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Biomedical subjects

J Nelson

Publications and source records attributed to J Nelson.

At least 37 records · Page 2Linked to original sources
PubMed2001

Advanced glycation alters expression of the 67kDa laminin receptor in retinal microvascular endothelial cells.

The 67kDa laminin receptor (67LR) plays an important role in vascular cell function and dysfunction. The present study has examined 67LR expression in retinal microvascular endothelial cells after exposure to AGEs. Retinal microvascular endothelial cells were exposed to either AGE-BSA, or were grown on methylglyoxal-modified laminin or Matrigel and expression of 67LR analysed by Western Blotting and RT-PCR/Southern blotting. Western blotting of plasma membrane and RT-PCR/Southern blotting revealed a significant upregulation of 67LR protein/mRNA expression after exposure to AGEs (p<0.05-0.01). The results show that 67LR is upregulated in cells exposed to AGEs and suggests a previously unrecognised role for this receptor in retinal microvascular endothelial cell interaction with glycated substrates.

Animals↗
PubMed2001

Genomewide survey of panic disorder.

We completed a genome scan of 23 multiplex families of panic disorder. Ninety family members had DSM-III-R panic disorder, and another 23 had recurrent, spontaneous panic attacks that did not satisfy these criteria. We typed 469 markers from the CHLC map (ver 8c7) with an average intermarker distance of 10.3 cM. Two-point lod scores were calculated with both a dominant and a recessive model, and maps of lod scores < -2.00, assuming genetic homogeneity, were constructed by using DSM-III-R panic disorder as the affected phenotype. Lod scores were < -2.00 over 94-95% of the genome. The greatest lod score was 2.23 (theta = 0.15) at the D7S2846 locus, located at 57.8 cM on chromosome 7 according to the Marshfield Clinic map. Flanking markers analyzed in a nonparametric, multipoint analysis using GENEHUNTER resulted in an NPL score of 2.97 at 63 cM on the Marshfield map. This region lies within 15 cM from the D7S435 locus, where Knowles et al. [1998] obtained a lod score of 1.71 (theta = 0.10) for panic disorder (now 2.45 with the addition of new families; James Knowles, personal communication). Thus, the maximum evidence of linkage from two genome scans of panic disorder lies within a small region of chromosome 7p.

Adult↗
PubMed2001

ICB database: the gyrB database for identification and classification of bacteria.

The Identification and Classification of Bacteria (ICB) database (http:/www.mbio.co.jp/icb) contains currently available information about the DNA gyrase subunit B (gyrB) gene in bacteria. The database is designed to provide the scientific community with a reference point for using gyrB as an evolutionary and taxonomic marker. Nucleic and amino acid sequence data are currently available for over 850 strains, along with alignments at several different taxonomic levels and an exhaustive review of primer selection and background information.

Bacteria↗
PubMed2001

Quantitative brain magnetic resonance imaging in girls with attention-deficit/hyperactivity disorder.

BACKGROUND: Anatomic studies of boys with attention-deficit/hyperactivity disorder (ADHD) have detected decreased volumes in total and frontal brain, basal ganglia, and cerebellar vermis. We tested these findings in a sample of girls with ADHD. METHODS: Anatomic brain magnetic resonance images from 50 girls with ADHD, of severity comparable with that in previously studied boys, and 50 healthy female control subjects, aged 5 to 15 years, were obtained with a 1.5-T scanner with contiguous 2-mm coronal slices and 1.5-mm axial slices. We measured volumes of total cerebrum, frontal lobes, caudate nucleus, globus pallidus, cerebellum, and cerebellar vermis. Behavioral measures included structured psychiatric interviews, parent and teacher ratings, and the Wechsler vocabulary and block design subtests. RESULTS: Total brain volume was smaller in girls with ADHD than in control subjects (effect size, 0.40; P =.05). As in our previous study in boys with ADHD, girls with ADHD had significantly smaller volumes in the posterior-inferior cerebellar vermis (lobules VIII-X; effect size, 0.54; P =.04), even when adjusted for total cerebral volume and vocabulary score. Patients and controls did not differ in asymmetry in any region. Morphometric differences correlated significantly with several ratings of ADHD severity and were not predicted by past or present stimulant drug exposure. CONCLUSIONS: These results confirm previous findings for boys in the posterior-inferior lobules of the cerebellar vermis. The influence of the cerebellar vermis on prefrontal and striatal circuitry should be explored.

Adolescent↗
PubMed2001

Management of heparin allergy in pregnancy.

Thromboembolic disease during pregnancy has traditionally been treated with heparin. If heparin cannot be used, then treatment options remain limited. Despite the recent availability of new anticoagulation agents, data relating to their use during pregnancy is lacking. Hirudin, a relatively new anti-thrombotic agent, through animal models has been shown to have a very low transplacental transfer, thus making it a candidate drug to be used during pregnancy in case of heparin allergy. This report describes a case of heparin allergy in a pregnant patient with recurrent DVT that was successfully managed with hirudin and coumadin.

Adult↗
PubMed2001

Karyotype, phenotype and parental origin in 19 cases of triploidy.

The parental origin of triploidy in 19 cases was examined by inheritance of DNA microsatellites and by methylation patterns of SNRPN or PW71 (where parents' blood was unavailable). The fetal and placental morphology on these cases was reviewed. The phenotype of the fetuses with non-mosaic triploidy was assessed in relation to the two types described by McFadden and Kalousek. Of the diandric fetuses three of the six showed mild-to-moderate symmetrical growth retardation and the other three had growth characteristics in accordance with their gestational ages. This study would suggest the fetal triploid 'Type 1' definition be modified to 'well grown to moderate symmetrical IUGR' to allow for such variation. In the digynic fetuses (McFadden/Kalousek Type 2) there were poor growth characteristics with IUGR being more severe and asymmetrical. The diandric fetuses were as common as digynic fetuses in this series. The ratio of diandric to digynic specimens was 11:8 but if only fetal specimens (not embryos or mosaic children) were included the ratio was 6:5. Many diandric conceptions end as partial moles but later in gestation diandric fetuses may be well grown. It is proposed that there may be a survival barrier for diandric fetuses early in gestation (possibly based on the proportion of vascularised placental villi), although once this is passed the diandric fetuses are comparatively more viable and better grown than digynic fetuses. In the XXY triploid fetuses, 5/6 had hypoplastic or ambiguous external genitalia (two were recorded as of female phenotype) as has been reported previously. In these, the gonadal histology was testicular in all the diandrics but in the single digynic XXY case, sex reversal was complete with normal uterus and Fallopian tubes and the gonads were histologically ovaries. Two triploid/diploid mosaics were proven to be due to digyny. The probable cause is delayed incorporation of the second polar body into a blastomere and there was evidence of identical alleles from the same sperm being present in both diploid and triploid cells. In one of these triploid/diploid mosaics in which there was a termination of pregnancy (TOP) after prenatal karyotyping the diploid cell line had trisomy 16 which was not evident in the triploid line. This trisomy was probably of post-zygotic origin and we suggest the fetus was rescued by the prominence of the triploid line.

Abortion, Spontaneous↗
PubMed2001

Expression of the 67 kDa laminin receptor (67LR) during retinal development: correlations with angiogenesis.

Interaction of vascular cells with the laminin component of basement membranes is important for normal cell function. Likewise, abnormal interactions may have a critical role in vascular pathology. It has been previously demonstrated that the 67 kDa laminin receptor (67LR) is expressed at high levels during proliferative retinopathy in a mouse model and in the current study we have examined 67LR in the neonatal mouse to determine if this receptor plays a role in aspects of developmental angiogenesis in the developing murine retina. Groups of C57/BL6 mice were killed at postnatal day P1, P3, P5, P7, P9 and P11 to assess the retinal vasculature. A number of mice were perfused with FITC-dextran and the eyes removed, fixed in 4% paraformaldehyde (PFA) and flat-mounted for confocal scanning laser microscopy. The eyes from the remaining mice were either placed in 4% PFA and embedded in paraffin-wax, or had the neural retina dissected off and total RNA or protein extracted. Immunofluorescence, in situ hybridization, quantitative reverse transcriptase polymerase chain reaction and Western blotting analysis were employed to locate and determine expression levels of 67LR. Both 67LR mRNA and protein expression showed a characteristic bi-phasic expression pattern which correlated with key stages of retinal vascular development in the murine retina. 67LR showed high expression levels at P1 (P < 0.05) (correlating with superficial vascular plexus formation) and at P7 (P < 0.05) (correlating with deep vascular plexus formation). Conversely, 67LR expression was decreased when active angiogenic activity was lowest. Significantly, optical sectioning of retinal flat-mounts revealed high levels of 67LR expression in developing segments of both superficial and deep capillary plexi, a pattern which co-localized strongly with laminin. 67LR is regulated during post-natal development of the retinal vasculature. High levels of 67LR during the two well-defined phases of retinal capillary plexus formation suggests that this receptor may play an important role in retinal angiogenesis.

Animals↗
PubMed2001

Lethal X-linked microcephaly with dysmorphic features, bilateral optic pathway aplasia and normal eyes.

We describe a family, consisting of two brothers and a maternal uncle who died of an apparently identical condition, within a few days of birth, suggestive of an X-linked mode of inheritance. The propositus (the older sibling) was investigated in detail and showed the following clinical features: microcephaly, facial dysmorphism, malformations of hands and feet, and cryptorchidism. Examination of the brain revealed arhinencephaly, a primitive gyral pattern, arrested cortical maturation, absence of corticofugal tracts and corpus callosum, agenesis of the optic pathway with preserved eyes and oculomotor system, absent auditory pathway, agenesis of the pars compacta of the substantia nigra and severe hypoplasia of the cerebellum and its connections. This family belongs to the group of X-linked microcephalies and has some features in common with the Juberg-Marsidi syndrome. The fact that the CNS abnormalities were incompatible with life and the facial dysmorphic features were quite different makes it unlikely that the affected individuals in this family had Juberg-Marsidi syndrome. However, this does not exclude the possibility that more restricted anterior induction defects may occur in some X-linked microcephalies such as Juberg-Marsidi syndrome resulting in prolonged survival.

Eye↗
PubMed2001

Electron self-exchange kinetics in two average-valence dicopper cryptates.

Electron self-exchange rates, reported for two average-valence dicopper cryptates are, at around 10(5) M-1 s-1, at the high end of the range for small-molecule model compounds. The cross-exchange reaction rate, and those for oxidation with [Co(ox)3]3-, are consistent with an outer-sphere reaction mechanism. Despite the necessity for copper-copper bond making and breaking in the course of redox for one of the cryptates, the self-exchange rate is not decreased relative to the other cryptate, showing that this step is not rate limiting.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed2001

Unexpected and variable phenotypes in a family with JAK3 deficiency.

Mutations of the Janus kinase 3 (JAK3) have been previously described to cause an autosomal recessive variant of severe combined immunodeficiency (SCID) usually characterized by the near absence of T and NK cells, but preserved numbers of B lymphocytes (T-B+SCID). We now report a family whose JAK3 mutations are associated with the persistence of circulating T cells, resulting in previously undescribed clinical presentations, ranging from a nearly unaffected 18-year-old subject to an 8-year-old sibling with a severe lymphoproliferative disorder. Both siblings were found to be compound heterozygotes for the same deleterious JAK3 mutations: an A96G initiation start site mutation, resulting in a dysfunctional, truncated protein product and a G2775(+3)C mutation in the splice donor site sequence of intron 18, resulting in a splicing defect and a predicted premature stop. These mutations were compatible with minimal amounts of functional JAK3 expression, leading to defective cytokine-dependent signaling. Activated T cells in these patients failed to express Fas ligand (FasL) in response to IL-2, which may explain the accumulation of T cells with an activated phenotype and a skewed T cell receptor (TcR) Vbeta family distribution. We speculate that residual JAK3 activity accounted for the maturation of thymocytes, but was insufficient to sustain IL-2-mediated homeostasis of peripheral T cells via Fas/FasL interactions. These data demonstrate that the clinical spectrum of JAK3 deficiency is quite broad and includes immunodeficient patients with accumulation of activated T cells, and indicate an essential role for JAK3 in the homeostasis of peripheral T cells in humans.

Adolescent↗
PubMed2001

Novel keratin 17 mutations in pachyonychia congenita type 2.

Pachyonychia congenita type 2 is an inherited ectodermal dysplasia characterized by hypertrophic nail dystrophy and multiple pilosebaceous cysts. Focal nonepidermolytic palmoplantar keratoderma, natal teeth, and pili torti may also be present. Epithelial tissues affected in pachyonychia congenita type 2 express the keratin pair K6b/K17. Here, we report three novel heterozygous mutations in the K17 gene (KRT17A) in patients presenting with pachyonychia congenita type 2. These mutations, R94-98del (deletion of the peptide sequence RLASY) and missense mutations R94P and L95Q, are all within the 1A domain hotspot for pathogenic keratin mutations.

Base Sequence↗
PubMed2001

Enhancement of human osteoblast proliferation and phenotypic expression when cultured in human serum.

Traditionally, culture medium is supplemented with foetal bovine serum (FBS). However, in cultures of osteoblasts intended for human re-implantation, such serum presents potential risks of foreign protein contamination and transmission of viral or prion-related material, if used. We cultured human osteoblasts from 16 patients in 10% autologous human serum, 10% pooled human serum, 10% FBS or 2% Ultroser G. Non-synthetic sera were tested in both heat-treated and non-heat-treated forms. We determined cell growth and osteoblast phenotype. Cell proliferation in all types of human serum was significantly greater than in FBS. This was most marked in heat-treated autologous human serum. Cells cultured in Ultroser G had less proliferation than all other groups. The phenotypic tests showed that cells cultured in human and foetal bovine serum displayed an osteoblast phenotype, with greater protein expression in cells cultured in human serum. We conclude that culture of human osteoblasts in autologous human serum enhances cell proliferation, while maintaining an osteoblast phenotype. These findings have implications for the use of cultured osteoblasts in self-cell therapy. Human osteoblast growth is supported by autologous human serum, which allows re-implantation of cultured cells, while avoiding the risk of foreign protein carry-over with enhancement of cell proliferation.

Aged↗
PubMed2001

Health span and life span in transgenic mice with modulated DNA repair.

One way to better understand the contribution of DNA repair, DNA damage, and mutagenesis in aging would be to enhance DNA repair activity, lower DNA damage, and lower mutagenesis. Because the repair protein O6-methylguanine-DNA methyltransferase (MGMT) acts alone and stoichiometrically, the human MGMT (hMGMT) cDNA was selected to test the feasibility of enhancing DNA repair activity in transgenic mice. MGMT activity is largely responsible for ameliorating the deleterious effects of O6-methylguanine (O6mG) lesions in DNA in a direct reversal mechanism. A transgene was constructed consisting of a portion of the human transferrin (TF) promoter and hMGMT cDNA such that hMGMT is expressed in transgenic mouse brain and liver. Expression of hMGMT was associated with a significant reduction in the occurrence of an age-related hepatocellular carcinoma in male mice at 15 months of age. Longitudinal and cross-sectional studies were initiated to determine whether the reduced incidence of hepatocellular carcinoma would impact median or maximum life span. The cross-sectional study performed on 15-month-old male animals confirmed the reduced occurrence of spontaneous hepatocellular carcinoma. At 30 months of age, however, the occurrence of hepatocellular carcinoma in at least one transgenic line was similar to that for nontransgenic animals. The longitudinal study is ongoing; however, at present no significant differences in life span have been detected. Tissues expressing the MGMT transgene also displayed greater resistance to alkylation-induced tumor formation. These results suggest that transgenes can be used to direct enhanced DNA repair gene expression and that enhanced expression can protect animals from certain spontaneous and induced tumors.

Age of Onset↗
PubMed2001

A study of the anti-invasive properties of N-alpha-phthalimidomethyl-ketomethylene tripeptide-based metalloprotease inhibitors.

We have developed matrix metalloprotease (MMP) inhibitors based on synthetic peptides incorporating a non-cleavable peptide-bond isostere at the site of the putative scissile bond. These inhibitors, N-alpha-phthaloyl-Gly-psi(CO-CH2)-Leu-Tyr-Ala-NH2 (Pht-G-CH2-LYA-NH2) and N-alpha-phthaloyl-Gly-psi(CO-CH2)-Leu-Tic-Ala-NH2 (Pht-G-CH2-LTcA-NH2) were kinetically evaluated against the type IV collagenases, gelatinase A (MMP-2) and B (MMP-9), and compared with an exactly analogous chelating-based inhibitor, N-alpha-mercaptoacetyl-Leu-Tyr-Ala-NH2 (HSCH2CO-LYA-NH2). The peptide inhibitors were also tested for their anti-invasive effects on breast carcinoma cell lines using a modification of the Boyden chamber assay. Gelatin zymography was utilized to identify gelatinolytic activities present in media removed from cultured breast cancer cells. Of the two N-alpha-phthalimidomethyl-ketomethylene peptide-based inhibitors, Pht-G-CH2-LYA-NH2 proved the more effective inhibitor of MMP-2 and MMP-9 (Ki 34.27 and 45.75 microM, respectively). However, when tested against two breast cancer cell lines, T47D and MDA-MB-231, both inhibitors were able to effectively reduce tumour cell invasion through a type IV collagen matrix by up to 91.2%. Of particular interest was the observation that Pht-G-CH2-LYA-NH2 was the most potent inhibitor of invasion by the highly aggressive MDA-MB-231 cells, despite the cells' relative lack of active secreted metalloprotease activity. The results obtained from this kinetic and anti-invasive analysis of the new inhibitors suggest that compounds incorporating the N-alpha-phthalimidomethyl-ketomethylene peptide-bond isostere may have potential for development as new agents with anti-metastatic properties.

Algorithms↗