Chiari malformations: diagnosis, treatments and failures.

Chiari malformations refer to abnormalities of the hindbrain originally described by the Austrian pathologist Hans Chiari in the early 1890s. These malformations range from herniation of the cerebellar tonsils through the foramen magnum to complete agenesis of the cerebellum. In this review, we review the different classification schemes of Chiari malformations. We discuss the different signs and symptoms that the two most common malformations present with and diagnostic criteria. We next discuss current treatment paradigms, including the new measure of possible in utero surgery to help decrease the incidence of Chiari type II malformations. There is also a small discussion of treatment failures and salvage procedures in these difficult cases. Chiari malformations are a difficult clinical entity to treat. As more is learned about the genetic and environmental factors relating to their characteristics, it will be interesting if we are able to predict which treatments are better suited for different patients. Similarly, with the evolution of in utero techniques especially for Chiari II malformations, it will be interesting to see if the incidence and practice of treating these difficult patients will change.

The atRA-responsive gene neuron navigator 2 functions in neurite outgrowth and axonal elongation.

Neuron navigator 2 (Nav2) was first identified as an all-trans retinoic acid (atRA)-responsive gene in human neuroblastoma cells (retinoic acid-induced in neuroblastoma 1, RAINB1) that extend neurites after exposure to atRA. It is structurally related to the Caenorhabditis elegans unc-53 gene that is required for cell migration and axonal outgrowth. To gain insight into NAV2 function, the full-length human protein was expressed in C. elegans unc-53 mutants under the control of a mechanosensory neuron promoter. Transgene expression of NAV2 rescued the defects in unc-53 mutant mechanosensory neuron elongation, indicating that Nav2 is an ortholog of unc-53. Using a loss-of-function approach, we also show that Nav2 induction is essential for atRA to induce neurite outgrowth in SH-SY5Y cells. The NAV2 protein is located both in the cell body and along the length of the growing neurites of SH-SY5Y cells in a pattern that closely mimics that of neurofilament and microtubule proteins. Transfection of Nav2 deletion constructs in Cos-1 cells reveals a region of the protein (aa 837-1065) that directs localization with the microtubule cytoskeleton. Collectively, this work supports a role for NAV2 in neurite outgrowth and axonal elongation and suggests this protein may act by facilitating interactions between microtubules and other proteins such as neurofilaments that are key players in the formation and stability of growing neurites.

The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway.

Autosomal dominant polycystic kidney disease (ADPKD) strikes 1 in 1000 individuals and often results in end-stage renal failure. Mutations in either PKD1 or PKD2 account for 95% of all cases [1-3]. It has recently been demonstrated that polycystin-1 and polycystin-2 (encoded by PKD1 and PKD2, respectively) assemble to form a cation channel in vitro [4]. Here we determine that the Caenorhabditis elegans PKD1 and PKD2 homologs, lov-1 [5] and pkd-2, act in the same pathway in vivo. Mutations in either lov-1 or pkd-2 result in identical male sensory behavioral defects. Also, pkd-2;lov-1 double mutants are no more severe than either of the single mutants, indicating that lov-1 and pkd-2 act together. LOV-1::GFP and PKD-2::GFP are expressed in the same male-specific sensory neurons and are concentrated in cilia and cell bodies. Cytoplasmic, nonnuclear staining in cell bodies is punctate, suggesting that one pool of PKD-2 is localized to intracellular membranes while another is found in sensory cilia. In contrast to defects in the C. elegans autosomal recessive PKD gene osm-5 [6-8], the cilia of lov-1 and pkd-2 single mutants and of lov-1;pkd-2 double mutants are normal as judged by electron microscopy, demonstrating that lov-1 and pkd-2 are not required for ultrastructural development of male-specific sensory cilia.

An autosomal recessive polycystic kidney disease gene homolog is involved in intraflagellar transport in C. elegans ciliated sensory neurons.

In this report, we show that the Caenorhabditis elegans gene osm-5 is homologous to the Chlamydomonas gene IFT88 and the mouse autosomal recessive polycystic kidney disease (ARPKD) gene, Tg737. The function of this ARPKD gene may be evolutionarily conserved: mutations result in defective ciliogenesis in worms [1], algae [2], and mice [2, 3]. Intraflagellar transport (IFT) is essential for the development and maintenance of motile and sensory cilia [4]. The biochemically isolated IFT particle from Chlamydomonas flagella is composed of 16 polypeptides in one of two Complexes (A and B) [5, 6] whose movement is powered by kinesin II (anterograde) and cytoplasmic dynein (retrograde) [7-9]. We demonstrate that OSM-5 (a Complex B polypeptide), DAF-10 and CHE-11 (two Complex A polypeptides), and CHE-2 [10], a previously uncategorized IFT polypeptide, all move at the same rate in C. elegans sensory cilia. In the absence of osm-5, the C. elegans autosomal dominant PKD (ADPKD) gene products [11] accumulate in stunted cilia, suggesting that abnormal or lack of cilia or defects in IFT may result in diseases such as polycystic kidney disease (PKD).

A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans.

The stereotyped mating behaviour of the Caenorhabditis elegans male is made up of several substeps: response, backing, turning, vulva location, spicule insertion and sperm transfer. The complexity of this behaviour is reflected in the sexually dimorphic anatomy and nervous system. Behavioural functions have been assigned to most of the male-specific sensory neurons by means of cell ablations; for example, the hook sensory neurons HOA and HOB are specifically required for vulva location. We have investigated how sensory perception of the hermaphrodite by the C. elegans male controls mating behaviours. Here we identify a gene, lov-1 (for location of vulva), that is required for two male sensory behaviours: response and vulva location. lov-1 encodes a putative membrane protein with a mucin-like, serine-threonine-rich amino terminus followed by two blocks of homology to human polycystins, products of the autosomal dominant polycystic kidney-disease loci PKD1 and PKD2. LOV-1 is the closest C. elegans homologue of PKD1. lov-1 is expressed in adult males in sensory neurons of the rays, hook and head, which mediate response, vulva location, and potentially chemotaxis to hermaphrodites, respectively. PKD-2, the C. elegans homologue of PKD2, is localized to the same neurons as LOV-1, suggesting that they function in the same pathway.

Identification of Ste4 as a potential regulator of Byr2 in the sexual response pathway of Schizosaccharomyces pombe.

A conserved MAP kinase cascade is central to signal transduction in both simple and complex eukaryotes. In the yeast Schizosaccharomyces pombe, Byr2, a homolog of mammalian MAPK/ERK kinase kinase and Saccharomyces cerevisiae STE11, is required for pheromone-induced sexual differentiation. A screen for S. pombe proteins that interact with Byr2 in a two-hybrid system led to the isolation of Ste4, a protein that is known to be required for sexual function. Ste4 binds to the regulatory region of Byr2. This binding site is separable from the binding site for Ras1. Both Ste4 and Ras1 act upstream of Byr2 and act at least partially independently. Ste4 contains a leucine zipper and is capable of homotypic interaction. Ste4 has regions of homology with STE50, an S. cerevisiae protein required for sexual differentiation that we show can bind to STE11.

Professional attitudes regarding counseling of hearing-impaired adults.

To determine contemporary thinking regarding initial counseling of hearing-impaired adults 500 questionnaires were mailed to otologists and otolaryngologists and 500 to clinical audiologists. Usable questionnaires total 136 for the former group and 266 for the latter. Some significant differences were found in the ways clinicians saw themselves as counselors and in the needs they perceived their patients as having. Respondents reported experiencing various methods of training and possessing diverse attitudes about the effectiveness of their preparation as counselors during their professional training.

Clinical ventilation imaging with In-113m aerosol: a comparison with Kr-81m.

Following routine ventilation (Kr-81m)/perfusion (Tc-99m) scanning, we obtained aerosol ventilation scans using a solution of In-113m albumin and a settling-bag system. The large-volume settling bag reduces deposition of particles in the large airway by removing large droplets. The patient inhales the aerosol with 5-10 min of tidal breathing, then lung scans are obtained on a gamma camera. The energy of In-113m allows the ventilation scanning to be performed after Tc-99m perfusion scanning. Semiquantitative scoring of regional ventilation showed a close correlation (r = 0.97) between Kr-81m and In-113m aerosol ventilation scans. The aerosol technique gave a slight underestimation of ventilation compared with Kr-81m. This is explained by a slightly reduced penetration of particles to the periphery of the lung in patients with severe obstructive airways disease. In all cases, however, the aerosol did visualize all ventilated regions. The results indicate that this readily available aerosol technique can be useful for clinical ventilation imaging in multiple views.