Mutation screening of the KCNN3 gene reveals a rare frameshift mutation.
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DNA Mutational Analysis↗
Biomedical subjects
G Jones
Publications and source records attributed to G Jones.
Is your bougie helping or hindering you?
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Equipment Failure↗
Expression of CYP27A, a gene encoding a vitamin D-25 hydroxylase in human liver and kidney.
Vitamin D3 (D3) is not active but must be hydroxylated at C-25 in liver before acquiring its hormonal potential in the kidney. The sterol-27 hydroxylase (gene symbol: CYP27A) catalyses the oxidation of sterol side chain in bile acid synthesis but the enzyme is also known as a D3-25 hydroxylase. The study examined the expression of the gene encoding CYP27A in adult and fetal human livers and kidneys. Thirty-nine adults (18 men and 21 women; mean age 58 years in men and 57 years in women) and three normal fetuses gestational age 17-19 weeks were studied. Tissue CYP27A mRNA and serum 25OHD concentrations were measured. Normal specimens: CYP27A transcript was found to be higher in adult than in fetal livers but its expression was similar in adult and fetal kidneys. In fetuses, no difference was observed between CYP27A levels in livers and kidneys. In adult livers CYP27A levels were higher in women than in men. Hepatic CYP27A mRNA and serum 25OHD concentrations were both found to be higher in summer than in winter. Multiple linear regression analyses indicate that the season of the year and the serum 25OHD concentrations (but not 1,25(OH)2D concentrations) are the best predictors of CYP27A mRNA abundance in normal adult livers. In situ hybridization illustrates a clear label in hepatocytes which increases in intensity in the perivenous region of the hepatic acinus. Pathological specimens: In one man with an hepatic carcinoma there was a very large increase in CYP27A (> 1000 fold) compared to the level found in the normal liver. In that patient, serum 25OHD concentrations were found to be high considering the level of CYP27A mRNA in the normal hepatic area suggesting that the neoplastic tissue contributed to the C-25 hydroxylation of vitamin D. Specimens obtained from two patients suffering from focal hepatic hyperplasia indicate that in one case the level of CYP27A mRNA was twice as high in the pathological than in the normal area while in the other its levels were similar in both areas. No difference in the CYP27A transcript was observed between specimens obtained from normal areas and those obtained form either an hepatic adenoma or from two intrahepatic colonic metastases. CYP27A is present not only in the human adult liver but also in the adult kidney, and in the fetal liver and kidney. Our findings illustrate that CYP27A can be significantly upregulated in certain pathological situations such as in hepatic carcinoma and that the neoplastic tissue could contribute to the circulating concentration of 25OHD.
Adenoma↗
A cross-sectional study of the association between Heberden's nodes, radiographic osteoarthritis of the hands, grip strength, disability and pain.
OBJECTIVE: To describe the associations between hand osteoarthritis (OA), pain and disability in males and females and to further validate the Australian/Canadian OA hand index (AUSCAN LK3.0). DESIGN: Cross-sectional study of 522 subjects from 101 Tasmanian families (males N=174, females N=348). Hand OA was assessed by two observers using the Altman atlas for joint space narrowing and osteophytes at distal interphalangeal and first carpometacarpal joints as well as a score for Heberden's nodes based on hand photography. Hand pain and function were assessed by the AUSCAN LK3.0 and grip strength by dynamometry in both hands on two occasions. RESULTS: The prevalence of hand OA was high in this sample at 44-71% (depending on site). Pain and dysfunction increased with age while grip strength decreased (all P< 0.001). All three measures were markedly worse in women, even after taking the severity of arthritis into account. Hand OA explained 5.7-10% of the variation in function, grip strength and pain scores, even after adjustment for age and sex. Further adjustment suggested that the osteoarthritic associations with function and grip strength were largely mediated by pain. Severity of disease was more strongly associated with these scores than presence or absence. Lastly, the AUSCAN LK3.0 showed a comparable association to grip strength with structural damage providing further evidence of index validity. CONCLUSIONS: Hand OA at these two sites makes substantial contributions to hand function, strength and pain. The associations with function and strength measures appear mediated by pain. Gender differences in all three measures persist after adjustment for variation in age and OA severity indicating that factors apart from radiographic disease are responsible.
Age Factors↗
Pre-competitive feeling states and directional anxiety interpretations.
In this study, we assessed differences in feeling states indicated by performers who reported being facilitated or debilitated by symptoms associated with competitive anxiety before competition. A sample of high-standard swimmers (n = 190) completed a modified version of the Competitive State Anxiety Inventory-2, including both intensity and direction subscales, and an exploratory checklist of feeling state labels, which comprised positive and negative feeling state labels. Our findings supported the general hypothesis that 'facilitators' report significantly more positive feelings than 'debilitators', who report significantly more negative feelings. Descriptive frequency counts of the largest percentage differences between 'facilitators' and 'debilitators' resulted in the selection of the 'confident' feeling state label on the positive subscales, with it being identified most frequently by the 'facilitators'. Furthermore, of the negative feelings, the groups indicated the label 'anxious' most frequently. This study has extended previous research into the notion of positive and negative anxiety and has revealed individual differences in the combination of feeling states experienced by performers during competition.
Adolescent↗
Association between urinary potassium, urinary sodium, current diet, and bone density in prepubertal children.
BACKGROUND: Our understanding of the role of nutrients in bone development in children is limited. OBJECTIVE: We examined the associations between urinary potassium, urinary sodium, usual dietary intake, and bone mineral density (BMD) in prepubertal children. DESIGN: This was a cross-sectional study of 330 boys and girls aged 8 y. Urinary measures were assessed in a single, timed, overnight urine specimen. Usual diet was assessed with a food-frequency questionnaire completed by a parent or guardian. BMD at the femoral neck, lumbar spine, and total body was measured by dual-energy X-ray absorptiometry. RESULTS: Urinary potassium correlated significantly with BMD at all sites (femoral neck: r = 0.20, P < 0.001; lumbar spine: r = 0.19, P = 0.001; total body: r = 0.24, P < 0.001). After adjustment for confounders (primarily lean body mass), this association was lower in magnitude but remained significant at 2 sites with a consistent trend at the third (femoral neck: P = 0.15; lumbar spine: P = 0.046; total body: P = 0.028). Urinary sodium was not associated with BMD at any site. No nutrient or food intake estimate was associated with BMD, although urinary potassium correlated significantly with potassium intake (r = 0.14, P = 0.016) and fruit and vegetable intake (r = 0.12, P = 0.033). CONCLUSIONS: Urinary potassium was associated with both dietary intake and BMD independent of lean body mass in these well-nourished, calcium-replete young children. These findings should be confirmed in further longitudinal studies. Nevertheless, this association is likely to represent dietary intake of potassium and suggests that measurement of urinary potassium is superior to food-frequency questionnaires for assessing potassium intake in this age group.
Absorptiometry, Photon↗
Arabidopsis genes essential for seedling viability: isolation of insertional mutants and molecular cloning.
We have undertaken a large-scale genetic screen to identify genes with a seedling-lethal mutant phenotype. From screening approximately 38,000 insertional mutant lines, we identified >500 seedling-lethal mutants, completed cosegregation analysis of the insertion and the lethal phenotype for >200 mutants, molecularly characterized 54 mutants, and provided a detailed description for 22 of them. Most of the seedling-lethal mutants seem to affect chloroplast function because they display altered pigmentation and affect genes encoding proteins predicted to have chloroplast localization. Although a high level of functional redundancy in Arabidopsis might be expected because 65% of genes are members of gene families, we found that 41% of the essential genes found in this study are members of Arabidopsis gene families. In addition, we isolated several interesting classes of mutants and genes. We found three mutants in the recently discovered nonmevalonate isoprenoid biosynthetic pathway and mutants disrupting genes similar to Tic40 and tatC, which are likely to be involved in chloroplast protein translocation. Finally, we directly compared T-DNA and Ac/Ds transposon mutagenesis methods in Arabidopsis on a genome scale. In each population, we found only about one-third of the insertion mutations cosegregated with a mutant phenotype.
Arabidopsis↗
Disulfide structure of alfimeprase: a recombinant analog of fibrolase.
The disulfide structure of alfimeprase, a recombinant analog of fibrolase, was experimentally determined by a combination of peptide mapping, Edman degradation, and mass spectrometry. The three disulfide bonds were determined to be Cys-116/196, Cys-156 /180, and Cys-158/163 with the residue number system of alfimeprase.
Amino Acid Sequence↗
Analyte identification in multivariate calibration.
In calibration experiments, an estimated relationship between covariate information for a sample and an observed response is used to infer the covariate information for unknown samples from their responses. In some situations, this covariate information comprises a nominal variable (e.g., identity of a chemical, sex of an animal) and a real-valued variable (e.g., concentration of the chemical, age of animal). If the calibrating relationship can be estimated separately for each candidate identity, the first step in analyzing unknown samples is to correctly determine their identity. A discrimination statistic is suggested for use in this situation and its asymptotic distribution is derived. The investigation is motivated by the possibility of using multiple immunoassays in environmental monitoring to identify and quantitate contaminated samples in situations where there are several candidate pollutants that cross-react significantly to single assays. An example is given of the use of a four-antibody assay for the simultaneous monitoring of the levels in water samples of several of the commonly used triazine herbicides and their derivatives.
Aging↗
Inhibition of human immunodeficiency virus type 1 gp120 presentation to CD4 T cells by antibodies specific for the CD4 binding domain of gp120.
Human immunodeficiency virus (HIV)-specific CD4 T-cell responses, particularly to the envelope glycoproteins of the virus, are weak or absent in most HIV-infected patients. Although these poor responses can be attributed simply to the destruction of the specific CD4 T cells by the virus, other factors also appear to contribute to the suppression of these virus-specific responses. We previously showed that human monoclonal antibodies (MAbs) specific for the CD4 binding domain of gp120 (gp120(CD4BD)), when complexed with gp120, inhibited the proliferative responses of gp120-specific CD4 T-cells. MAbs to other gp120 epitopes did not exhibit this activity. The present study investigated the inhibitory mechanisms of the anti-gp120(CD4BD) MAbs. The anti-gp120(CD4BD) MAbs complexed with gp120 suppressed gamma interferon production as well as proliferation of gp120-specific CD4 T cells. Notably, the T-cell responses to gp120 were inhibited only when the MAbs were added to antigen-presenting cells (APCs) during antigen pulse; the addition of the MAbs after pulsing caused no inhibition. However, the anti-gp120(CD4BD) MAbs by themselves, or as MAb/gp120 complexes, did not affect the presentation of gp120-derived peptides by the APCs to T cells. These MAb/gp120 complexes also did not inhibit the ability of APCs to process and present unrelated antigens. To test whether the suppressive effect of anti-gp120(CD4BD) antibodies is caused by the antibodies' ability to block gp120-CD4 interaction, APCs were treated during antigen pulse with anti-CD4 MAbs. These treated APCs remained capable of presenting gp120 to the T cells. These results suggest that anti-gp120(CD4BD) Abs inhibit gp120 presentation by altering the uptake and/or processing of gp120 by the APCs but their inhibitory activity is not due to blocking of gp120 attachment to CD4 on the surface of APCs.
AIDS Vaccines↗
Alterations in development, behavior, and physiology in Drosophila larva that have reduced ecdysone production.
We investigated behavior, physiology, sensitivity to exogenous application of ecdysone, and nerve terminal structure for differences between the reduced ecdysone genotype, ecd(1)/ecd(1), and wild-type control ecd(1)/TM6B animals during the early and late third instars when raised at 25 degrees C. The ecd(1) mutants were able to survive through larval development and form pupae. However, the results demonstrate that the time to pupation is lengthened by about 50 h for the ecd(1)/ecd(1) as compared with the wild-type control siblings. In addition to the lengthened larval cycle in the mutant, ecd(1)/ecd(1) animals, they also display behavioral differences as compared with controls. The rate of body wall contraction and mouth hook movements are reduced in the early third instar of ecd(1)/ecd(1) as compared with controls. The physiological measure of excitatory junction potential amplitude for the combined Is and Ib terminals did not reveal any differences among the two genotypes during the early third instar but the synaptic strength is reduced in the late third instars for controls. Application of exogenous ecdysone is still effective during the late third instar for the ecd(1)/ecd(1) but not the controls. This suggests that endogenous production of ecdysone have already taken place in the wild-type but not the ecd(1)/ecd(1) larvae, thus the rapid nongenomic responses could still be observed in the late third ecd(1)/ecd(1) larvae. Structurally the number of varicosities and the terminal length showed significant differences between ecd(1)/ecd(1) and the wild-type ecd(1)/TM6B genotype in the late third instars.
Animals↗
Furano pyrimidines as novel potent and selective anti-VZV agents.
Bicyclic furano pyrimidine nucleosides have been found to be highly potent and selective inhibitors of varicella zoster virus (VZV). They are inactive against herpes simplex virus and have been known for several decades as (unwanted) synthetic by-products in the Pd-catalysed coupling of acetylenes to 5-iodo nucleosides. These fluorescent bicyclic nucleosides are now established as a new family of potent antivirals. They are unusual in that they exhibit complete specificity for VZV and require an alkyl (or alkylaryl) side-chain for biological activity. The latter requirement confers extremely high lipophilicities on these compounds, unknown amongst chemotherapeutic nucleosides, which may be of considerable importance in formulation, dosing and tissue distribution. The most potent compounds reported are p-alkylaryl compounds, with EC50 values below 1 nM versus VZV and selectivity index values of around 1,000,000. Here, we review the discovery, synthesis, characterization, antiviral profile, SAR, mechanism of action and development prospects for this new family of antivirals.
Antiviral Agents↗
Aggressive behaviour in patients with schizophrenia is associated with catechol-O-methyltransferase genotype.
BACKGROUND: Evidence exists for an association between aggression and schizophrenia. Although the aetiology of aggression is multifactorial, three studies have reported associations between polymorphisms of the catechol-O-methyltransferase (COMT) gene and aggression in schizophrenia. AIMS: To replicate these findings in a larger sample using the Overt Aggression Scale (OAS). METHOD: A sample of 180 people with DSM-IV schizophrenia were rated for aggression using the OAS. Kruskal-Wallis and contingency table analyses were applied to the OAS results. RESULTS: The high-activity homozygotes showed significantly higher scores of aggression, whereas the heterozygotes showed significantly lower scores. The odds ratio for aggression for the high-activity homozygotes was 2.07 (95% Cl=1.03-4.15), whereas that for the heterozygotes was 0.54 (95% Cl=0.30-1.00). CONCLUSIONS; The high-activity COMT homozygote confers a higher risk of recorded aggression in schizophrenia. Heterozygotes had a significantly lower risk, which may represent an example of heterosis/heterozygote advantage.
Aggression↗
Steady-state end-tidal alveolar dead space fraction and D-dimer: bedside tests to exclude pulmonary embolism.
STUDY OBJECTIVE: Less than 35% of patients suspected of having pulmonary embolism (PE) actually have PE. Safe bedside methods to exclude PE could save health-care resources and improve access to diagnostic testing for suspected PE. In patients with suspected PE, we sought to determine the sensitivity, specificity, and negative predictive value of (1) a steady-state end-tidal alveolar dead space fraction (AVDSf) of < 0.15, (2) a negative D-dimer result, and (3) the combination of a steady-state end-tidal AVDSf of < 0.15 and a negative D-dimer result. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary-care center in Ottawa, Ontario, Canada. PATIENTS: Consecutive inpatients, outpatients, and emergency department patients with suspected PE referred to the Departments of Nuclear Medicine or Radiology for investigation of suspected PE. INTERVENTIONS AND MEASUREMENTS: All study patients had D-Dimer and alveolar dead space measurements prior to determining outcome (PE or no PE) with ventilation/perfusion scans and/or noninvasive leg vein imaging and/or pulmonary angiography. RESULTS: Two hundred forty-six eligible and consenting patients underwent diagnostic imaging that excluded PE in 163 patients, diagnosed PE in 49 patients, and was indeterminant in 34 patients. A negative D-dimer result excluded PE with a sensitivity of 83.0% (95% confidence interval [CI], 69.2 to 92.4%), a negative predictive value of 91.2% (95% CI, 83.4 to 96.1%), and a specificity of 57.6%. A steady-state end-tidal AVDSf of < 0.15 excluded PE with a sensitivity of 79.5% (95% CI, 63.5 to 90.7%), a negative predictive value of 90.7% (95% CI, 82.5 to 95.9%), and a specificity of 70.3%. The combination of a negative D-dimer result and a steady-state end-tidal AVDSf of < 0.15 excluded PE with a sensitivity of 97.8% (95% CI, 88.5 to 99.9%), a negative predictive value of 98.0% (95% CI, 89.4 to 99.9%), and a specificity of 38.0%. CONCLUSION: This simple combination of bedside tests may safely rule out PE without further diagnostic testing in large numbers of patients with suspected PE.
Diagnosis, Differential↗
Maturation of human oocytes in vitro and their developmental competence.
Complete maturation of oocytes is essential for the developmental competence of embryos. Any interventions in the growth phase of the oocyte and the follicle in the ovary will affect oocyte maturation, fertilization and subsequent embryo development. Oocyte size is associated with maturation and embryo development in most species examined and this may indicate that a certain size is necessary to initiate the molecular cascade of normal nuclear and cytoplasmic maturation. The minimum size of follicle required for developmental competence in humans is 5-7 mm in diameter. Maturation in vitro can be accomplished in humans, but is associated with a loss of developmental competence unless the oocyte is near completion of its preovulatory growth phase. This loss of developmental competence is associated with the absence of specific proteins in oocytes cultured to metaphase II in vitro. The composition of culture medium used successfully for maturation of human oocytes is surprisingly similar to that originally developed for maturation of oocytes in follicle culture in vitro. The presence of follicle support cells in culture is necessary for the gonadotrophin-mediated response required to mature oocytes in vitro. Gonadotrophin concentration and the sequence of FSH and FSH-LH exposure may be important for human oocytes, particularly those not exposed to the gonadotrophin surge in vivo. More research is needed to describe the molecular and cellular events, the presence of checkpoints and the role of gene expression, translation and protein uptake on completing oocyte maturation in vitro and in vivo. In the meantime, there are very clear applications for maturing oocytes in human reproductive medicine and the success rates achieved in some of these special applications are clinically valuable.
Animals↗
Combined intraarterial carboplatin, intraarterial etoposide phosphate, and IV Cytoxan chemotherapy for progressive optic-hypothalamic gliomas in young children.
BACKGROUND AND PURPOSE: Optic pathway and/or hypothalamic astrocytomas in children are often quiescent, but in some cases, more aggressive tumors may cause progressive visual, endocrine, and neurologic deterioration. The initial treatment of these gliomas includes surgery and IV chemotherapy. Radiotherapy is not recommended in young children because of its severe adverse effects on cognitive and neuroendocrine function. This report suggests a new approach using combined intraarterial and IV carboplatin-based chemotherapy for patients for whom first line treatment has already failed. METHODS: Six children (mean age, 57 months) with the diagnosis of optic pathway hypothalamic gliomas, who had tumor progression after surgery and underwent IV chemotherapy, were treated monthly with intraarterially administered carboplatin, intraarterially administered etoposide phosphate, and IV administered Cytoxan. Four of the children had histologically verified pilocytic astrocytomas, and in two cases, diagnosis was made on the basis of clinical findings. Administration of the intraarterial chemotherapy required catheter placement in both internal carotid arteries at the level of C2-C3 and into one of the vertebral arteries at the level of C6-C7, with the patient under general anesthesia. RESULTS: Four of six patients had partial radiographic response, one had stable disease, and one had progressive disease after one cycle. Three patients showed clinical improvement. There were no serious complications associated with the angiographic procedures. Toxicities included bronchospasm that resolved after 3 to 4 minutes in one patient. One patient showed mild ototoxicity, and four patients needed platelet transfusion because of hematologic toxicity of drugs. CONCLUSION: These results suggest that this modality of chemotherapy (administered after failure of systemic [ie, IV] chemotherapy), of progressive optic-hypothalamic astrocytomas in young children may be an effective treatment prior to radiotherapy.
Antineoplastic Agents↗
Xenotransplantation: hope or delusion?
Having moved from the realms of science fiction to a rapidly growing research area, xenotransplantation promises numerous benefits to patients in the future. However, deep suspicions of this technology are rife. We suggest an alternative viewpoint to that given in E M Engels' article in Biologist 46(2).
Animal Welfare↗
'Captain of all these men of death'. The history of tuberculosis in nineteenth and twentieth century Ireland.
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Disease Outbreaks↗