Biomedical subjects

S L Keeling

Publications and source records attributed to S L Keeling.

8 recordsLinked to original sources

PubMed2001

Interstitial deletion 4q32-34 with ulnar deficiency: 4q33 may be the critical region in 4q terminal deletion syndrome.

We report on an infant with Robin sequence; mild developmental delay; a left ulnar ray defect with absent ulna and associated metacarpals, carpals and phalanges; and a right ulnar nerve hypoplasia. He had a de novo interstitial deletion of 4q32-->q34. The critical region involved in the 4q terminal deletion syndrome may be 4q33. This conclusion was suggested by showing that del(4)(q31qter), del(4)(q32qter), and del(4)(q33qter) result in a similarly severe phenotype. In addition, we propose that genes for distal arm development, in particular for development of the left ulnar ray, central nervous system development, and cleft lip and palate, may be located at 4q33.

Chromosome Banding↗

PubMed2001

Improved diffusion-weighted single-shot echo-planar imaging (EPI) in stroke using sensitivity encoding (SENSE).

Diffusion-weighted single-shot EPI (sshEPI) is one of the most important tools for the diagnostic assessment of stroke patients, but it suffers from well known artifacts. Therefore, sshEPI was combined with SENSitivity Encoding (SENSE) to further increase EPI's potential for stroke imaging. Eight healthy volunteers and a consecutive series of patients (N = 8) with suspected stroke were examined with diffusion-weighted SENSE-sshEPI using different reduction factors (1.0 < or = R < or = 3.0). Additionally, a high-resolution diffusion-weighted SENSE-sshEPI scan was included. All examinations were diagnostic and of better quality than conventional sshEPI. No ghostings or aliasing artifacts were discernible, and EPI-related image distortions were markedly diminished. Chemical shift artifacts and eddy current-induced image warping were still present, although to a markedly smaller extent. Measured direction-dependent diffusion-coefficients and isotropic diffusion values were comparable to previous findings but showed less fluctuation. We have demonstrated the technical feasibility and clinical applicability of diffusion-weighted SENSE-sshEPI in patients with subacute stroke. Because of the faster k-space traversal, this novel technique is able to reduce typical EPI artifacts and increase spatial resolution while simultaneously remaining insensitive to bulk motion.

Adult↗

PubMed2001

Mutational analysis in X-linked spondyloepiphyseal dysplasia tarda.

Spondyloepiphyseal dysplasia tarda (SEDT) is an X-linked recessive disorder characterized by short stature due to defective growth of the vertebral bodies. In addition, deformities of the femoral heads result in early onset secondary osteoarthritis of the hips. The disorder affects males only with heterozygous female carriers showing no consistent abnormalities. The gene causing SEDT, which is located on Xp22.12-p22.31, consists of 6 exons of which only exons 3, 4, 5, and 6 are translated to yield an 140 amino acid protein, referred to as SEDLIN. SEDLIN mutations have been observed in SEDT patients, and we have undertaken studies to characterize such mutations in four unrelated SEDT kindreds by DNA sequence analysis. We identified two nonsense and two intragenic deletional frameshift mutations. The nonsense mutations occurred in exons 4 (TGG-->TGA, Trp70Stop) and 6 (CGA-->TGA, Arg122Stop). Both of the intragenic deletions, which were approximately 750 bp and 1300-1445 bp in size, involved intron 5 and part of exon 6 and resulted in frameshifts that lead to premature termination (Stop) signals. Thus, all four mutations are predicted to result in truncated proteins. The results of our study expand the spectrum of SEDLIN mutations associated with SEDT, and this will help to elucidate further the role of this novel protein in the etiology of this form of osteochondrodysplasia.

Codon, Nonsense↗

PubMed2000

The spatial and temporal expression patterns of netrin receptors, DCC and neogenin, in the developing mouse retina.

Recently it has been demonstrated that the guidance of retinal ganglion cell (rgc) axons through the optic disc is dependent on the DCC/netrin-1 axonal guidance system. To gain further insight into the function of the netrin receptors, DCC and Neogenin, in retinal development we have studied the expression patterns of these receptors in the embryonic mouse retina. Neogenin mRNA was restricted to a single neural cell type, the rgc. However, strong Neogenin mRNA expression was observed in the extending fiber cells of the developing lens suggesting a role for Neogenin in the migration events shaping the early lens. Our studies demonstrated that DCC mRNA was expressed at high levels in chains of closely opposed neurons as they migrated towards the emerging mantle layer in the early retina (E12.5-E13.5) suggesting a role for DCC in the migration of neurons out of the ventricular zone. DCC protein expression was high on rgc axons as they actively navigated through the optic disc into the optic nerve. At birth, when the majority of rgc axons had projected through the optic disc, DCC protein was no longer detectable on the distal axonal segments within the optic nerve despite significant DCC protein expression on the proximal axonal membranes in the nerve fiber layer. These observations suggest that a localized down-regulation of DCC protein occurs on projecting axonal membranes once the DCC guidance function is no longer required. We also demonstrated that DCC mRNA and protein were expressed by amacrine cells and Müller glial cells while DCC mRNA was detected in horizontal cells. Taken together, these expression patterns suggest a role for DCC in axon outgrowth and/or pathfinding for a variety of retinal neurons and in the migration of newly born neurons within the developing retina.

Animals↗

PubMed1999

The Deleted in Colorectal Cancer netrin guidance system: a molecular strategy for neuronal navigation.

1. Neuronal migration is one of the principal events in laying out the architectural plan of the embryonic central nervous system (CNS). In addition, the correct navigation of axonal growth cones to their specific targets is essential for the establishment of the intricate network of axon projections found within the mature CNS. 2. The Deleted in Colorectal Cancer (DCC) guidance receptor, together with its ligands, the netrins, is now emerging as a major navigational system driving both neuronal and axonal migrations. Members of the netrin family of secreted guidance cues are also likely to be ligands for a second DCC-like receptor, neogenin. 3. The present paper reviews the current understanding of DCC-netrin-dependent axon pathfinding within the embryonic spinal cord and suggests novel modes of action for both DCC and neogenin.

Animals↗

PubMed1997

The expression patterns of guidance receptors, DCC and Neogenin, are spatially and temporally distinct throughout mouse embryogenesis.

To gain a better understanding of the role of DCC and Neogenin in neural and nonneural tissues during vertebrate development we have carried out in situ hybridization studies to determine their expression patterns throughout the mid to late stages of mouse embryogenesis. This analysis revealed striking contrasts in both the spatial and temporal expression patterns of these closely related molecules. While DCC mRNA expression was predominantly restricted to the developing central nervous system (CNS), Neogenin mRNA was detected in a broad spectrum of embryonic tissues. Outside the CNS, Neogenin expression was observed mainly in mesodermal derivatives such as organ primordia and cartilage condensations of many developing embryonic structures. Within the CNS, initiation of DCC expression correlated with the onset of neurogenesis and was maintained at high levels in all regions of the developing CNS actively undergoing neurogenesis. By E18.5, DCC expression was detected only in structures such as the olfactory bulb, the hippocampus, and the cerebellum, that are known to sustain active neurogenesis well into postnatal life. In contrast, Neogenin expression was weak in the early developing CNS but broadened and intensified as neurogenesis proceeded. In summary, these observations indicate that Neogenin is the predominant member of this subfamily in mesodermal tissues, while DCC and Neogenin may play complementary roles in the generation of the fully functional CNS.

Animals↗

PubMed1997

Mouse Neogenin, a DCC-like molecule, has four splice variants and is expressed widely in the adult mouse and during embryogenesis.

Neogenin is a member of the N-CAM family of cell adhesion molecules and is closely related to the DCC tumor suppressor gene product. Recently, it has been demonstrated that the DCC/Neogenin subfamily plays a key role in axonal guidance within the embryonic nervous system, however little is known about the function of DCC or Neogenin in non-neuronal tissues in vertebrates. To gain an understanding of Neogenin function outside of the nervous system we have cloned and sequenced the mouse homologue of Neogenin. We describe three alternatively spliced exons within the extracellular domain of Neogenin and a fourth alternatively spliced exon within the cytoplasmic domain. We further demonstrate that three of these alternatively spliced exons are developmentally regulated. Analysis of Neogenin mRNA expression showed that two distinct Neogenin transcripts are expressed at significant levels in a broad spectrum of adult mouse tissues and throughout the mid to late stages of embryogenesis. In situ hybridization studies on day 15.5 mouse embryos revealed that Neogenin is expressed widely throughout the developing mouse embryo, in both neuronal and non-neuronal tissues. These observations suggests that Neogenin may play an integral role in regulating differentiation programmes and/or cell migration events within many embryonic and adult tissues.

Alternative Splicing↗

PubMed1993

Deep venous thrombosis caused by femoral exostosis.

OBJECTIVE: To present the first case of deep venous thrombosis caused by femoral exostosis reported in Australia. CLINICAL FEATURES: An 11-year-old prepubertal Caucasian girl had a two-year history of a posterior femoral exostosis. She then presented with a deep venous thrombosis 24 hours after riding a horse for the first time. The deep venous thrombosis was diagnosed by Doppler ultrasound, which showed an intimate relationship between the femoral exostosis and the femoral vein. Coagulation abnormalities were excluded. INTERVENTION AND OUTCOME: The patient was given anticoagulation therapy with heparin intravenously and warfarin orally. The popliteal vein recanalised within two days. The exostosis was excised 10 weeks after initial presentation, with warfarin being continued for four weeks postoperatively. Two months after excision the patient was symptom free. CONCLUSIONS: It is possible for venous compression by an exostosis to result in thrombosis in a patient with no underlying coagulation abnormality. Palpation and plain radiography of the region will demonstrate the exostosis; ultrasound is the next investigation of choice.

Anticoagulants↗