive cells to the lesion, and find disrupted CXCR4-mediated neural stem cell migration in vitro, which is likely driven by LRP1-mediated loss of CXCR4 expression in vivo. Our results suggest that LRP1 is a novel regulator of CXCR4 in neural stem cells. This heretofore unknown interaction between LRP1 and CXCR4 could have significant consequences for multiple aspects of neural stem cell physiology.

Structural and functional cardiac profile after prolonged duration of mechanical unloading: potential implications for myocardial recovery.

Clinical and experimental studies have suggested that the duration of left ventricular assist device (LVAD) support may affect remodeling of the failing heart. We aimed to 1) characterize the changes in Ca2+/calmodulin-dependent protein kinase type-IIδ (CaMKIIδ), growth signaling, structural proteins, fibrosis, apoptosis, and gene expression before and after LVAD support and 2) assess whether the duration of support correlated with improvement or worsening of reverse remodeling. Left ventricular apex tissue and serum pairs were collected in patients with dilated cardiomyopathy ( n = 25, 23 men and 2 women) at LVAD implantation and after LVAD support at cardiac transplantation/LVAD explantation. Normal cardiac tissue was obtained from healthy hearts ( n = 4) and normal serum from age-matched control hearts ( n = 4). The duration of LVAD support ranged from 48 to 1,170 days (median duration: 270 days). LVAD support was associated with CaMKIIδ activation, increased nuclear myocyte enhancer factor 2, sustained histone deacetylase-4 phosphorylation, increased circulating and cardiac myostatin (MSTN) and MSTN signaling mediated by SMAD2, ongoing structural protein dysregulation and sustained fibrosis and apoptosis (all P < 0.05). Increased CaMKIIδ phosphorylation, nuclear myocyte enhancer factor 2, and cardiac MSTN significantly correlated with the duration of support. Phosphorylation of SMAD2 and apoptosis decreased with a shorter duration of LVAD support but increased with a longer duration of LVAD support. Further study is needed to define the optimal duration of LVAD support in patients with dilated cardiomyopathy. NEW & NOTEWORTHY A long duration of left ventricular assist device support may be detrimental for myocardial recovery, based on myocardial tissue experiments in patients with prolonged support showing significantly worsened activation of Ca2+/calmodulin-dependent protein kinase-IIδ, increased nuclear myocyte enhancer factor 2, increased myostatin and its signaling by SMAD2, and apoptosis as well as sustained histone deacetylase-4 phosphorylation, structural protein dysregulation, and fibrosis.

Sarcomatoid carcinoma of the gallbladder: A rare form of gallbladder cancer.

Sarcomatoid carcinoma of the gallbladder or gallbladder carcinosarcoma is an exceedingly rare malignancy. Unfortunately, patients typically present with advanced disease at diagnosis. Symptoms may include abdominal pain, jaundice, anorexia, nausea, weight loss, and a palpable abdominal mass. This malignant tumor has a poor prognosis, and treatment options include surgical resection, radiation, and chemotherapy. We detail the case of a 57-year-old male who presented with diffuse abdominal pain and jaundice. Computed tomography scan of the abdomen and pelvis showed a large mass within the gallbladder, intrahepatic ductal dilation, gastrohepatic lymph node enlargement, and liver lesions concerning for metastatic disease. A core needle biopsy from one of the liver lesions revealed poorly differentiated sarcomatoid carcinoma of the gallbladder. He was assessed to have stage IV disease and deemed not to be a surgical candidate. Palliative chemotherapy was planned; however, treatment was never started due to the development of cholangitis with sepsis. The patient ultimately opted for hospice care and passed away shortly thereafter.

Microsurgery for Unruptured Cerebral Arteriovenous Malformations in the National Inpatient Sample is More Common Post-ARUBA.

BACKGROUND: The ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) was the first randomized control trial to investigate unruptured cerebral arteriovenous malformation (cAVM) treatments and concluded that medical management was superior to interventional therapy for the treatment of unruptured cAVMs. This conclusion generated considerable controversy and was followed by rebuttals and meta-analyses of the ARUBA methodology and results. We sought to determine whether the ARUBA results altered treatment trends of cAVMs within the United States. METHODS: Using the National Inpatient Sample, the largest all-payer inpatient care database within the United States, we isolated patients who were admitted on an elective basis for cAVM treatment and determined the treatment modality undergone by these patients. The cohort was dichotomized separately at 2 ARUBA time points: the European Stroke Conference presentation in May 2013, and The Lancet publication in February 2014. RESULTS: We found that the overall treatment rate of unruptured cAVMs decreased after both time points. However, the rate of surgical excision alone, relative to other modalities, was significantly increased, and endovascular intervention demonstrated a nonsignificant decrease. CONCLUSIONS: Our findings suggest that the ARUBA trial has influenced unruptured cAVM treatment patterns within the United States. Although the overall treatment rate has decreased, unruptured cAVMs, when treated post-ARUBA, are most commonly approached with surgical excision alone.