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1.  Genome-wide association analyses of child genotype effects and parent-of-origin effects in specific language impairment 
Genes, Brain, and Behavior  2014;13(4):418-429.
Specific language impairment (SLI) is a neurodevelopmental disorder that affects linguistic abilities when development is otherwise normal. We report the results of a genome-wide association study of SLI which included parent-of-origin effects and child genotype effects and used 278 families of language-impaired children. The child genotype effects analysis did not identify significant associations. We found genome-wide significant paternal parent-of-origin effects on chromosome 14q12 (P = 3.74 × 10−8) and suggestive maternal parent-of-origin effects on chromosome 5p13 (P = 1.16 × 10−7). A subsequent targeted association of six single-nucleotide-polymorphisms (SNPs) on chromosome 5 in 313 language-impaired individuals and their mothers from the ALSPAC cohort replicated the maternal effects, albeit in the opposite direction (P = 0.001); as fathers’ genotypes were not available in the ALSPAC study, the replication analysis did not include paternal parent-of-origin effects. The paternally-associated SNP on chromosome 14 yields a non-synonymous coding change within the NOP9 gene. This gene encodes an RNA-binding protein that has been reported to be significantly dysregulated in individuals with schizophrenia. The region of maternal association on chromosome 5 falls between the PTGER4 and DAB2 genes, in a region previously implicated in autism and ADHD. The top SNP in this association locus is a potential expression QTL of ARHGEF19 (also called WGEF) on chromosome 1. Members of this protein family have been implicated in intellectual disability. In summary, this study implicates parent-of-origin effects in language impairment, and adds an interesting new dimension to the emerging picture of shared genetic etiology across various neurodevelopmental disorders.
PMCID: PMC4114547  PMID: 24571439
ALSPAC; GWAS; imprinting; neurodevelopmental disorder; specific language impairment
2.  The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex 
Archives of Disease in Childhood  2004;89(6):530-533.
Background: The aetiology of the learning difficulty in tuberous sclerosis is debated. It may be related to the amount of tubers in the brain or caused by the infantile spasms that occur in early life.
Aims: To examine the relative contributions to final intelligence (IQ) made by both cerebral tubers and infantile spasms.
Methods: As part of an epidemiological study of tuberous sclerosis in the south of England, patients were recruited who were able to undergo magnetic resonance imaging (MRI) without the need for an anaesthetic. Epilepsy history was determined by interview and review of clinical records. IQ was assessed using either Wechsler intelligence scales or Raven's matrices.
Results: A total of 41 patients consented to have an MRI scan. IQ scores were normally distributed about a mean of 91. Twenty six patients had a positive history of epilepsy, and 11 had suffered from infantile spasms. There was a significant relation between the number of tubers and IQ. Infantile spasm status partly confounded the relation between tubers and IQ, but did not render the relation statistically insignificant. The relation between infantile spasms and learning difficulty remained strong even when controlling for the number of tubers.
PMCID: PMC1719953  PMID: 15155396
4.  Genotype-phenotype correlations in tuberous sclerosis 
PMCID: PMC1734582  PMID: 10807702
5.  6-Thioguanine alters the structure and stability of duplex DNA and inhibits quadruplex DNA formation. 
Nucleic Acids Research  1999;27(14):2860-2867.
The ability to chemically synthesize biomolecules has opened up the opportunity to observe changes in structure and activity that occur upon single atom substitution. In favorable cases this can provide information about the roles of individual atoms. The substitution of 6-thioguanine (6SG) for guanine is a potentially very useful single atom substitution as 6SG has optical, photocrosslinking, metal ion binding and other properties of potential utility. In addition, 6-mercaptopurine is a clinically important pro-drug that is activated by conversion into 6SG by cells. The results presented here indicate that the presence of 6SG blocks the formation of quadruplex DNA. The presence of 6SG alters the structure and lowers the thermal stability of duplex DNA, but duplex DNA can be formed in the presence of 6SG. These results indicate that some of the cytotoxic activity of 6SG may be due to disruption of the quadruplex structures formed by telomere and other DNAs. This additional mode of action is consistent with the delayed onset of cytotoxicity.
PMCID: PMC148499  PMID: 10390526
6.  Damage increases the flexibility of duplex DNA. 
Nucleic Acids Research  1999;27(8):1854-1858.
It is proposed that much of the recognition of specific types of damaged DNAs is based on accessible structural features, while much of the recognition of damaged DNAs, as a class, is based on flexibility. The more flexible a DNA the faster its diffusion rate. The diffusion rates of each member of a series of damaged duplex DNAs has been found to be significantly faster than that of the corresponding undamaged duplex DNA. The damaged sites studied include apurinic and apyrimidinic a basic sites, thymine glycol and urea. The presence of mismatched sites also increases the diffusion. Thus, damaged DNAs appear to have sufficient flexibility for recognition and the flexibility may allow damaged sites to act as a universal joint or hinge that allows distant sites on the DNA to come together.
PMCID: PMC148393  PMID: 10101193
7.  Intelligent split menus for data entry: a simulation study in general practice medicine. 
A compelling notion in menu design is that a few of the most frequently selected items should be placed as a hot list at the top of the menu. A few researchers have explored this type of interface control, known as a split menu, and have investigated the identification of the hot-list items by statistical analysis of past data. We extend the technique to automated development of dynamic hot-lists for entry of medication data in a General Practice setting. Using clinical data from 113,000 visits, a statistical model is developed and evaluated by simulated data entry of cases held back from training. Simulated SOAP note entry shows 12-item hot lists to hold over 70% of desired drug and diagnosis selections. Intelligent split menus should improve user efficiency if current selection methods require 3 seconds or more per item. A demonstration prototype can be downloaded over the Web.
PMCID: PMC2232653  PMID: 10566399
8.  Fluorescent dyes specific for quadruplex DNA. 
Nucleic Acids Research  1998;26(16):3724-3728.
Fluorescent dyes which are specific for duplex DNA have found a wide range of applications from staining gels to visualization of chromosomes. Porphyrin dyes have been found which are highly fluorescent in the presence of quadruplex but not duplex DNA. These dyes may offer a route to the specific detection of quadruplex DNA under biologically important conditions. There are three types of DNA quadruplex structures, and these may play important roles in telomere, centromere, triplet repeat, integration sites and other DNAs, and this first set of porphyrin dyes show some selectivity between the quadruplex types.
PMCID: PMC147777  PMID: 9685488
9.  Deficiencies in current childhood immunization indicators. 
Public Health Reports  1998;113(6):527-532.
OBJECTIVE: To investigate "up-to-date" and "age-appropriate" indicators of preschool vaccination status and their implications for vaccination policy. METHODS: The authors analyzed medical records data from the Baltimore Immunization Study for 525 2-year-olds born from August 1988 through March 1989 to mothers living in low-income Census tracts of the city of Baltimore. RESULTS: While only 54% of 24-month-old children were up-to-date for the primary series, indicators of up-to-date coverage were consistently higher, by 37 or more percentage points, than corresponding age-appropriate indicators. Almost 80% of children who failed to receive the first dose of DTP or OPV age-appropriately failed to be up-to-date by 24 months of age for the primary series. CONCLUSIONS: Age-appropriate immunization indicators more accurately reflect adequacy of protection for preschoolers than up-to-date indicators at both the individual and population levels. Age-appropriate receipt of the first dose of DTP should be monitored to identify children likely to be underimmunized. Age-appropriate indicators should also be incorporated as vaccination coverage estimators in population-based surveys and as quality of care indicators for managed care organizations. These changes would require accurate dates for each vaccination and support the need to develop population-based registries.
PMCID: PMC1308436  PMID: 9847924
10.  Estimating vaccination coverage using parental recall, vaccination cards, and medical records. 
Public Health Reports  1998;113(6):521-526.
OBJECTIVE: To compare estimates based on vaccination cards, parental recall, and medical records of the percentages of children up-to-date on vaccinations for diphtheria, tetanus, and pertussis; polio; and measles, mumps, and rubella. METHOD: The authors analyzed parent interview and medical records data from the Baltimore Immunization Study for 525 2-year-olds born from August 1988 through March 1989 to mothers living in low-income Census tracts of the city of Baltimore. RESULTS: Only one-third of children had vaccination cards; based on medical records, these children had higher up-to-date coverage at 24 months of age than did children without cards. For individual vaccines, only two-thirds of parents could provide information to calculate coverage rates; however, almost all provided enough information to estimate coverage for the primary series. For each vaccine and the series, parental recall estimates were at least 17 percentage points higher than estimates from medical records. For children without vaccination cards whose parents could not provide coverage information, up-to-date rates based on medical records were consistently lower than for children with cards or with parents who provided coverage information. CONCLUSIONS: Population-based vaccine coverage surveys that rely on vaccination cards or parental recall or both may overestimate vaccination coverage.
PMCID: PMC1308435  PMID: 9847923
11.  Pregnancy after surgical correction of tetralogy of Fallot. 
Forty pregnancies have been documented in 27 patients with surgically corrected tetralogy of Fallot. Infertility was uncommon and there were no premature births and few abortions or small-for-dates babies; this suggests that surgery that corrects cyanosis improves the outcome of pregnancy by correcting the fetal environment. Pregnancy was well tolerated and there were no serious cardiac complications. Thirty of the 31 infants examined were normal, the one abnormal infant having pulmonary atresia. A patient with no major residual defects after surgery for tetralogy of Fallot may be reassured that pregnancy will be well tolerated and that delivery may be managed in the normal manner.
PMCID: PMC1499340  PMID: 6807393
13.  A search for a transmissible agent in Crohn's disease. 
Gut  1975;16(7):528-532.
Controversy exists as to whether a transmissible agent is responsible for Crohn's disease. Previous reports have suggested that sarcoid-like granulomas can develop in animals following inoculation of homogenates derived from bowel affected by Crohn's disease. This study involved the injection of Crohn's tissue homogenates into experimental animals under a variety of conditions which might be expected to favour the demonstration of such an agent. Homogenates have been inoculated into the ileum of rats, mice, and rabbits and also given inoculated into ileum and footpads of rats which have previously been rendered lymphoedematous by surgical interruption of the draining lymphatics. Bowel homogenates from a total of 17 patients with Crohn's disease have been injected into 91 experimental animals. No macroscopic or microscopic changes indicative of Crohn's disease were detected. Thus study does not support the suggestion that a transmissible agent is present in Crohn's disease.
PMCID: PMC1410978  PMID: 1158189
14.  Cellular immunity in cancer: comparison of delayed hypersensitivity skin tests in three common cancers. 
British Medical Journal  1975;3(5974):18-20.
Cellular immunity was studied in three homogenous groups of patients with cancer to determine whether the pattern of depression of immune competence varied between solid tumours with different patterns of clinical behaviour. Delayed hypersensitivity skin responses were measured in patients with carcinoma of the breast, stomach, and colon and matched controls. Response to 2,4-dinitrochlorobenzene (DNCB) was used as an indication of primary responses and the Mantoux reaction as an index of recall responses. Responses were diminished in all three cancer groups, but there were significant differences between each type of cancer and even between different control groups. Cellular immunity was lost earliest and to the greatest extent in patients with colonic cancers and tended to be retained until a late stage in breast cancer, with gastric cancer occupying an intermediate position. Thus, while there was some degree of correlation between depressed immunity and prognosis our results gave no evidence that general host immune competence could explain the worse prognosis of gastric than colonic cancer. Paradoxical findings in patients with breast cancer suggested a great complexity in the host tumour interaction. Assessments of immune competence in cancer patients must be related to specific types of neoplasms with appropriate control groups if the results are to be meaningful.
PMCID: PMC1673694  PMID: 1131654
16.  The immune competence of patients with inflammatory bowel disease 
Gut  1974;15(3):213-219.
Previous investigations of immune function in patients with Crohn's disease have yielded conflicting results. A comprehensive study of immune competence—peripheral lymphocyte count, serum immunoglobulin levels (IgG, IgA and IgM), lymphocyte response to PHA, Mantoux test, and DNCB response—has been performed in a large number of patients with inflammatory bowel disease. A total of 52 patients with Crohn's disease, 20 patients with ulcerative colitis, and 46 control patients with benign gastrointestinal disease were investigated. The patient groups were subdivided into `well' and `ill' in view of the differing clinical states of patients with inflammatory bowel disease. Some of the Crohn's and colitis patients were receiving steroid therapy.
The peripheral blood lymphocyte count and lymphocyte response to PHA were similar in all patient groups. Serum IgA levels were elevated in Crohn's disease but fell significantly in `ill' Crohn's patients following excisional surgery. Serum IgM levels rose significantly in `ill' Crohn's patients after surgery. Steroid therapy was associated with diminution of both Mantoux and DNCB responses in the `ill' Crohn's patients. There was no evidence of impairment of immune competence in either Crohn's disease or ulcerative colitis.
PMCID: PMC1412882  PMID: 4841278
18.  Spectroscopic properties of ethidium monoazide: a fluorescent photoaffinity label for nucleic acids. 
Nucleic Acids Research  1978;5(12):4891-4903.
The non-covalent binding of ethidium monoazide to nucleic acids is entirely analogous to that of ethidium (binding constant approximately 2-3 X 10(5) M). The ethidium monoazide can be photochemically covalently linked to nucleic acids in high yield, up to 75%, by long wavelength light. The fluorescence of ethidium monoazide and ethidium crosslinked to nucleic acids show the same environmental sensitivity as does the fluorescence of ethidium. These properties of ethidium monoazide indicate its use as a fluorescent photoaffinity label for nucleic acids. Ethidium diazide can be photochemically linked to nucleic acids but appears to have properties substantially different from those of ethidium.
PMCID: PMC342796  PMID: 745997
19.  Hydrogen bonding interactions of polyamines with the 2' OH of RNA. 
Nucleic Acids Research  1978;5(4):1315-1324.
Polyamines and other charged amines bind to RNA by hydrogen bonding to the 3' phosphate and to the 2' OH. This mode of binding suggests a mechanism by which DNA and RNA might be distinguished by enzymes.
PMCID: PMC342079  PMID: 652523
20.  Determination of the number and location of the manganese binding sites of DNA quadruplexes in solution by EPR and NMR. 
Nucleic Acids Research  1995;23(5):844-848.
The paramagnetic metal ion Mn2+ has been used to probe the electrostatic potentials of a DNA quadruplex that has two quartets with an overall fold of the chair type. A quadruplex with a basket type structure has also been examined. The binding of the paramagnetic ion manganese to these quadruplex DNAs has been investigated by solution state electron paramagnetic resonance (EPR) and nuclear magnetic resonance (NMR) spectroscopies. The EPR results indicate that the DNA aptamer, d(GGTTGGTGTGGTTGG), binds two manganese ions and that the binding constants for each of these sites is approximately 10(5) M-1. The NMR results indicate that the binding sites of the manganese are in the narrow grooves of this quadruplex DNA. The binding sites of the DNA quadruplex formed by dimers of d(GGGGTTTTGGGG) which forms a basket structure are also in the narrow groove. These results indicate that the close approach of phosphates in the narrow minor grooves of the quadruplex structures provide strong binding sites for the manganese ions and that EPR and NMR monitoring of manganese binding can be used to distinguish between the different types of quadruplex structures.
PMCID: PMC306768  PMID: 7708501

Results 1-20 (20)