The effects of a dominant connexin32 mutant in myelinating Schwann cells.

Mutations in GJB1, the gene encoding the gap junction protein connexin32 (Cx32), cause X-linked Charcot-Marie-Tooth disease, an inherited demyelinating peripheral neuropathy. We generated transgenic mice that express the R142W mutation in myelinating Schwann cells. The R142W mutant protein was aberrantly localized to the Golgi, indicating that it does not traffic properly, but the molecular organization of the myelin sheath, including the localization of Cx29, another connexin expressed by myelinating Schwann cells, was not disrupted.

A novel local thresholding algorithm for trabecular bone volume fraction mapping in the limited spatial resolution regime of in vivo MRI.

Recent advances in micro-magnetic resonance imaging have shown the possibility of in vivo assessment of trabecular bone architecture. However, the small feature size and relatively low signal-to-noise ratio (SNR) achievable in vivo cause the intensity histogram to be unimodal. The critical first step in the processing of these images is the extraction of bone volume fraction for each voxel.

The pediatric mandible: II. Management of traumatic injury or fracture.

Learning Objectives: After studying this article, the participant should be able to: 1. Describe the changing epidemiology of mandibular fractures in children and adolescents. 2.

Prenylation-defective human connexin32 mutants are normally localized and function equivalently to wild-type connexin32 in myelinating Schwann cells.

Mutations in GJB1, the gene encoding the gap junction protein connexin32 (Cx32), cause the X-linked form of Charcot-Marie-Tooth disease, an inherited demyelinating neuropathy. The C terminus of human Cx32 contains a putative prenylation motif that is conserved in Cx32 orthologs. Using [3H]mevalonolactone ([3H]MVA) incorporation, we demonstrated that wild-type human connexin32 can be prenylated in COS7 cells, in contrast to disease-associated mutations that are predicted to disrupt the prenylation motif.

AKT activation and response to interferon-beta in human cancer cells.

Significant growth inhibition and induction of apoptosis by IFN-beta in cancer cells including colorectal cancer cells have been observed. We and others have previously reported the Stat 1 induction of TRAIL is a crucial step in the IFN-beta induced apoptosis pathway. However, when evaluating the sensitivity of a panel of colorectal cancer cell lines, we found no clear correlation between activation of the Jak/Stat signaling pathway and response to interferon.

VAV1: a new target in pancreatic cancer?

Pancreatic ductal adenocarcinoma (PDA) is arguably the most lethal malignancy in the United States. Despite the identification of many molecular alterations in PDA, this information has not translated into effective therapeutic strategies to date. A recent report in Cancer Cell (Fernandez-Zapico et al, Cancer Cell 2005, 7:39-49) reveals an unexpected role for the hematopoietic-specific RhoGEF VAV1 in pancreatic tumorigenesis, where ectopic expression of VAV1 as a result of promoter demethylation was identified in the majority of established cell lines and PDA tissue samples.

Transgenic expression of human connexin32 in myelinating Schwann cells prevents demyelination in connexin32-null mice.

Mutations in Gap Junction beta1 (GJB1), the gene encoding the gap junction protein connexin32 (Cx32), cause the X-linked form of Charcot-Marie-Tooth disease (CMT1X), an inherited demyelinating neuropathy. We investigated the possibility that the expression of mutant Cx32 in other cells besides myelinating Schwann cells contributes to the development of demyelination. Human Cx32 was expressed in transgenic mice using a rat myelin protein zero (Mpz) promoter, which is exclusively expressed by myelinating Schwann cells.

Twist induces an epithelial-mesenchymal transition to facilitate tumor metastasis.

Tumor metastasis-the spreading of primary tumor cells to distal organs - is the major cause of death of cancer patients. The metastatic process consists of four distinct steps, invasion, intravasation, extravasation, and metastatic growth, and primary tumor cells need to acquire different genetic characteristics to accomplish each step. The main players during the metastatic process remain, however, largely unknown.

Acute demyelination disrupts the molecular organization of peripheral nervous system nodes.

Intraneurally injected lysolecithin causes both segmental and paranodal demyelination. In demyelinated internodes, axonal components of nodes fragment and disappear, glial and axonal paranodal and juxtaparanodal proteins no longer cluster, and axonal Kv1.1/Kv1.

Voice rehabilitation after external partial laryngeal surgery.

Excising part or all of a larynx as a cancer operation results in changes that transgress anatomic, physiologic, psychologic, and social common principles. The treatment of laryngeal cancer has evolved significantly over the prior 5 decades, and better diagnostic procedures, combined with an improved understanding of the anatomico-clinical behavior of laryngeal tumors, has allowed the development of external partial or "organ-preservation" laryngeal surgery. When total or partial laryngectomy procedures are performed,profound changes in anatomy and physiology and, thus,voice are inevitable.

Highlights from the Tenth World Conference on Lung Cancer.

Should adjuvant chemotherapy for resected non-small cell lung cancer (NSCLC) be the standard of care? That question has been much debated since the presentation of results from the International Adjuvant Lung Cancer Trial (IALT) in May 2003 at the plenary session of the American Society of Clinical Oncology annual meeting. The IALT study showed a statistically significant survival advantage for patients treated with cisplatin-based adjuvant chemotherapy. The topic of adjuvant chemotherapy permeated the Tenth World Conference on Lung Cancer held from August 10-14, 2003 in Vancouver, Canada.

Combined 5-fluorouracil/systemic interferon-beta gene therapy results in long-term survival in mice with established colorectal liver metastases.

Preclinical in vitro and in vivo studies have demonstrated synergistic interactions between 5-fluorouracil (5-FU) and type I and II IFNs against human colorectal cancer cells. Despite these activities, randomized human trials have failed to identify a clinical benefit for this combination treatment. These limited clinical results may be secondary to the short half-life of recombinant IFN protein and the increased systemic toxicities of 5-FU/IFN combinations.

Kv3.1b is a novel component of CNS nodes.

We herein demonstrate that Kv3.1b subunits are present at nodes of Ranvier in the CNS of both rats and mice. Kv3.

Mutations in Nop60B, the Drosophila homolog of human dyskeratosis congenita 1, affect the maintenance of the germ-line stem cell lineage during spermatogenesis.

Spermatogenesis in Drosophila is maintained by germ-line stem cells. These cells undergo self-renewing divisions and also generate daughter gonial cells, whose function is to amplify the germ cell pool. Gonial cells subsequently differentiate into spermatocytes that undergo meiosis and generate haploid gametes.

The role of positive examinations in training for the focused assessment sonogram in trauma (FAST) examination.

The purpose of this study is to determine whether the inclusion of known positive patients to the practical portion of a Focused Assessment Sonogram in Trauma (FAST) training course improves overall training and increases FAST accuracy. This is a prospective double-blind design. Original course participants (PRE) underwent a 2-hour didactic session and practicum with ten normal volunteers.

Fetal therapy: state of the art.

Objective: To review our experience with the use of sonography in evaluating potential candidates for in utero fetal therapy performed at The Center for Fetal Diagnosis and Treatment at The Children's Hospital of Philadelphia.

Methods: This review article was designed to discuss open hysterotomy for the 4 fetal surgical procedures that have been performed at our institution. The procedures included surgical repair of myelomeningocele, resection of sacrococcygeal teratoma in fetuses with nonimmune hydrops, resection of an enlarging congenital cystic adenomatoid malformation that is not amenable to thoracoamniotic shunting, and tracheal clip occlusion for severe left congenital diaphragmatic hernia.

Unique patterns of allelic imbalance distinguish type 1 from type 2 sporadic papillary renal cell carcinoma.

The molecular genetic correlates of a recently proposed subclassification of papillary renal cell carcinoma (PRCC) that designates tumors as type 1 and type 2 based on histological features have not yet been established. Alterations of known genes in PRCC include missense mutations in the MET oncogene (7q31) and rare translocations fusing TFE3 at Xp11.2 with a variety of other loci.

Recent progress on the molecular organization of myelinated axons.

The structure of myelinated axons was well described 100 years ago by Ramón y Cajal, and now their molecular organization is being revealed. The basal lamina of myelinating Schwann cells contains laminin-2, and their abaxonal/outer membrane contains two laminin-2 receptors, alpha6beta4 integrin and dystroglycan. Dystroglycan binds utrophin, a short dystrophin isoform (Dp116), and dystroglycan-related protein 2 (DRP2), all of which are part of a macromolecular complex.

Genetic dysmyelination alters the molecular architecture of the nodal region.

We have examined the molecular organization of axons in the spinal cords of myelin-deficient (md) rats, which have profound CNS dysmyelination associated with oligodendrocyte cell death. Although myelin sheaths are rare, most large axons are at least partially surrounded by oligodendrocyte processes. At postnatal day 7 (P7), almost all node-like clusters of voltage-gated Na+ channels and ankyrinG are adjacent to axonal segments ensheathed by oligodendrocytes, but at P21, many node-like clusters are found in axonal segments that lack oligodendrocyte ensheathment.

Mortised genioplasty in the treatment of obstructive sleep apnea: an historical perspective and modification of design.

We describe a modified technique for mortised genioglossus advancement for treating obstructive sleep apnea and review the history of osteotomies in this region. This new osteotomy technique allows for greater soft tissue advancement of the hypopharyngeal region. Anatomical data from a previous study were used to evaluate the dimensions of the anterior mandible and design an osteotomy that overcomes shortcomings of previous designs.

Larynx preservation with supracricoid partial laryngectomy with cricohyoidoepiglottopexy. Correlation of videostroboscopic findings and voice parameters.

Classically, the formation of a mucosal wave is dependent on the pliable mucosa present in the vocal fold. The supracricoid partial laryngectomy with cricohyoidoepiglottopexy is an organ preservation surgical technique in which both true vocal folds, both false vocal folds, both paraglottic spaces, and the entire thyroid cartilage are resected. The functional goal is speech and swallowing without a permanent tracheostomy.

Myelination: some receptors required.

Feltri et al. (2001)(this issue) succeed in disrupting beta 1 integrin specifically in Schwann cells, and in so doing, demonstrate that it is required for normal myelination. Their results reveal that signaling by an extracellular matrix receptor plays a key role in the differentiation of myelinating Schwann cells.

Bartholin's gland hyperplasia in a postmenopausal woman.

Background: Benign solid tumors of Bartholin's gland are rare, with only six cases reported in the English language literature since 1966. Bartholin's gland hyperplasia has not been described.

Case: A postmenopausal woman with painless bilateral vulvar masses underwent surgical removal of one of the masses, which revealed a well-circumscribed, nonencapsulated tumor composed of mucous glands and ducts within a dense fibrous stroma, most consistent with hyperplasia of Bartholin's gland.