PubMed Health⌕ Search

Biomedical subjects

K M Allen

Publications and source records attributed to K M Allen.

At least 19 recordsLinked to original sources
PubMed2004

Bone biomechanical properties in LRP5 mutant mice.

The mutation responsible for the high bone mass (HBM) phenotype has been postulated to act through the adaptive response of bone to mechanical load resulting in denser and stronger skeletons in humans and animals. The bone phenotype of members of a HBM family is characterized by normally shaped bones that are exceptionally dense, particularly at load bearing sites [Cancer Res. 59 (1999) 1572]. The high bone mass (HBM) mutation was identified as a glycine to valine substitution at amino acid residue 171 in the gene coding for low-density lipoprotein receptor-related protein 5 (LRP5) [Bone Miner. Res. 16(4) (2001) 758]. Thus, efforts have focused on the examination of the role of LRP5 and the G171V mutation in bone mechanotransduction responses [J. Bone Miner. Res 18 (2002) 960]. Transgenic mice expressing the human G171V mutation have been shown to have skeletal phenotypes remarkably similar to those seen in affected individuals. In this study, we have identified differences in biomechanical (structural and apparent material) properties, bone mass/ash, and bone stiffness of cortical and cancellous bone driven by the G171V mutation in LRP5. As in humans, the LRP5 G171V plays an important role in regulating bone structural phenotypes in mice. These bone phenotypes include greater structural and apparent material properties in HBM HET as compared to non-transgenic littermates (NTG) mice. Body size and weight in HBM HET were similar to that in NTG control mice. However, the LRP5 G171V mutation in HET mice results in a skeleton that has greater structural (femoral shaft, femoral neck, tibiae, vertebral body) and apparent material (vertebral body) strength, percent bone ash weight (ulnae), and tibial stiffness. Despite similar body weight to NTG mice, the denser and stiffer bones in G171V mice may represent greater bone formation sensitivity to normal mechanical stimuli resulting in an overadaptation of skeleton to weight-related forces.

Amino Acid Substitution↗
PubMed2000

Cross-cultural differences in tolerance for crowding: fact or fiction?

It is widely believed that cultures vary in their tolerance for crowding. There is, however, little evidence to substantiate this belief, coupled with serious shortcomings in the extant literature. Tolerance for crowding has been confused with cultural differences in personal space preferences along with perceived crowding. Furthermore, the few studies that have examined cultural variability in reactions to crowding have compared subgroup correlations, which is not equivalent to a statistical interaction. Although the authors found a statistical interaction indicating that Asian Americans and Latin Americans differ in the way they perceive crowding in comparison to their fellow Anglo-American and African American citizens, all four ethnic groups suffer similar, negative psychological distress sequelae of high-density housing. These results hold independently of household income.

Adult↗
PubMed1999

Release of Ca(2+) from intracellular stores and entry of extracellular Ca(2+) are involved in sea squirt sperm activation.

A rise in intracellular free Ca(2+) concentration ([Ca(2+)](i)) is required to activate sperm of all organisms studied. Such elevation of [Ca(2+)](i) can occur either by influx of extracellular Ca(2+) or by release of Ca(2+) from intracellular stores. We have examined these sources of Ca(2+) in sperm from the sea squirt Ascidia ceratodes using mitochondrial translocation to evaluate activation and the Ca(2+)-sensitive dye fura-2 to monitor [Ca(2+)](i) by bulk spectrofluorometry. Sperm activation artificially evoked by incubation in high-pH seawater was inhibited by reducing seawater [Ca(2+)], as well as by the presence of high [K(+)](o) or the Ca channel blockers pimozide, penfluridol, or Ni(2+), but not nifedipine or Co(2+). The accompanying rise in [Ca(2+)](i) was also blocked by pimozide or penfluridol. These results indicate that activation produced by alkaline incubation involves opening of plasmalemmal voltage-dependent Ca channels and Ca(2+) entry to initiate mitochondrial translocation. Incubation in thimerosal or thapsigargin, but not ryanodine (even if combined with caffeine pretreatment), evoked sperm activation. Activation by thimerosal was insensitive to reduced external calcium and to Ca channel blockers. Sperm [Ca(2+)](i) increased upon incubation in high-pH or thimerosal-containing seawater, but only the high-pH-dependent elevation in [Ca(2+)](i) could be inhibited by pimozide or penfluridol. Treatment with the protonophore CCCP indicated that only a small percentage of sperm could release enough Ca(2+) from mitochondria to cause activation. Inositol 1,4,5-trisphosphate (IP(3)) delivered by liposomes or by permeabilization increased sperm activation. Both of these effects were blocked by heparin. We conclude that high external pH induces intracellular alkalization that directly or indirectly activates plasma membrane voltage-dependent Ca channels allowing entry of external Ca(2+) and that thimerosal stimulates release of Ca(2+) from IP(3)-sensitive intracellular stores.

Animals↗
PubMed1999

Characterization of mutations in the gene doublecortin in patients with double cortex syndrome.

Mutations in the X-linked gene doublecortin, which encodes a protein with no dear structural homologues, are found in pedigrees in which affected females show "double cortex" syndrome (DC; also known as subcortical band heterotopia or laminar heterotopia) and affected males show X-linked lissencephaly. Mutations in doublecortin also cause sporadic DC in females. To determine the incidence of doublecortin mutations in DC, we investigated a cohort of eight pedigrees and 47 sporadic patients with DC for mutations in the doublecortin open reading frame as assessed by single-stranded conformational polymorphism analysis. Mutations were identified in each of the eight DC pedigrees (100%), and in 18 of the 47 sporadic DC patients (38%). Identified mutations were of two types, protein truncation mutations and single amino acid substitution mutations. However, pedigrees with DC displayed almost exclusively single amino acid substitution mutations, suggesting that patients with these mutations may have less of a reproductive disadvantage versus those patients with protein truncation mutations. Single amino acid substitution mutations were tightly clustered in two regions of the open reading frame, suggesting that these two regions are critical for the function of the Doublecortin protein.

Brain Diseases↗
PubMed1999

Studies of the candidate genes in X-linked congenital cerebellar hypoplasia.

A gene for X-linked congenital cerebellar hypoplasia was recently localized to chromosome Xp11.21-q24. This region comprises several brain-specific genes responsible for various neurological disorders, including the proteolipid protein (PLP), doublecortin, and PAK3 genes. We screened these genes for mutations in patients with X-linked congenital cerebellar hypoplasia and found no pathogenic nucleotide changes or gene dose alterations. These findings allow the ruling out of PLP, doublecortin, and PAK3 as the disease-causing genes in this hereditary neurological syndrome.

Cerebellum↗
PubMed1999

Genes that regulate neuronal migration in the cerebral cortex.

Malformations of cortical development are increasingly recognized as causes of mental retardation and epilepsy. However, little is known about the molecular and biochemical signals that control the proliferation, migration, and organization of the cells involved in normal cerebral cortical development. Analysis of genes required for cortical development will help elucidate the pathogenesis of some epilepsies. In humans, two striking examples of abnormal cortical development, with varying degrees of epilepsy and mental retardation, are 'double cortex' and lissencephaly. Double cortex (DC), also known as subcortical band heterotopia, shows an abnormal band of neurons in the white matter underlying a relatively normal cortex. In pedigrees, DC often occurs in females, whereas affected males show more severe lissencephaly (XLIS), i.e. an abnormally thick cortex with decreased or absent surface convolutions. We and others have identified a novel brain specific gene, doublecortin, that is mutated in Double Cortex/X-linked lissencephaly (DC/XLIS) patients. Although the cellular function of doublecortin (DCX) is unknown, sequence analysis reveals a cytoplasmic protein with potential MAP kinase phosphorylation sites, as well as a site that is likely to be phosphorylated by c-Abl, suggesting that doublecortin functions as an intracellular signaling molecule critical for the migration of developing neurons. Interestingly, the scrambler mouse mutant demonstrates abnormal lamination with some similarity to lissencephaly and reflects a mutation in the murine homolog of the Drosophila disabled gene, mdab1, which binds c-Abl. Although a direct interaction between doublecortin and mDab1 has not been demonstrated, it is plausible that these two proteins may be part of a common signaling pathway. Therefore, abnormalities in signal transduction may be an underlying mechanism for the neuronal migration defects in DC/XLIS and the scrambler mouse, but further research is necessary to determine how such abnormalities give rise to cortical malformations and epilepsy.

Animals↗
PubMed1998

A YAC contig in Xq22.3-q23, from DXS287 to DXS8088, spanning the brain-specific genes doublecortin (DCX) and PAK3.

Although several genes for mental retardation and epilepsy, including double cortex/X-linked lissencephaly (DC/XLIS), have been localized to Xq21.3-q23, there has been no complete physical map of this region available. We constructed a YAC/STS contig map by initiating two yeast artificial chromosome (YAC) walks from the markers that flanked the DC/XLIS candidate gene region. We report an approximately 4-Mb contig extending from DXS287 to DXS8088, encompassing DXS1072 and DXS1059, and composed of 52 YACs identified with 15 previously published STSs and 19 novel YAC-end STSs. This contig also contains two brain-specific genes, doublecortin (HGMW-approved symbol DCX), responsible for DC/XLIS, and PAK3, which may be responsible for neurological diseases localized to this region. The new contig extends and incorporates several previously published contigs, providing a total overlapping contig extending approximately 34 Mb from DXS441 in Xq13.1 to DXS8088 in Xq23.

Brain↗
PubMed1998

Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein.

X-linked lissencephaly and "double cortex" are allelic human disorders mapping to Xq22.3-Xq23 associated with arrest of migrating cerebral cortical neurons. We identified a novel 10 kb brain-specific cDNA interrupted by a balanced translocation in an XLIS patient that encodes a novel 40 kDa predicted protein named Doublecortin. Four double cortex/X-linked lissencephaly families and three sporadic double cortex patients show independent doublecortin mutations, at least one of them a de novo mutation. Doublecortin contains a consensus Abl phosphorylation site and other sites of potential phosphorylation. Although Doublecortin does not contain a kinase domain, it is homologous to the amino terminus of a predicted kinase protein, indicating a likely role in signal transduction. Doublecortin, along with the newly characterized mDab1, may define an Abl-dependent pathway regulating neuronal migration.

Amino Acid Sequence↗
PubMed1998

PAK3 mutation in nonsyndromic X-linked mental retardation.

Nonsyndromic X-linked mental retardation (MRX) syndromes are clinically homogeneous but genetically heterogeneous disorders, whose genetic bases are largely unknown. Affected individuals in a multiplex pedigree with MRX (MRX30), previously mapped to Xq22, show a point mutation in the PAK3 (p21-activated kinase) gene, which encodes a serine-threonine kinase. PAK proteins are crucial effectors linking Rho GTPases to cytoskeletal reorganization and to nuclear signalling. The mutation produces premature termination, disrupting kinase function. MRI analysis showed no gross defects in brain development. Immunofluorescence analysis showed that PAK3 protein is highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus. Signal transduction through Rho GTPases and PAK3 may be critical for human cognitive function.

Animals↗
PubMed1998

LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation.

Classical lissencephaly (LIS) is a neuronal migration disorder resulting in brain malformation, epilepsy and mental retardation. Deletions or mutations of LIS1 on 17p13.3 and mutations in XLIS ( DCX ) on Xq22.3-q23 produce LIS. Direct DNA sequencing of LIS1 and XLIS was performed in 25 children with sporadic LIS and no deletion of LIS1 by fluorescence in situ hybridization. Mutations of LIS1 were found by sequencing ( n = 8) and Southern blot ( n = 2) in a total of 10 patients (40%) of both sexes and mutations of XLIS in five males (20%). Combined with previous data, deletions or mutations of these two genes account for approximately 76% of isolated LIS. These data demonstrate that LIS1 and XLIS mutations cause the majority of, though not all, human LIS. The mutations in LIS1 were predicted to result in protein truncation in six of eight patients and splice site mutations in two, all of which disrupt one or more of the seven WD40 repeats contained in the LIS1 protein. Point mutations in XLIS identified the C-terminal serine/proline-rich region as potentially important for protein function. The patients with mutations were included in a genotype-phenotype analysis of 32 subjects with deletions or other mutations of these two genes. Whereas the brain malformation due to LIS1 mutations was more severe over the parietal and occipital regions, XLIS mutations produced the reverse gradient, which was more severe over the frontal cortex. The distinct LIS patterns suggest that LIS1 and XLIS may be part of overlapping, but distinct, signaling pathways that promote neuronal migration.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1997

Genomic imprinting and audiogenic seizures in mice.

Audiogenic seizure (AGS) susceptibility in mice is a multifactorial behavioral disorder that involves severe generalized convulsions in response to loud, high-frequency sound. The inheritance of AGS susceptibility was examined in crosses between AGS-susceptible DBA/2J (D2) mice and epilepsy-prone (EP) mice. The EP mice were selected for high AGS susceptibility in a BALB/c-derived line. The AGS phenotype was similar in the EP and D2 mice at 30 days of age. The frequency of generalized clonic-tonic AGS was high in both the D2 and the EP mice (53 and 83%, respectively) but was low in the reciprocal EPD2F1 and D2EPF1 hybrids (14 and 19%, respectively). In the backcross to the EP parent, no significant associations were found between AGS susceptibility and microsatellite markers linked to Asp1 or Asp2, AGS genes located on Chromosomes 12 and 4, respectively. Significant associations were found for markers linked to Asp3, which is located in the proximal region of Chromosome 7. The influence of Asp3 on AGS susceptibility was seen in the EP x EPD2F1 backcross but not in the reciprocal EPD2F1 x EP backcross, suggesting that Asp3 expression is influenced by genomic imprinting. A model is proposed where genomic imprinting represses the maternal Asp3 allele, providing an influence largely from the paternal allele.

Acoustic Stimulation↗
PubMed1997

Linkage and physical mapping of X-linked lissencephaly/SBH (XLIS): a gene causing neuronal migration defects in human brain.

While disorders of neuronal migration are associated with as much as 25% of recurrent childhood seizures, few of the genes required to establish neuronal position in cerebral cortex are known. Subcortical band heterotopia (SBH) and lissencephaly (LIS), two distinct neuronal migration disorders producing epilepsy and variable cognitive impairment, can be inherited alone or together in a single pedigree. Here we report a new genetic locus, XLIS, mapped by linkage analysis of five families and physical mapping of a balanced X;2 translocation in a girl with LIS. Linkage places the critical region in Xq21-q24, containing the breakpoint that maps to Xq22.3-q23 by high-resolution chromosome analysis. Markers used for somatic cell hybrid and fluorescence in situ hybridization analyses place the XLIS region within a 1 cM interval. These data suggest that SBH and X-linked lissencephaly are caused by mutation of a single gene, XLIS, that the milder SBH phenotype in females results from random X-inactivation (Lyonization), and that cloning of genes from the breakpoint region on X will yield XLIS.

Cerebral Cortex↗
PubMed1997

Outcome of trauma patients after brief intervention by a substance abuse consultation service.

The Substance Abuse Consultation Service (SACS) at the University of Maryland Medical System (UMMS) conducts assessments and brief interventions for patients at the University Hospital and the Shock Trauma Center of the UMMS. This project examined a 10-week sample of trauma patients (N = 30) seen by the SACS, for whom consultations and recommendations (including participation in formal treatment programs as well as 12-step meetings) were provided. The authors used medical record reviews for background information and telephone interviews for follow-up. Of 22 subjects reached by telephone, 6 reported that they had followed the SACS recommendations completely or partially, and 16 subjects reported they had not. Of the latter group, a majority reported self-imposed abstinence or decreased use. No relationships existed between demographic characteristics or patterns of substance abuse and whether or not subjects acted upon SACS recommendations.

Adult↗
PubMed1996

Analytical methodology in quantitative digital subtraction radiography: analyses of the aluminum reference wedge.

An aluminum wedge can be used to quantify volumetric change in crestal alveolar bone which has been identified through subtraction radiography. This study compares two methods for using an aluminum wedge for this purpose: 1) the aluminum wedge is present in both radiographs and used to determine the aluminum equivalent bone density present in the region of change for each radiograph; and 2) the aluminum wedge is present in only one radiograph and the difference image of the wedge in the subtraction image is used to calculate the aluminum equivalent change in bone density. Pairs of standardized x-rays were taken with synthetic bone chips of known weights placed when the second x-ray was taken. The volumetric change produced by the bone chips was calculated by the two methods. The relationship of the calculated volumes to the chip weights had a higher r2 value (P < 0.05) for the two-wedge method than for the one-wedge method. The two-wedge method is recommended for volumetric quantification of alveolar bone change. The influence of the clarity of the aluminum wedge image in the x-ray pairs was also examined in this study and found to be significant. Attention must be given to factors which affect the aluminum wedge image characteristics to achieve optimal results.

Aluminum↗
PubMed1995

Model fit and measurement outcome in attachment measurements: a simulation study.

Serial attachment level measurements were simulated based on 2 hypothetical models of true change: 1) a burst model, where attachment changes rapidly over the duration of one measurement interval, but is unchanging before and after, and 2) a linear model, where attachment changes at a constant rate over time. Normally distributed measurement error was added to the modeled attachment level change to produce the series of measurement simulations. It was then determined for each series whether a burst model or a linear model best fit the simulated measurement series for a range of overall attachment level changes. For series generated by a burst model, the burst model fit better than a linear model a significant proportion of the time at all attachment level changes. However, for series generated by a linear model, the burst model provided the best fit for attachment level changes that were less than 4 times the standard deviation of the measurement error. Estimates of change based on a linear model slightly overestimated change when the true underlying model was a burst model. Estimates of change based on a burst model slightly underestimated change when the true model was a burst model, but substantially underestimated change when the underlying model was a linear model. Model fit when assessed by the least squares criterion may not be a reliable guide to model validity.

Bias↗