Early negative results not the last word on secretin/autism story.
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Autistic Disorder↗
Biomedical subjects
D Gordon
Publications and source records attributed to D Gordon.
Severe preeclampsia and high frequency of genetic thrombophilic mutations.
OBJECTIVE: To determine whether severe preeclampsia is associated with genetic thrombophilic mutations or other types of thrombophilia. METHODS: A case-control study compared 63 consecutive women with severe preeclampsia evaluated at our institution between November 1997 and April 1999 with 126 control women matched for age and ethnicity. All of these women were tested several months after delivery for mutations of factor V Leiden, methylenetetrahydrofolate reductase, and prothrombin gene; for deficiencies of protein C, protein S, and antithrombin-III; and for the presence of anticardiolipin antibodies. RESULTS: Thirty-five study women (56%) had a thrombophilic mutation compared with 24 control women (19%), P <.001. Seven other study women (11%) had other thrombophilias, compared with one control woman (0.8%), P <.01. Within the study group, women with thrombophilia delivered at an earlier gestational age, and their neonates' birth weights were lower compared with those of women without thrombophilia. CONCLUSION: Because thrombophilia was found in 67% of women with severe preeclampsia, we suggest that women who have severe preeclampsia should be tested for thrombophilia.
Adult↗
Increasing mortality differentials by residential area level of poverty: Britain 1981-1997.
This paper considers mortality for ages 15-64 for the period 1981-97 in Britain according to population deciles defined by an area-based poverty measure. Over the study period there has been a polarization of life chances such that by 1994-97 almost one quarter of deaths in this age group can be attributed to unfavourable socioeconomic circumstances. Mortality differentials according to socioeconomic circumstances increased in tandem with increases in income inequality. A commitment to redistributive social policies is necessary if the trend of increasing inequality is to be reversed.
Adolescent↗
Epidermolytic hyperkeratosis in a Hispanic family resulting from a mutation in the keratin 1 gene.
Epidermolytic hyperkeratosis (EHK; bullous congenital ichthyosiform erythroderma) is a genodermatosis resulting from mutations in either the keratin 1 (K1) or keratin 10 (K10) genes. It is characterized by erythroderma and blistering at birth, and the development of ichthyotic hyperkeratosis and palmoplantar keratoderma. A wide variety of mutations within the highly conserved helix initiation and termination motifs of the central rod domains of the K1 or K10 genes correlate with the highly variable phenotypic severity observed in EHK. We report a novel missense mutation designated L214P in a large Hispanic pedigree with EHK. The mutation is located in the highly conserved 1A segment of the alpha-helical rod domain. The presence of this mutation underscores the importance of sequence alterations located in the central rod domain in the pathogenesis of EHK.
Female↗
Scorpion alpha and alpha-like toxins differentially interact with sodium channels in mammalian CNS and periphery.
Scorpion alpha-toxins from Leiurus quinquestriatus hebraeus, LqhII and LqhIII, are similarly toxic to mice when administered by a subcutaneous route, but in mouse brain LqhII is 25-fold more toxic. Examination of the two toxins effects in central nervous system (CNS), peripheral preparations and expressed sodium channels revealed the basis for their differential toxicity. In rat brain synaptosomes, LqhII binds with high affinity, whereas LqhIII competes only at high concentration for LqhII-binding sites in a voltage-dependent manner. LqhII strongly inhibits sodium current inactivation of brain rBII subtype expressed in HEK293 cells, whereas LqhIII is weakly active at 2 microM, suggesting that LqhIII affects sodium channel subtypes other than rBII in the brain. In the periphery, both toxins inhibit tetrodotoxin-sensitive sodium current inactivation in dorsal root ganglion neurons, and are strongly active directly on the muscle and on expressed muI channels. Only LqhII, however, induced repetitive end-plate potentials in mouse phrenic nerve-hemidiaphragm muscle preparation by direct effect on the motor nerve. Thus, rBII and sodium channel subtypes expressed in peripheral nervous system (PNS) serve as the main targets for LqhII but are mostly not sensitive to LqhIII. Toxicity of both toxins in periphery may be attributed to the direct effect on muscle. Our data elucidate, for the first time, how different toxins affect mammalian central and peripheral excitable cells, and reveal unexpected subtype specificity of toxins that interact with receptor site 3.
Animals↗
Macular oedema with associated uveitis and cataract following presentation of Type 1 diabetes mellitus in severe ketoacidosis.
We present a case of cystoid macular oedema presenting in a newly diagnosed diabetic teenager. She had developed anterior uveitis prior to diabetes and whether this contributed to the subsequent ocular complications remains speculative. The macular changes resolved spontaneously over 6 months without the use of grid laser photocoagulation.
Adolescent↗
Structural implications on the interaction of scorpion alpha-like toxins with the sodium channel receptor site inferred from toxin iodination and pH-dependent binding.
The alpha-like toxin from the venom of the scorpion Leiurus quinquestriatus hebraeus (Lqh III) binds with high affinity to receptor site 3 on insect sodium channels but does not bind to rat brain synaptosomes. The binding affinity of Lqh III to cockroach neuronal membranes was fivefold higher at pH 6.5 than at pH 7.5. This correlated with an increase in the electropositive charge on the toxin surface resulting from protonation of its four histidines. Radioiodination of Tyr(14) of Lqh III abolished its binding to locust but not cockroach sodium channels, whereas the noniodinated toxin bound equally well to both neuronal preparations. Radioiodination of Tyr(10) or Tyr(21) of the structurally similar alpha-toxin from L. quinquestriatus hebraeus (LqhalphaIT), as well as their substitution by phenylalanine, had only minor effects on binding to cockroach neuronal membranes. However, substitution of Tyr(21), but not Tyr(14), by leucine decreased the binding affinity of LqhalphaIT approximately 87-fold. Thus, Tyr(14) is involved in the bioactivity of Lqh III to locust receptor site 3 and is not crucial for the binding of LqhalphaIT to this site. In turn, the aromatic ring of Tyr(21) takes part in the bioactivity of LqhalphaIT to insects. These results highlight subtle architectural variations between locust and cockroach receptor site 3, in addition to previous results demonstrating the competence of Lqh III to differentiate between insect and mammalian sodium channel subtypes.
Amino Acid Substitution↗
A Phe 486 thyrotropin receptor mutation in an autonomously functioning follicular carcinoma that was causing hyperthyroidism.
Hot nodules are rarely found to be carcinomas. We report a case of a nonmetastatic follicular carcinoma that presented as a hot nodule that was causing hyperthyroidism. A base substitution (ATC for TTC) was found in codon 486 of the TSH receptor gene and this resulted in the substitution of an isoleucine for a phenylalanine in the first extracellular loop of the receptor. This was absent in the deoxyribonucleic acid from the surrounding normal thyroid tissue indicating its somatic origin. This mutation, which was previously reported to activate both cyclic adenosine monophosphate and the inositol phosphate-diacylglycerol cascades, may have been responsible for the constitutive activation of the thyrotropin receptor and resulting hyperfunction of this follicular carcinoma.
Adenocarcinoma, Follicular↗
Comparison of high dose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice.
BACKGROUND: Theophylline is widely used in the treatment of asthma, and there is evidence that theophylline has anti-inflammatory or immunomodulatory effects. A study was undertaken to determine whether theophylline added to low dose inhaled steroids would be as efficacious as high dose inhaled steroids in asthma. METHODS: In a study in general practice of 155 recruited asthmatic patients with continuing symptomatic asthma while on 400 microgram beclomethasone dipropionate (BDP) daily and inhaled beta(2) agonist as required, the effect of (1) continuing low dose inhaled steroids alone (LDS, 200 microgram BDP twice daily), (2) low dose inhaled steroids plus low dose theophylline (LDT, 400 mg daily), or (3) high dose inhaled steroids (HDS, 500 microgram BDP) over a six month period was examined. RESULTS: One hundred and thirty patients completed the study. Between group comparison using analysis of variance showed no overall differences in peak flow measurements, diurnal variation, and symptom scores. Changes in evening peak flows approached significance at the 5% level (p=0.077). The mean improvement in evening peak flow in the LDT compared with the LDS group was 20.6 l/min (95% confidence interval (CI) -2.5 to 38.8). In the LDT group there was an increase in evening peak flows at the end of the study compared with entry values (22.5 l/min), while in the LDS and HDS groups evening peak flows increased by 1.9 and 8.3 l/min, respectively. There was no significant difference in exacerbations or in side effects. CONCLUSION: There were no overall significant differences between the low dose steroid, low dose steroid with theophylline, and the high dose steroid groups. The greatest within-group improvement in evening peak flows was found after theophylline. A larger study may be necessary to show significant effects.
Adolescent↗
An analytic solution to single nucleotide polymorphism error-detection rates in nuclear families: implications for study design.
Recently, there has been increased interest in using Single Nucleotide Polymorphisms (SNPs) as a method for detecting genes for complex traits. SNPs are diallelic markers that have the potential to be inexpensively produced using chip technology. It has been suggested that SNPs will be beneficial in study designs that utilize trio data (father, mother, child). In our previous work, we calculated the probability of detecting Mendelian errors at a SNP locus for a trio randomly selected from a population in Hardy-Weinberg equilibrium. The highest error-detection rate was 30%. Here we investigate the error-detection rate when additional sibs are genotyped. We define an error to be a change from a 1 allele to a 2 allele, or vice versa. Typing one additional sib increases the detection rate on average by 10-13%. Typing two additional sibs increases the detection rate on average by 14-19%. The increase in the detection rate is dependent on the allele frequencies. Equal allele frequencies produce the lowest detection rates, independent of true error rates and number of offspring genotyped. Typing additional siblings not only improves error-detection rates, but can also provide additional linkage information. In order to increase linkage information and error-detection rates, at least two additional siblings should be ascertained when available.
Alleles↗
Transvaginal sonohysterography for the evaluation and treatment of retained products of conception.
Diagnosing retained products of conception in a woman presenting with postpartum or postabortion bleeding presents a clinical challenge. Although ultrasonographic examination may be potentially useful in detecting retained products of conception, its accuracy has not yet been established. Saline infusion sonohysterography is a simple ultrasonographic technique for enhanced transvaginal sonographic imaging of the endometrial cavity by the instillation of saline into the uterine cavity during ultrasonographic evaluation. This technique enhanced our ability to diagnose retained products of conception, and we describe our experience in evacuating them under sonographic guidance while performing saline infusion sonohysterography.
Dilatation and Curettage↗
Atherosclerosis progression in LDL receptor-deficient and apolipoprotein E-deficient mice is independent of genetic alterations in plasminogen activator inhibitor-1.
Impaired fibrinolysis has been linked to atherosclerosis in a number of experimental and clinical studies. Plasminogen activator inhibitor type 1 (PAI-1) is the primary inhibitor of plasminogen activation and has been proposed to promote atherosclerosis by facilitating fibrin deposition within developing lesions. We examined the contribution of PAI-1 to disease progression in 2 established mouse models of atherosclerosis. Mice lacking apolipoprotein E (apoE-/-) and mice lacking the low density lipoprotein receptor (LDLR-/-) were crossbred with transgenic mice overexpressing PAI-1 (resulting in PAI-1 Tg(+)/apoE-/- and PAI-1 Tg(+)/LDLR-/-, respectively) or were crossbred with mice completely deficient in PAI-1 gene expression (resulting in PAI-1-/-/apoE-/- and PAI-1-/-/LDLR-/-, respectively). All animals were placed on a western diet (21% fat and 0.15% cholesterol) at 4 weeks of age and analyzed for the extent of atherosclerosis after an additional 6, 15, or 30 weeks. Intimal and medial areas were determined by computer-assisted morphometric analysis of standardized microscopic sections from the base of the aorta. Atherosclerotic lesions were also characterized by histochemical analyses with the use of markers for smooth muscle cells, macrophages, and fibrin deposition. Typical atherosclerotic lesions were observed in all experimental animals, with greater severity at the later time points and generally more extensive lesions in apoE-/- than in comparable LDLR-/- mice. No significant differences in lesion size or histological appearance were observed among PAI-1-/-, PAI-1 Tg(+), or PAI-1 wild-type mice at any of the time points on either the apoE-/- or LDLR-/- genetic background. We conclude that genetic modification of PAI-1 expression does not significantly alter the progression of atherosclerosis in either of these well-established mouse models. These results suggest that fibrinolytic balance (as well as the potential contribution of PAI-1 to the regulation of cell migration) plays only a limited role in the pathogenesis of the simple atherosclerotic lesions observed in the mouse.
Animals↗
Regulation of lysyl oxidase by interferon-gamma in rat aortic smooth muscle cells.
Lysyl oxidase is an essential catalyst for the cross-linking of extracellular collagen and elastin. Abnormalities in lysyl oxidase activity may contribute to the pathogenesis of arterial diseases characterized by abnormal matrix remodeling. This study tested the hypothesis that interferon (IFN)-gamma, a proinflammatory cytokine present in aortic aneurysm and arteriosclerotic plaque rupture, downregulates lysyl oxidase gene expression in rat aortic smooth muscle cells. Steady-state lysyl oxidase mRNA levels decreased in a concentration- and time-dependent manner to 30% of control levels after 24 hours of treatment with IFN-gamma. Cell layer lysyl oxidase activity decreased in parallel with the observed changes in steady-state mRNA. Nuclear runoff studies suggested that transcriptional regulation was responsible for at least 40% of the observed downregulation. mRNA decay studies suggested that IFN-gamma also decreased lysyl oxidase mRNA half-life from 9 to 6 hours. Downregulation of lysyl oxidase by IFN-gamma did not appear to require new protein synthesis. This study documents that IFN-gamma downregulates lysyl oxidase gene expression in rat aortic smooth muscle cells by transcriptional and posttranscriptional mechanisms. If similar regulation occurs in vivo, it is possible that IFN-gamma-mediated changes in lysyl oxidase may contribute to arterial diseases characterized by abnormal extracellular matrix.
Animals↗
Use of fluorescent microspheres to localize in vivo gene transfer injection sites.
The potential for using gene therapy to treat a variety of disease states is growing rapidly. Many vector types and delivery systems have been developed that allow the optimization of protein production levels and kinetics for a given therapeutic gene product. In cases in which a transient, localized delivery of gene product is desired, any determination of the locale of transfected tissue by non-marker genes is problematic. We describe a technique by which the use of fluorescent microspheres can help in identifying potentially transfected tissue. Adenovirus containing the gene for beta-galactosidase (beta-gal) was mixed with fluorescent microspheres and injected into rat skeletal muscle and porcine myocardium. The injection sites could be visualized under ultraviolet light and correlated with beta-gal enzyme expression. This method is simple, inexpensive and generally useful for in vivo gene transfer experiments.
Adenoviridae↗
Rat sponge implant model: a new system for evaluating angiogenic gene transfer.
Therapeutic angiogenesis, either by protein injection or gene therapy, holds considerable promise for the treatment of coronary and peripheral artery diseases. Given the large number of angiogenic genes available, a simple, well defined, standard system to compare the relative angiogenic efficacy of such genes would be valuable. We have employed a replication-deficient adenovirus vector (complete E1a-, partial E1b- and partial E3-) to deliver the beta-galactosidase (beta-gal, AdLacZ) reporter gene or the human VEGF121 gene (AdGV VEGF121.10) to a rat sponge implant model of angiogenesis. beta-gal staining results reveal a transfection efficiency as high as 60% 24 h after 2x1010 particle units AdLacZ injection. Our results also indicate that a single injection of 2x1010 particle units of AdGVVEGF121.10 in the sponge results in >10, 000 pg VEGF protein expression per milligram of sponge tissue 24 h later. VEGF121 protein concentrations decreased 10-fold within 3 days and 100-fold within 7 days after injection. Significant VEGF121 protein levels were still detectable 14 days after initial virus injection. The high level of gene transfection efficiency was accompanied by enhanced angiogenesis in the sponge, a tissue devoid of any vessels before implantation. Compared to control (AdNull: adenovirus vector without the VEGF gene), AdGVVEGF121.10 induced a 2- to 3-fold up-regulation of angiogenesis at 7 and 14 days post vector injection as determined by both increased capillary number and increased tissue ingrowth. The angiogenic effects of AdGVVEGF121. 10 were dose-related in this model system. These findings demonstrate a dose-related angiogenic response to adenovirus-mediated gene therapy in this model.
Adenoviridae↗
The significance of the American Urological Association symptom index score in the evaluation of women with bladder outlet obstruction.
PURPOSE: The American Urological Association (AUA) symptom index was originally designed to assess the severity of lower urinary tract symptoms in men with benign prostatic hyperplasia. Data concerning the clinical application of the AUA symptom index to women are sparse. We evaluated the significance of the AUA symptom index in women with urodynamically defined bladder outlet obstruction. MATERIALS AND METHODS: From a urodynamic database of 587 consecutive women 38 (6.5%) were identified with bladder outlet obstruction, defined as a maximum flow rate of less than 12 ml. per second on repeat noninvasive uroflowmetry studies with a detrusor pressure at a maximum flow of greater than 20 cm. water on pressure flow study. All patients underwent a complete clinical and urodynamic evaluation, and completed the AUA symptom index questionnaire. Results in women with urodynamic obstruction were compared with those in 2 control groups, including women without obstruction but with sphincteric incontinence and asymptomatic healthy women. RESULTS: Mean symptom score was significantly higher in women with obstruction than in those with sphincteric incontinence or no symptoms (15.8+/-8.4 versus 10.3+/-6.4 and 2.1+/-2.7, respectively). Likewise, scores were classified as severe in 34% of women with obstruction compared with only 7% of those with sphincteric incontinence. However, no correlation was noted between symptom index scores and objective urodynamic parameters, which is similar to data already reported in male populations. CONCLUSIONS: The AUA symptom index score may be useful as a bothersomeness index in women with bladder outlet obstruction. However, subjective symptoms associated with bladder outlet obstruction are nonspecific and a complete urodynamic evaluation is essential for making the diagnosis.
Female↗
Duties of a doctor: UK doctors and good medical practice.
OBJECTIVE: To assess the responses of UK doctors to the General Medical Council's (GMC) Good Medical Practice and the Duties of a Doctor, and to the GMC's performance procedures for which they provide the professional underpinning. DESIGN: Questionnaire study of a representative sample of UK doctors. SUBJECTS: 794 UK doctors, stratified by year of qualification, sex, place of qualification (UK v non-UK), and type of practice (hospital v general practice) of whom 591/759 (78%) replied to the questionnaire (35 undelivered). MAIN OUTCOME MEASURES: A specially written questionnaire asking about awareness of Good Medical Practice, agreement with Duties of a Doctor, amount heard about the performance procedures, changes in own practice, awareness of cases perhaps requiring performance procedures, and attitudes to the performance procedures. Background measures of stress (General Health Questionnaire, GHQ-12), burnout, responses to uncertainty, and social desirability. RESULTS: Most doctors were aware of Good Medical Practice, had heard the performance procedures being discussed or had received information about them, and agreed with the stated duties of a doctor, although some items to do with doctor-patient communication and attitudes were more controversial. Nearly half of the doctors had made or were contemplating some change in their practice because of the performance procedures; a third of doctors had come across a case in the previous two years in their own professional practice that they thought might merit the performance procedures. Attitudes towards the performance procedures were variable. On the positive side, 60% or more of doctors saw them as reassuring the general public, making it necessary for doctors to report deficient performance in their colleagues, did not think they would impair morale, were not principally window dressing, and were not only appropriate for problems of technical competence. On the negative side, 60% or more of doctors thought the performance procedures were not well understood by most doctors, were a reason for more defensive practice, and could not be used for problems of attitude. Few differences were found among older and younger doctors, hospital doctors, or general practitioners, or UK and non-UK graduates, although some differences were present. CONCLUSIONS: Most doctors working in the UK are aware of Good Medical Practice and the performance procedures, and are in broad sympathy with Duties of a Doctor. Many attitudes expressed by doctors are not positive, however, and provide areas where the GMC in particular may wish to encourage further discussion and awareness. The present results provide a good baseline for assessing changes as the performance procedures become active and cases come before the GMC over the next few years.
Attitude of Health Personnel↗
Is amniotic fluid volume influenced by a 24-hour fast?
OBJECTIVE: To assess the influence of fasting for 24 hours on the amniotic fluid index (AFI). STUDY DESIGN: The AFI of 22 parturients in the second trimester of uncomplicated pregnancy was evaluated on the morning after a 24-hour fast. Patients were prospectively matched to another group of 25 patients who did not fast. Both groups were reevaluated after one week. Two different observers, blind to each other's results, performed the examinations. RESULTS: A statistically significant difference was found in the AFI between the two groups on the day after fasting (11.73 +/- 2.12 versus 15.4 +/- 1.2, respectively; P < .01). After one week there was no difference in AFI between the two groups (15.35 +/- 1.2 and 15.42 +/- 1.2, respectively; P > .01). CONCLUSION: Fasting may reduce the amniotic fluid volume as shown by the AFI, and fluid intake may restore the normal amount of amniotic fluid volume.
Amniotic Fluid↗