The Portal Vertex of KSHV Promotes Docking of Capsids at the Nuclear Pores

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a cancer-related herpesvirus. Like other herpesviruses, the KSHV icosahedral capsid includes a portal vertex, composed of 12 protein subunits encoded by open reading frame (ORF) 43, which enables packaging and release of the viral genome into the nucleus through the nuclear pore complex (NPC). Capsid vertex-specific component (CVSC) tegument proteins, which directly mediate docking at the NPCs, are organized on the capsid vertices and are enriched on the portal vertex. Whether and how the portal vertex is selected for docking at the NPC is unknown. Here, we investigated the docking of incoming ORF43-null KSHV capsids at the NPCs, and describe a significantly lower fraction of capsids attached to the nuclear envelope compared to wild-type (WT) capsids. Like WT capsids, nuclear envelope-associated ORF43-null capsids co-localized with different nucleoporins (Nups) and did not detach upon salt treatment. Inhibition of nuclear export did not alter WT capsid docking. As ORF43-null capsids exhibit lower extent of association with the NPCs, we conclude that although not essential, the portal has a role in mediating the interaction of the CVSC proteins with Nups, and suggest a model whereby WT capsids can dock at the nuclear envelope through a non-portal penton vertex, resulting in an infection ‘dead end’.     

Recombinant α-Interferon May be Efficacious in Acute Hepatitis B

Whereas, in chronic type B hepatitis, the therapeutic effect of alpha-interferon has been studied extensively, data on the effect of interferon on the course and prognosis of acute hepatitis B are scarce in the literature. We report a case of acute type B hepatitis complicated by life-threatening extrahepatic manifestations where recombinant alpha-interferon facilitated clinical, biochemical, and serological recovery.     

Cerebrofacial venous metameric syndrome—spectrum of imaging findings

Cerebrofacial venous metameric syndrome (CVMS) is a complex craniofacial vascular malformation disorder in which patients have a constellation of venous vascular malformations affecting soft tissues, bone, dura, and neural structures including the eye and brain. It is hypothesized that a somatic mutation responsible for the venous abnormalities occurred prior to migration of the neural crest cells, and because of this, facial, osseous, and cerebral involvement typically follows a segmental or “metameric” distribution. The most commonly recognized form of CVMS is Sturge-Weber syndrome. However, a wide spectrum of CVMS phenotypical presentations exist with various metameric distributions of slow-flow vascular lesions including facial venous vascular malformations, developmental venous anomalies, venous angiomas, cavernous malformations (cavernomas), dural sinus malformations, and maybe even vascular tumors such as cavernous hemangiomas. Awareness of the various manifestations as described herewith is important for treatment and screening purposes.     

Myotonia in DNM2-related centronuclear myopathy

Centronuclear myopathy (CNM) is a rare hereditary myopathy characterized by centrally located muscle fiber nuclei. Mutations in the dynamin 2 (DNM2) gene are estimated to account for about 50 % of CNM cases. Electromyographic recordings in CNM may show myopathic motor unit potentials without spontaneous activity at rest. Myotonic discharges, a distinctive electrical activity caused by membrane hyperexcitability, are characteristic of certain neuromuscular disorders. Such activity has been reported in only one CNM case without a known genetic cause. We sequenced the DNM2 gene and the genes associated with myotonia (CLCN1, SCN4A, DMPK and ZNF9) in a sporadic adult patient with CNM and myotonic discharges. Sequencing the entire coding region and exon–intron boundaries revealed a heterozygous c.1106g-a substitution in exon 8, resulting in a R369Q change in the DNM2. Sequencing the CLCN1, SCN4A, DMPK and ZNF9 genes ruled out mutations in these genes. This is the first report of DNM2-related CNM presenting with myotonia. The diagnosis of CNM should be considered in patients with myotonic discharges of an unknown cause.     

Outcomes of Laparoscopic Sleeve Gastrectomy in Patients Older than 60 Years

Background

Morbidity and mortality following laparoscopic sleeve gastrectomy (LSG) occur at acceptable rates, but its safety and efficacy in the elderly are unknown.

Methods

A retrospective review was performed of all patients aged >60 years who underwent LSG from 2008 to 2012. These patients were 1:2 matched, by gender and body mass index (BMI) to young patients, 18?<?age?<?50. Data analyzed included demographics, preoperative and postoperative BMI, postoperative complications, and improvement or resolution of obesity-related comorbidities.

Results

Fifty-two morbid obese patients older than 60 years underwent LSG (mean age, 62.9?±?0.3 years). These were matched to 104 young patients, age 18–50 years (mean age, 35.7?±?0.8 years). Groups did not differ in male gender (44 vs. 43 %, p?=?0.9), preoperative BMI (42.6?±?0.7 vs. 42.6?±?0.6, p?=?0.97), and length of follow-up (17?±?2 vs. 22?±?1.4 months, p?=?0.06). Obesity-related comorbidities were significantly higher in the older group (96 vs. 65 %, p?<?0.001). Excess weight loss (EWL) was higher in the younger group (75?±?2.4 vs. 62?±?3 %, p?=?0.001). Older patients had a significantly higher rate of a concurrent hiatal hernia repair (23 vs. 1.9 %, p?<?0.001). Overall postoperative minor complication rate was higher in the older group (25 vs. 4.8 %, p?<?0.001). This included atrial fibrillation (9.5 %), urinary tract infection (7 %), trocar site hernia (4 %), dysphagia, surgical site infection, bleeding, bowel obstruction, colitis, and nutritional deficiency (2 %, each). No perioperative mortality occurred. Comorbidity resolution or improvement was comparable between groups (88 vs. 80 %, p?=?0.13).

Conclusions

LSG is safe and very efficient in patients aged >60, despite higher rates of perioperative comorbidities.     

Characterization and Epitope Mapping of the Polyclonal Antibody Repertoire Elicited by Ricin Holotoxin-Based Vaccination

Ricin, one of the most potent and lethal toxins known, is classified by the Centers for Disease Control and Prevention (CDC) as a select agent. Currently, there is no available antidote against ricin exposure, and the most promising therapy is based on neutralizing antibodies elicited by active vaccination or that are given passively. The aim of this study was to characterize the repertoire of anti-ricin antibodies generated in rabbits immunized with ricin toxoid. These anti-ricin antibodies exhibit an exceptionally high avidity (thiocyanate-based avidity index, 9 M) toward ricin and an apparent affinity of 1 nM. Utilizing a novel tissue culture-based assay that enables the determination of ricin activity within a short time period, we found that the anti-ricin antibodies also possess a very high neutralizing titer. In line with these findings, these antibodies conferred mice with full protection against pulmonary ricinosis when administered as a passive vaccination. Epitope mapping analysis using phage display random peptide libraries revealed that the polyclonal serum contains four immunodominant epitopes, three of which are located on the A subunit and one on the B subunit of ricin. Only two of the four epitopes were found to have a significant role in ricin neutralization. To the best of our knowledge, this is the first work that characterizes these immunological aspects of the polyclonal response to ricin holotoxin-based vaccination. These findings provide useful information and a possible strategy for the development and design of an improved ricin holotoxin-based vaccine.     

Collective cell migration of the nephric duct requires FGF signaling

Background : During the course of development, the vertebrate nephric duct (ND) extends and migrates from the place of its initial formation, adjacent to the anterior somites, until it inserts into the bladder or cloaca in the posterior region of the embryo. The molecular mechanisms that guide ND migration are poorly understood. Results : A novel Gata3‐enhancer‐Gfp‐based chick embryo live imaging system was developed that permits documentation of ND migration at the individual cell level for the first time. FGF Receptors and FGF response genes are expressed in the ND, and FGF ligands are expressed in surrounding tissues. FGF receptor inhibition blocked nephric duct migration. Individual inhibitors of the Erk, p38, or Jnk pathways did not affect duct migration, but inhibition of all three pathways together did inhibit migration of the duct. A localized source of FGF8 placed adjacent to the nephric duct did not affect the duct migration path. Conclusions : FGF signaling acts as a “motor” that is required for duct migration, but other signals are needed to determine the directionality of the duct migration pathway. Developmental Dynamics 244:157–167, 2015. © 2014 Wiley Periodicals, Inc.