The Accumulation of Progerin Underlies the Loss of Aortic Smooth Muscle Cells in Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a progeroid disorder characterized by multiple aging-like phenotypes, including disease in large arteries. HGPS is caused by an internally truncated prelamin A (progerin) that cannot undergo the ZMPSTE24-mediated processing step that converts farnesyl-prelamin A to mature lamin A; consequently, progerin retains a carboxyl-terminal farnesyl lipid anchor. In cultured cells, progerin and full-length farnesyl-prelamin A (produced in cells) form an abnormal nuclear lamin meshwork accompanied by nuclear membrane ruptures and cell death; however, these proteins differ in their capacity to cause arterial disease.

Distinct strategies for intravascular triglyceride metabolism in hearts of mammals and lower vertebrate species.

Lipoprotein lipase (LPL) and multiple regulators of LPL activity (e.g., APOC2 and ANGPTL4) are present in all vertebrates, but GPIHBP1-the endothelial cell (EC) protein that captures LPL within the subendothelial spaces and transports it to its site of action in the capillary lumen-is present in mammals but in not chickens or other lower vertebrates.

Progerin forms an abnormal meshwork and has a dominant-negative effect on the nuclear lamina.

Progerin, the protein that causes Hutchinson-Gilford progeria syndrome, triggers nuclear membrane (NM) ruptures and blebs, but the mechanisms are unclear. We suspected that the expression of progerin changes the overall structure of the nuclear lamina. High-resolution microscopy of smooth muscle cells (SMCs) revealed that lamin A and lamin B1 form independent meshworks with uniformly spaced openings (~0.

Nuclear membrane ruptures underlie the vascular pathology in a mouse model of Hutchinson-Gilford progeria syndrome.

The mutant nuclear lamin protein (progerin) produced in Hutchinson-Gilford progeria syndrome (HGPS) results in loss of arterial smooth muscle cells (SMCs), but the mechanism has been unclear. We found that progerin induces repetitive nuclear membrane (NM) ruptures, DNA damage, and cell death in cultured SMCs. Reducing lamin B1 expression and exposing cells to mechanical stress - to mirror conditions in the aorta - triggered more frequent NM ruptures.

Increased expression of LAP2β eliminates nuclear membrane ruptures in nuclear lamin-deficient neurons and fibroblasts.

Defects or deficiencies in nuclear lamins cause pathology in many cell types, and recent studies have implicated nuclear membrane (NM) ruptures as a cause of cell toxicity. We previously observed NM ruptures and progressive cell death in the developing brain of lamin B1-deficient mouse embryos. We also observed frequent NM ruptures and DNA damage in nuclear lamin-deficient fibroblasts.

Nuclear membrane ruptures, cell death, and tissue damage in the setting of nuclear lamin deficiencies.

The nuclear membranes function as a barrier to separate the cell nucleus from the cytoplasm, but this barrier can be compromised by nuclear membrane ruptures, leading to intermixing of nuclear and cytoplasmic contents. Spontaneous nuclear membrane ruptures (., ruptures occurring in the absence of mechanical stress) have been observed in cultured cells, but they are more frequent in the setting of defects or deficiencies in nuclear lamins and when cells are subjected to mechanical stress.

Cultured macrophages transfer surplus cholesterol into adjacent cells in the absence of serum or high-density lipoproteins.

Cholesterol-laden macrophage foam cells are a hallmark of atherosclerosis. For that reason, cholesterol metabolism in macrophages has attracted considerable scrutiny, particularly the mechanisms by which macrophages unload surplus cholesterol (a process referred to as "cholesterol efflux"). Many studies of cholesterol efflux in macrophages have focused on the role of ABC transporters in moving cholesterol onto high-density lipoproteins (HDLs), but other mechanisms for cholesterol efflux likely exist.

Deficiency in ZMPSTE24 and resulting farnesyl-prelamin A accumulation only modestly affect mouse adipose tissue stores.

Zinc metallopeptidase STE24 (ZMPSTE24) is essential for the conversion of farnesyl-prelamin A to mature lamin A, a key component of the nuclear lamina. In the absence of ZMPSTE24, farnesyl-prelamin A accumulates in the nucleus and exerts toxicity, causing a variety of disease phenotypes. By ∼4 months of age, both male and female mice manifest a near-complete loss of adipose tissue, but it has never been clear whether this phenotype is a direct consequence of farnesyl-prelamin A toxicity in adipocytes.

DYT1 Dystonia Patient-Derived Fibroblasts Have Increased Deformability and Susceptibility to Damage by Mechanical Forces.

DYT1 dystonia is a neurological movement disorder that is caused by a loss-of-function mutation in the / gene, which encodes torsinA, a conserved luminal ATPases-associated with various cellular activities (AAA+) protein. TorsinA is required for the assembly of functional linker of nucleoskeleton and cytoskeleton (LINC) complexes, and consequently the mechanical integration of the nucleus and the cytoskeleton. Despite the potential implications of altered mechanobiology in dystonia pathogenesis, the role of torsinA in regulating cellular mechanical phenotype, or mechanotype, in DYT1 dystonia remains unknown.

Disrupting the LINC complex in smooth muscle cells reduces aortic disease in a mouse model of Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome is a disorder of premature aging in children caused by de novo mutations in that lead to the synthesis of an internally truncated form of prelamin A (commonly called progerin). The production of progerin causes multiple disease phenotypes, including an unusual vascular phenotype characterized by the loss of smooth muscle cells in the arterial media and fibrosis of the adventitia. We show that progerin expression, combined with mechanical stress, promotes smooth muscle cell death.

Moberg Osteotomy Shifts Contact Pressure Plantarly in the First Metatarsophalangeal Joint in a Biomechanical Model.

Background: A proximal phalangeal dorsiflexion osteotomy (Moberg osteotomy) is commonly used to treat hallux rigidus, but the mechanical explanation for its effectiveness is unclear. The purpose of our study was to test the effect of a Moberg osteotomy on first metatarsophalangeal joint contact mechanics.

Methods: Ten cadaveric first ray specimens were dissected, with the medial band of the plantar aponeurosis preserved at its origin, and placed in a custom testing apparatus.

Spontaneous Ankylosis of Occiput to C2 following Closed Traction and Halo Treatment of Atlantoaxial Rotary Fixation.

Study Design Case report. Objective We report a case of spontaneous atlantoaxial rotatory fixation (AARF) presenting 9 months after onset in an 11-year-old boy. Methods This is a retrospective case report of spontaneous ankylosis of occiput to C2 following traction, manipulative reduction, and halo immobilization for refractory atlantoaxial rotatory fixation.

Chlamydia public health programs and the epidemiology of pelvic inflammatory disease and ectopic pregnancy.

Background: Many countries have witnessed a disturbing increase in cases of Chlamydia trachomatis infection despite enhanced control programs. Since the goal of Chlamydia control is to prevent reproductive complications such as pelvic inflammatory disease and ectopic pregnancy, an understanding of recent trends in these conditions is needed to fully evaluate the effect of control efforts.

Methods: We analyzed 2 provincial, comprehensive health services administrative databases (encompassing hospitalizations and all physician-delivered services) for pelvic inflammatory disease and ectopic pregnancy trends from 1992 through 2009 in women of reproductive age in British Columbia, Canada.

Characterization of a high-affinity human antibody with a disulfide bridge in the third complementarity-determining region of the heavy chain.

Disulfide bridges are common in the antigen-binding site from sharks (new antigen receptor) and camels (single variable heavy-chain domain, VHH), in which they confer both structural diversity and domain stability. In human antibodies, cysteine residues in the third complementarity-determining region of the heavy chain (CDR-H3) are rare but naturally encoded in the IGHD germline genes. Here, by panning a phage display library designed based on human germline genes and synthetic CDR-H3 regions against a human cytokine, we identified an antibody (M3) containing two cysteine residues in the CDR-H3.

Interleukin-4, Oxidative Stress, Vascular Inflammation and Atherosclerosis.

The pro-oxidative and pro-inflammatory pathways in vascular endothelium have been implicated in the initiation and progression of atherosclerosis. In fact, inflammatory responses in vascular endothelium are primarily regulated through oxidative stress-mediated signaling pathways leading to overexpression of pro-inflammatory mediators. Enhanced expression of cytokines, chemokines and adhesion molecules in endothelial cells and their close interactions facilitate recruiting and adhering blood leukocytes to vessel wall, and subsequently stimulate transendothelial migration, which are thought to be critical early pathologic events in atherogenesis.

HCV co-infection in HIV positive population in British Columbia, Canada.

Background: As HIV and hepatitis C (HCV) share some modes of transmission co-infection is not uncommon. This study used a population-based sample of HIV and HCV tested individuals to determine the prevalence of HIV/HCV co-infection, the sequence of virus diagnoses, and demographic and associated risk factors.

Methods: Positive cases of HIV were linked to the combined laboratory database (of negative and positive HCV antibody results) and HCV reported cases in British Columbia (BC).

Role of NADPH oxidase in interleukin-4-induced monocyte chemoattractant protein-1 expression in vascular endothelium.

Objective And Design: The pro-oxidative and pro-inflammatory pathways in vascular endothelium have been implicated in the development of atherosclerosis. In the present study, we investigated effect of interleukin-4 (IL-4) on monocyte chemoattractant protein-1 (MCP-1) expression in vascular endothelium and examined the role of distinct sources of reactive oxygen species (ROS) in this process.

Methods And Results: Real-time reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay showed that IL-4 significantly up-regulated mRNA and protein expression of MCP-1 in human aortic endothelial cells (HAEC) and C57BL/6 mice.

Oxidative mechanisms of IL-4-induced IL-6 expression in vascular endothelium.

The present study is designed to investigate the effects of interleukin-4 (IL-4) on expression of interleukin-6 (IL-6), as well as to examine the role of distinct sources of reactive oxygen species (ROS) in this process. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) showed that IL-4 significantly up-regulated the mRNA and protein expression of IL-6 in human aortic endothelial cells (HAEC) and C57BL/6 mice. Dihydroethidium (DHE) and dichlorofluorescein (DCF) fluorescence staining demonstrated that IL-4 significantly increased ROS generation in HAEC.

A population-based study of infectious syphilis rediagnosis in British Columbia, 1995-2005.

Background: The Canadian province of British Columbia has experienced an ongoing heterosexual infectious syphilis epidemic since July 1997. In this study, we sought to characterize individuals who received a diagnosis of syphilis more than once in a cohort of reported cases from 1995 through 2005 in British Columbia.

Methods: Data for all cases of primary, secondary, and early latent syphilis from 1 January 1995 through 31 December 2005 were extracted from the British Columbia Provincial Sexually Transmitted Disease Surveillance Database.

2',5'-linked DNA is a template for polymerase-directed DNA synthesis.

Genomes are composed of nucleic acids bearing 3',5'-phosphodiester-linked sugars. The 2',5'-phosphodiester linkage is a fundamental alternative to the natural linkage and is the predominant product of most nontemplate, nonenzymatic oligomerizations of nucleotide monomers. This fact suggests a chemical bias for the formation of 2',5'-phosphodiester bonds, an important consideration in the context of molecular evolution on Earth or elsewhere.