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Showing papers by "St Thomas' Hospital published in 2001"


Journal ArticleDOI
TL;DR: Development of retinopathy (incidence) was strongly associated with baseline glycaemia, glycaemic exposure over 6 years, higher blood pressure and with not smoking and progression was associated with older age, male sex, hyperglycaemia (as evidenced by a higher HbA1 c) and withNot smoking.
Abstract: Aims/hypothesis. To determine risk factors related to the incidence and progression of diabetic retinopathy over 6 years from diagnosis of Type II (non-insulin-dependent) diabetes mellitus. Methods. This report describes 1919 patients from within the United Kingdom Prospective Diabetes Study (UKPDS), with retinal photographs taken at diagnosis and 6 years later and with complete data available. Photographs were centrally graded for lesions of diabetic retinopathy using the modified Early Treatment of Diabetic Retinopathy Study Final scale. Risk factors were assessed after 3 months diet from the time of diagnosis of diabetes. Patients were seen every 3 months in a hospital setting. Biochemical measurements were done by a central laboratory. End points of vitreous haemorrhage and photocagulation were confirmed by independent adjudication of systematically collected clinical data. The main outcome measures were incidence and progression of retinopathy defined as a two-step Early Treatment of Diabetic Retinopathy Study (ETDRS) final scale change. Results. Of the 1919 patients, 1216 (63 %) had no retinopathy at diagnosis. By 6 years, 22 % of these had developed retinopathy, that is microaneurysms in both eyes or worse. In the 703 (37 %) patients with retinopathy at diagnosis, 29 % progressed by two scale steps or more. Development of retinopathy (incidence) was strongly associated with baseline glycaemia, glycaemic exposure over 6 years, higher blood pressure and with not smoking. In those who already had retinopathy, progression was associated with older age, male sex, hyperglycaemia (as evidenced by a higher HbA1 c) and with not smoking. Conclusion/interpretation. The findings re-emphasise the need for good glycaemic control and assiduous treatment of hypertension if diabetic retinopathy is to be minimised. [Diabetologia (2001) 44: 156–163]

892 citations


Journal ArticleDOI
01 Jun 2001-Stroke
TL;DR: The extent of these findings indicates that an acute assessment of impairments and disability is necessary to determine the appropriate nursing and rehabilitation needs of patients with stroke.
Abstract: Background and Purpose—The goals of the present study were to estimate the prevalence of acute impairments and disability in a multiethnic population of first-ever stroke and to identify differences in impairment and early disability between pathological and Bamford subtypes. Associations between impairments and death and disability at 3 months were identifed. Methods—Impairments that occur at the time of maximum neurological deficit were recorded, and disability according to the Barthel Index (BI) was assessed 1 week and 3 months after stroke in patients in the South London Stroke Register. Results—Of 1259 registered patients, 6% had 1 or 2, 31.1% had 3 to 5, 50.6% had 6 to 10, and 10.6% had >10 impairments. Common impairments were weakness (upper limb, 77.4%), urinary incontinence (48.2%), impaired consciousness (44.7%), dysphagia (44.7%), and impaired cognition (43.9%). Patients with total anterior circulation infarcts had the highest age-adjusted prevalence of weakness, dysphagia, urinary incontinence...

697 citations


Journal ArticleDOI
TL;DR: The presence of bone marrow‐derived cells was noted in both histologically normal mouse kidneys and in human transplanted kidneys suffering damage from a variety of causes, indicating that bone marrow cells contribute to both normal turnover of renal epithelia and regeneration after damage, and is suggested that this could be exploited therapeutically.
Abstract: In order to establish whether extra-renal cells contribute to the turnover and repair of renal tissues, this study examined kidneys of female mice that had received a male bone marrow transplant and kidney biopsies from male patients who had received kidney transplants from female donors. By using in situ hybridization to detect Y-chromosomes it could be demonstrated that circulating stem cells frequently engraft into the kidney and differentiate into renal parenchymal cells. In the human renal grafts it was confirmed that some of the recipient-derived cells within the kidney exhibited a tubular epithelial phenotype, by combining in situ hybridization with immunostaining for the epithelial markers CAM 5.2 and the lectin Ulex europaeus. Female mouse recipients of male bone marrow grafts showed co-localization of Y-chromosomes and tubular epithelial markers Ricinus communis and Lens culinaris, and a specific cytochrome P450 enzyme (CYP1A2) indicating an appropriate functional capability of clustered newly formed marrow-derived tubular epithelial cells. Y-chromosome-containing cells were observed within glomeruli, with morphology and location appropriate for podocytes. Within the murine kidney, these Y-chromosome-positive cells were negative for the mouse macrophage marker F4/80 antigen and leukocyte common antigen, but were vimentin-positive. The presence of bone marrow-derived cells was noted in both histologically normal mouse kidneys and in human transplanted kidneys suffering damage from a variety of causes. These data indicate that bone marrow cells contribute to both normal turnover of renal epithelia and regeneration after damage, and it is suggested that this could be exploited therapeutically.

640 citations


Journal ArticleDOI
TL;DR: There appears to be no benefit to combining an intraarticular anterior cruciate ligament reconstruction with an extraarticular procedure; however, the patellar tendon autograft may provide better objective stability in the long term.
Abstract: A prospective randomized study was performed to determine the differences in results between three methods of anterior cruciate ligament reconstruction: autogenous bone-patellar tendon-bone graft (group 1), semitendinosus and gracilis tendon graft reconstruction combined with an extraarticular procedure (group 2), and semitendinosus and gracilis tendon graft reconstruction alone (group 3). Preoperatively, there were no significant differences between groups. At a mean of 35.4±11.6 months postoperatively, 102 patients returned for evaluation. International Knee Documentation Committee knee evaluation revealed no significant differences in symptoms, function, return to pre-injury activity, harvest site abnormalities, or limitation of motion between groups 1 and 3. Patients in group 2 had a higher incidence of patellofemoral crepitation and loss of motion than did patients in group 3. The mean manual maximum KT-1000 arthrometer side-to-side difference was 2.1±2.0 mm in group 1, which was statistically signif...

621 citations


Journal ArticleDOI
TL;DR: The results of twin studies can be generalised to singleton populations for these measures and disease outcomes, and volunteer twins were not found to differ from age-matched singleton women in distribution or prevalence of diseases.
Abstract: The classic twin study is sometimes described as "the perfect natural experiment" for the investigation of the aetiology of complex disease, but assumptions of the twin design need to be empirically tested if their results are to be considered unbiased and representative of singleton populations. In this study comparisons of disease and prevalence of lifestyle characteristics have been made between twin participants in the St Thomas' Hospital UK adult twin registry, the largest twin volunteer register in the UK for the study of diseases of ageing, and a parallel population-based study of singleton women. The only differences found were for weight, where monozygotic (MZ) twins were lighter and had a smaller variance than dizygotic (DZ) twins and singletons. For the other variables studied, volunteer twins were not found to differ from age-matched singleton women in distribution or prevalence of: bone mineral density, osteoarthritis, blood pressure, hypertensive drug use, height, history of hysterectomy and ovariectomy, menopausal status and current alcohol and overall tobacco consumption. We conclude that the results of twin studies can be generalised to singleton populations for these measures and disease outcomes.

451 citations


Journal Article
TL;DR: Genetic effects are of major importance in myopia/hyperopia; astigmatism appears to be dominantly inherited.
Abstract: PURPOSE. A classical twin study was performed to examine the relative importance of genes and environment in refractive error. METHODS. Refractive error was examined in 226 monozygotic (MZ) and 280 dizygotic (DZ) twin pairs aged 49 to 79 years (mean age, 62.4 years). Using a Humphrey-670 automatic refractor, continuous measures of spherical equivalent, total astigmatism, and corneal astigmatism were recorded. Univariate and bivariate maximum likelihood model fitting was used to estimate genetic and environmental variance components using information from both eyes. RESULTS. For the continuous spectrum of myopia/hyperopia, a model specifying additive genetic and unique environmental factors showed the best fit to the data, yielding a heritability of 84% to 86% (95% confidence interval [CI], 81%-89%). If myopia and hyperopia (≤ -0.5 D and ≥ 0.5 D, respectively) were treated as binary traits, the heritability was 90% (95% CI, 81%-95%) for myopia and 89% (95% CI, 81%-94%) for hyperopia. For total and corneal astigmatism, modeling showed dominant genetic effects are important; dominant genetic effects accounted for 47% to 49% of the variance of total astigmatism (95% CI, 37%-55%) and 42% to 61% of corneal astigmatism variance (95% CI, 8%-71%), with additive genetic factors accounting for 1% to 4% and 4% to 18%, respectively (95% CIs, 0%-13% and 0%-60%, respectively). CONCLUSIONS. Genetic effects are of major importance in myopia/hyperopia; astigmatism appears to be dominantly inherited.

447 citations


Journal ArticleDOI
TL;DR: Complete anatomic and, to some extent, functional recovery can be induced by intravitreal TA despite long-term refractory inflammatory CME, and optical coherence tomography aids in the management of these cases.

445 citations


Journal ArticleDOI
TL;DR: Which patient groups are more at risk for this syndrome and the clinical management of the condition are described, as well as which patient groups should be considered to be at risk of developing thiamine deficiency.

424 citations


Journal ArticleDOI
TL;DR: The study data support the hypothesis that sex differences in anterior cruciate ligament tear rates are caused primarily by several interrelated intrinsic factors, most importantly, stiffness and muscular strength increase stress on the anterior cruiser ligament in female athletes.
Abstract: We performed a prospective study based on the hypothesis that physiologic differences exist between men and women in strength after adjustments for body weight; that the size of the anterior cruciate ligament is proportionate to the strength of its antagonists, the quadriceps muscles; and that women have a relatively small anterior cruciate ligament, thus predisposing them to a disproportionate number of anterior cruciate ligament injuries. One hundred matched high school basketball players, 50 male and 50 female, were evaluated with anthropometric measurements, body fat analysis, muscle strength evaluation, and magnetic resonance imaging measurements of the intercondylar notch and cross-sectional area of the anterior cruciate ligament at the outlet. The male players were taller and heavier than their female counterparts, although they had 11% less body fat. Male players had statistically greater quadriceps and hamstring muscle strength than female players, even when adjustments were made for body weight. With adjustments for body weight, the size of the anterior cruciate ligament in girls was found to be statistically smaller than in boys. There was no statistically significant difference in the notch width index between the sexes. The study data support our hypothesis that sex differences in anterior cruciate ligament tear rates are caused primarily by several interrelated intrinsic factors. Most importantly, stiffness and muscular strength increase stress on the anterior cruciate ligament in female athletes. The anterior cruciate ligament, when adjustments have been made for body weight, is smaller in female athletes, and therefore, probably does not compensate for the lack of stiffness and strength.

359 citations


Journal ArticleDOI
TL;DR: A five-point severity grading scheme is proposed and the entry criteria detailed and the five severity points are: slight, mild, moderate, severe and catastrophic.
Abstract: Tinnitus is a common experience with up to one third of the adult population experiencing it at some time in their life. Less than 1% of the adult population have tinnitus of sufficient severity to affect their quality of life seriously (although up to 8% may seek medical advice about it). Much of the severity of tinnitus relates to the individuals' psychological response to the abnormal tinnitus signal. The prevalence of tinnitus increases in association with high frequency hearing loss. There is, unfortunately, no diagnostic test that either confirms the presence of tinnitus or its severity. Currently there is no satisfactory severity grading system. A five-point severity grading scheme is therefore proposed and the entry criteria detailed. The five severity points are: slight, mild, moderate, severe and catastrophic. Categorization as 'severe' or 'catastrophic' should be, by epidemiological definition, very rare. General guidance, theory and evidential support are contained within.

346 citations


Journal ArticleDOI
TL;DR: The topical application of DNA repair enzymes to sun-damaged skin of patients with xeroderma pigmentosum lowered the rate of development of two forms of these lesions during a year of treatment.

Journal ArticleDOI
TL;DR: The literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical Practice and Practice Economics Committee and were approved by the Committee on September 23, 2000 and by the AGA governing board on November 12, 2000.

Journal ArticleDOI
TL;DR: It is provided the first evidence that PKCα or a PKC α‐associated serine/threonine kinase can phosphorylate the ERM C‐terminal threonine residue within a kinase–ezrin molecular complex in vivo.
Abstract: Protein kinase C (PKC) α has been implicated in β1 integrin-mediated cell migration. Stable expression of PKCα is shown here to enhance wound closure. This PKC-driven migratory response directly correlates with increased C-terminal threonine phosphorylation of ezrin/moesin/radixin (ERM) at the wound edge. Both the wound migratory response and ERM phosphorylation are dependent upon the catalytic function of PKC and are susceptible to inhibition by phosphatidylinositol 3-kinase blockade. Upon phorbol 12,13-dibutyrate stimulation, green fluorescent protein–PKCα and β1 integrins co-sediment with ERM proteins in low-density sucrose gradient fractions that are enriched in transferrin receptors. Using fluorescence lifetime imaging microscopy, PKCα is shown to form a molecular complex with ezrin, and the PKC-co-precipitated endogenous ERM is hyperphosphorylated at the C-terminal threonine residue, i.e. activated. Electron microscopy showed an enrichment of both proteins in plasma membrane protrusions. Finally, overexpression of the C-terminal threonine phosphorylation site mutant of ezrin has a dominant inhibitory effect on PKCα-induced cell migration. We provide the first evidence that PKCα or a PKCα-associated serine/threonine kinase can phosphorylate the ERM C-terminal threonine residue within a kinase–ezrin molecular complex in vivo.

Journal ArticleDOI
TL;DR: FGF-23, the gene mutated in ADHR, is a secreted protein and its mRNA is abundantly expressed by several different OHO tumors, indicating that FGF- 23 may be a candidate phosphate wasting factor, previously designated "phosphatonin".
Abstract: The gene mutated in autosomal dominant hypophosphatemic rickets (ADHR), a phosphate wasting disorder, has been identified as FGF-23, a protein that shares sequence homology with fibroblast growth factors (FGFs). Patients with ADHR display many of the clinical and laboratory characteristics that are observed in patients with oncogenic hypophosphatemic osteomalacia (OHO), a disorder thought to arise by the secretion of a phosphate wasting factor from different mesenchymal tumors. In the present studies, we therefore investigated whether FGF-23 is a secreted factor and whether it is abundantly expressed in OHO tumors. After transient transfection of OK-E, COS-7, and HEK293 cells with the plasmid encoding full-length FGF-23, all three cell lines efficiently secreted two protein species into the medium that were approximately 32 and 12 kDa upon SDS-PAGE and subsequent Western blot analysis using an affinity-purified polyclonal antibody to FGF-23. Furthermore, Northern blot analysis using total RNA from five different OHO tumors revealed extremely high levels of FGF-23 mRNA, and Western blot analysis of extracts from a sixth tumor detected the 32 kDa FGF-23 protein species. In summary, FGF-23, the gene mutated in ADHR, is a secreted protein and its mRNA is abundantly expressed by several different OHO tumors. Our findings indicate that FGF-23 may be a candidate phosphate wasting factor, previously designated "phosphatonin".

Journal ArticleDOI
TL;DR: The results stress the importance of research into the genetic regulation of proteins involved in haemostasis and atherothrombotic disorders, including myocardial infarction and stroke, by showing that genetic factors have a major effect on plasma concentrations of haemOSTatic proteins.

Journal ArticleDOI
TL;DR: Seven cases are described in which neurological damage followed spinal or combined spinal‐epidural anaesthesia using an atraumatic spinal needle, and anaesthetists need to relearn the rule that a spinal needle should not be inserted above L3.
Abstract: Seven cases are described in which neurological damage followed spinal or combined spinal-epidural anaesthesia using an atraumatic spinal needle. All patients were women, six obstetric and one surgical. All experienced pain during insertion of the needle, which was usually believed to be introduced at the L2-3 interspace. In all cases, there was free flow of cerebrospinal fluid before spinal injection. There was one patchy block but, in the rest, anaesthesia was successful. Unilateral sensory loss at the levels of L4-S1 (and sometimes pain) persisted in all patients; there was foot drop in six and urinary symptoms in three. Magnetic resonance imaging showed a spinal cord of normal length with a syrinx in the conus (n = 6) on the same side as both the persisting clinical deficit and the symptoms that had occurred at insertion of the needle. The tip of the conus usually lies at L1-2, although it may extend further. Tuffier's line is an unreliable method of identifying the lumbar interspaces, and anaesthetists commonly select a space that is one or more segments higher than they assume. Because of these sources of error, anaesthetists need to relearn the rule that a spinal needle should not be inserted above L3.

Journal ArticleDOI
TL;DR: The results support the current practice of reserving ICSI only for severe male-factor problems and offer no advantage over IVF in terms of clinical outcome in cases of non-male-factor infertility.

Journal ArticleDOI
09 Mar 2001-Science
TL;DR: Twin study results suggest that variation in musical pitch recognition is primarily due to highly heritable differences in auditory functions not tested by conventional audiologic methods.
Abstract: We used a twin study to investigate the genetic and environmental contributions to differences in musical pitch perception abilities in humans. We administered a Distorted Tunes Test (DTT), which requires subjects to judge whether simple popular melodies contain notes with incorrect pitch, to 136 monozygotic twin pairs and 148 dizygotic twin pairs. The correlation of DTT scores between twins was estimated at 0.67 for monozygotic pairs and 0.44 for dizygotic pairs. Genetic model-fitting techniques supported an additive genetic model, with heritability estimated at 0.71 to 0.80, depending on how subjects were categorized, and with no effect of shared environment. DTT scores were only weakly correlated with measures of peripheral hearing. This suggests that variation in musical pitch recognition is primarily due to highly heritable differences in auditory functions not tested by conventional audiologic methods.

Journal ArticleDOI
TL;DR: Endothelial activation mediated by anti-beta2GPI antibody can be inhibited by statins, and this data provide a rationale for using statins as an additional therapeutic tool in APS.
Abstract: Objective To investigate the ability of statins, the inhibitors of the hydroxymethylglutaryl–coenzyme A reductase enzyme, to affect endothelial cell activation induced by anti–β2-glycoprotein I (anti-β2GPI) antibodies in vitro. Methods Human umbilical vein endothelial cell (HUVEC) activation was evaluated as U937 monocyte adhesion, E-selectin, and intercellular adhesion molecule 1 (ICAM-1) expression by cell enzyme-linked immunosorbent assay and as interleukin-6 (IL-6) messenger RNA (mRNA) expression by RNA protection assay. E-selectin–specific nuclear factor κB (NF-κB) DNA-binding activity was evaluated by the gel-shift assay. HUVECs were activated by polyclonal affinity-purified IgG, human monoclonal IgM anti-β2GPI antibodies, human recombinant IL-1β, tumor necrosis factor α, or lipopolysaccharide (LPS). Results Fluvastatin reduced, in a concentration-dependent manner (1–10 μM), the adhesion of U937 to HUVECs and the expression of E-selectin and ICAM-1 induced by anti-β2GPI antibodies as well as by cytokines or LPS. Another lipophilic statin, simvastatin, display similar effects but to a lesser extent than fluvastatin. The inhibition of E-selectin expression exerted by fluvastatin was related to the impairment of NF-κB binding to DNA. Moreover, the drug attenuated the expression of IL-6 mRNA in HUVEC exposed to anti-β2GPI antibodies or cytokines. Incubation of HUVECs with mevalonate (100 μM), concomitantly with fluvastatin, greatly prevented the inhibitory effect of statin. Conclusion Endothelial activation mediated by anti-β2GPI antibody can be inhibited by statins. Because of the suggested role of endothelial cell activation in the pathogenesis of antiphospholipid syndrome (APS), our data provide, for the first time, a rationale for using statins as an additional therapeutic tool in APS.

Journal ArticleDOI
TL;DR: UK laboratories should be aware of grossly anomalous combinations of species and phenotype, demanding reference laboratory confirmation; useful indicator drugs, where resistance implies a mechanism conferring other resistances that may be less obvious in direct tests; and antibiotics that are prone to select resistant mutants of particular species during therapy.
Abstract: If isolates are speciated and if a sufficient range of antibiotics is tested, underlying resistance mechanisms can often be inferred from the antibiogram data. This allows: (i) anomalous combinations of phenotype and organism to be reconsidered; (ii) prediction of further antibiotics that deserve testing; and (iii) the suppression of susceptibilities that are anomalous in the light of the inferred mechanism. This 'interpretative reading' is widely undertaken in France but is largely precluded in the UK by limited speciation and the testing of narrow ranges of antibiotics. Nevertheless, UK laboratories should be aware of: (i) grossly anomalous combinations of species and phenotype, demanding reference laboratory confirmation; (ii) useful indicator drugs, where resistance implies a mechanism conferring other resistances that may be less obvious in direct tests; and (iii) antibiotics that are prone to select resistant mutants of particular species during therapy. Details of these combinations of organism and resistance are presented. Relationships between antibiogram and mechanism are also presented to allow full interpretative reading for those testing wide panels of drugs versus speciated isolates.

Journal ArticleDOI
TL;DR: Evidence is provided for the first time a clear genetic effect on bone resorption in premenopausal women and the regulation of PTH, vitamin D metabolism, and calcium excretion and the hormones regulating these processes.
Abstract: A classical twin study was performed to assess the relative contribution of genetic and environmental factors to bone metabolism, calcium homeostasis, and the hormones regulating them. It was examined further whether the genetic effect is menopause dependent. The subjects were 2136 adult twins (98.3% female): 384 monozygotic (MZ) and 684 dizygotic (DZ) twin pairs. The intraclass correlations were calculated, and maximum likelihood model fitting was used to estimate genetic and environmental variance components. The intraclass correlations for all of the variables assessed were higher in MZ twin pairs. The heritabilities (95% CIs) obtained from model fitting for hormones regulating bone metabolism and calcium homeostasis were parathyroid hormone (PTH), 60% (54-65%); 25-hydroxyvitamin D [25(OH)D]; 43% (28-57%), 1,25-hydroxyvitamin D [1,25(OH)], 65% (53-74%); and vitamin D binding protein 62% (56-66%). The heritabilities (95% CIs) for markers of bone formation also were assessed; bone-specific alkaline phosphatase (BSAP), 74% (67-80%), and osteocalcin, 29% (14-44%); marker of bone resorption deoxypyridinoline (DPD), 58% (52-64%); and measure of calcium homeostasis 24 h urine calcium, creatinine (Cr), 52% (41-61%). The magnitude of genetic influence differed with menopause for most variables. This study provides evidence for the importance of genetic factors in determining bone resorption and formation, calcium excretion, and the hormones regulating these processes. It shows for the first time a clear genetic effect on bone resorption in premenopausal women and the regulation of PTH, vitamin D metabolism, and calcium excretion. The genes controlling bone hormones and markers are likely to be useful therapeutic and diagnostic targets.

Journal ArticleDOI
01 Jan 2001-Stroke
TL;DR: Research into a strategy of screening for subclinical VTE in patients is needed, with a view to identifying a subgroup at risk of progression to symptomatic and life-threatening events, in whom outcome might be improved by anticoagulation.
Abstract: Background—Treatment for venous thromboembolism (VTE) is highly effective in preventing morbidity and mortality, yet pulmonary embolism (PE) accounts for up to 25% of early deaths after stroke. This is because the current diagnostic paradigm is reactive rather than proactive: the clinician responds to VTE when it becomes symptomatic, in the expectation that initiation of treatment will prevent progression to more serious manifestations. This approach is flawed, because sudden death from PE is frequently unheralded and nonfatal symptomatic pulmonary emboli are often unrecognized or misdiagnosed. Summary of Comment—Morbidity and mortality from PE could be reduced either by more effective thromboprophylaxis or earlier diagnosis and treatment of established VTE. The fact that early use of short-term, low-dose, unfractionated heparin (UFH) is not associated with sustained, clinically meaningful benefit suggests that a fundamental change in the diagnostic approach to VTE is needed, one which requires a greater ...

Journal ArticleDOI
TL;DR: Past studies using indirect immunofluorescence (IIF) as a measure of pemphigus antibody levels have failed to demonstrate consistently a relationship between disease severity and IIF titres, unlike enzyme‐linked immunosorbent assays (ELISA), which utilize recombinant proteins.
Abstract: Background Pemphigus vulgaris (PV) and foliaceus (PF) are characterized by antibodies to the desmosomal proteins desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1), respectively. Past studies using indirect immunofluorescence (IIF) as a measure of pemphigus antibody levels have failed to demonstrate consistently a relationship between disease severity and IIF titres. However, IIF is not able to measure separately Dsg1 and 3 antibodies, unlike enzyme-linked immunosorbent assays (ELISA), which utilize recombinant proteins. Objectives To compare independently Dsg1 and 3 antibody levels with the severity of both cutaneous and oral involvement in PV and PF. Patients and methods Four hundred and twenty-four serum samples were analysed from 80 subjects with PV and 24 with PF. IgG antibodies to Dsg1 and 3 were measured by ELISA. For every sample analysed, the associated severity of skin and oral disease were graded from 0 to 3; quiescent, mild, moderate and severe. Results A relationship between Dsg1 antibodies and skin severity was demonstrated such that a 10-unit increase in Dsg1 ELISA value was associated with a 34% chance of having a higher severity score [95% confidence interval (CI), 25–45%, P < 0·0005]. This was observed in both PV and PF. Oral severity was associated with Dsg3 antibody levels and a 10-unit increase in the Dsg3 ELISA value was associated with a 25% chance of a higher oral severity score (CI 17–33%, P < 0·0005). We were unable to demonstrate a relationship between Dsg1 antibodies and oral severity, even after adjusting for the effect of Dsg3 antibodies. Similarly, there was no relationship between Dsg3 antibodies and skin severity. Conclusions This study suggests that the clinical phenotype of pemphigus, in particular the balance of skin and oral disease, is determined principally by the quantities of Dsg1 and 3 autoantibodies, respectively.

Journal ArticleDOI
TL;DR: It is demonstrated that an intramural fibroid halves the chances of an ongoing pregnancy following assisted conception.
Abstract: BACKGROUND: Although uterine fibroids occur in 30% of women and are associated with a degree of subfertility, the effect of intramural fibroids on the outcome of IVF or ICSI treatment has not been prospectively studied. METHODS: Data were prospectively collected on 434 women undergoing IVF/ICSI in the assisted conception unit of an inner London teaching hospital. Patients were assessed for the presence of fibroids by transvaginal ultrasound and hysterosonography or hysteroscopy where appropriate. RESULTS: During the study period, 112 women with (study), and 322 women without (controls), intramural fibroids were treated. Patients were similar regarding the cause and duration of their infertility, number of previous treatments, and basal serum FSH concentration. Women in the study group were on average 2 years older (36.4 versus 34.6 years; P < 0.01). There was no significant difference in the duration of ovarian stimulation or gonadotrophin requirement, number of follicles developed, oocytes collected, embryos available for transfer or replaced. When analysing only women with intramural fibroids of ≤5 cm in size (n = 106) pregnancy, implantation and ongoing pregnancy rates were significantly reduced: 23.3, 11.9 and 15.1 respectively compared with 34.1, 20.2 and 28.3% in the control group (P = 0.016, P = 0.018 and P = 0.003). The mean size of the largest fibroids was 2.3 cm (90% range 2.1-2.5 cm). Logistic regression analysis demonstrated that the presence of intramural fibroids was one of the significant variables affecting the chance of an ongoing pregnancy, even after controlling for the number of embryos available for replacement and increasing age, particularly age ≥40 years, odds ratio 0.46 (CI 0.24-0.88; P = 0.019). CONCLUSION: This study demonstrated that an intramural fibroid halves the chances of an ongoing pregnancy following assisted conception.

Journal ArticleDOI
TL;DR: It is concluded that most ILCs show genetic or epigenetic changes affecting the E‐cadherin gene and that many of these tumours lack E‐ cadher in expression, consistent with biallelic inactivation of CDH1 by promoter methylation, mutation or allelic loss in any combination.
Abstract: The cell-cell adhesion receptor gene E-cadherin (CDH1) is expressed by epithelial cells, in which it mediates adhesion and morphogenesis. Invasive lobular carcinoma (ILC) characteristically infiltrates diffusely as single cells; by immunohistochemistry, many of these tumours lack E-cadherin expression. In the present study we investigated various ways in which loss of function of the E-cadherin gene could occur in ILCs, namely, promoter methylation, mutation and allelic loss. We analysed 22 ILCs and found 12 (55%) E-cadherin-negative samples by immunohistochemical analysis. Methylation-specific polymerase chain reaction (PCR) showed that 17/22 (77%) of these tumours had methylation of the CDH1 promoter, including 11/12 (91%) of the E-cadherin-negative tumours. All 16 exons of E-cadherin (including intron-exon boundaries) were amplified from chromosomal DNA and screened for mutations by conformation-sensitive gel electrophoresis (CSGE). Bands with altered mobility were analysed by direct sequencing. We identified five frameshift mutations, which resulted in downstream stop codons and one splice site mutation in six different tumours (29%). Loss of heterozygosity (LOH) was assessed using microsatellite markers, and 9/18 (50%) informative tumours showed LOH. We conclude that most ILCs show genetic or epigenetic changes affecting the E-cadherin gene and that many of these tumours lack E-cadherin expression. In all cases in which there was loss of expression, this was consistent with biallelic inactivation of CDH1 by promoter methylation, mutation or allelic loss in any combination.

Journal ArticleDOI
TL;DR: There is evidence that the use of screening instruments in combination with asking parents about their concerns improves the efficiency of an instrument, but the number and type of concerns that parents have about their child's behaviour and development determine whether using a screening instrument within the clinic setting is effective.
Abstract: Screening and surveillance are different but related activities involving the detection of impairments with a view to prevention or amelioration of consequent disability and handicap. Screening is the prospective identification of unrecognised disorder by the application of specific tests or examinations. Surveillance refers to the ongoing and systematic collection of data relevant to the identification of a disorder over time by an integrated health system. The review by Hall1 in Health for all children concluded that most screening tests that set out to identify neurodevelopmental disorders do not meet the stringent criteria outlined by Cochrane and Holland2 and Wilson and Jungner.3 In some conditions, for example language disorders, this is because there is uncertainty about “caseness” and tests tend to have low sensitivity and specificity.4 5 This is particularly the case for screening tests that attempt to identify a specific condition rather than general developmental delay, and for the identification of relatively rare disorders. In the latter case, even when the sensitivity and specificity of a screen remain constant, the positive predictive value (the proportion of children with a positive screen result and who have the disorder) is lower the rarer a disorder is within the population.6 The concept of developmental surveillance is a parent–professional partnership that takes a broader look at developmental and behavioural skills and progress over time. It combines the observations of parents with the developmental knowledge of the professional and the deployment of specific tests. There is evidence that the use of screening instruments in combination with asking parents about their concerns improves the efficiency of an instrument.7 8 However, the number and type of concerns that parents have about their child's behaviour and development determine whether using a screening instrument within the clinic setting is effective. For example, Glascoe, …

Journal ArticleDOI
TL;DR: In this article, the authors report on the development and implementation of this technique as the first such routine service within a diagnostic department of the UK National Health Service (NHS), which has led to the rapid diagnosis of abnormalities and early reassurance for women with normal results.

Journal ArticleDOI
TL;DR: The patterns of KIR locus frequencies combined with the similar linkage disequilibrium values suggest that there was a distinction in the distribution of the two broad haplotype groups between the populations studied.
Abstract: Killer cell immunoglobulin-like receptors (KIRs) are members of a group of molecules that specifically recognize HLA class I ligands and are found on subsets of human lymphopoetic cells. The number of KIR loci can vary between individuals, resulting in a heterogeneous array of possible KIR genes. The range of observed profiles has been explained by the occurrence of two haplotype families termed A and B which can be distinguished on the basis of certain KIR sequences. Here we attempted to determine whether the frequencies of putative KIR loci and the two haplotype groups vary in three ethnically defined, healthy, and unrelated control populations, namely UK Caucasoid (n=136), Palestinian (n=105) and Thai (n=119). We molecularly typed genomic DNA for the presence of 12 putative KIR loci, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, and KIR3DS1, using modified PCR sequence-specific primers. The patterns of KIR locus frequencies combined with the similar linkage disequilibrium values suggest that there was a distinction in the distribution of the two broad haplotype groups between the populations studied. The A haplotype was always the most prevalent, but the ratio of A to B varied between populations. The frequency of B haplotype was highest in the Palestinians and lowest in the Thais (Pc<0.0001).

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TL;DR: Genistein causes l-arginine/NO-dependent vasodilation in forearm vasculature of human subjects with similar potency to 17&bgr;-estradiol and potentiates endothelium-dependent Vasodilation to acetylcholine.
Abstract: Background—Genistein, a phytoestrogen, may have estrogenic cardioprotective actions. We investigated whether genistein influences endothelium-dependent vasodilation in forearm vasculature of healthy human subjects and compared the effects of genistein with those of 17β-estradiol. Methods and Results—The brachial arterial was cannulated with a 27-gauge needle for drug infusion. Forearm blood flow responses were measured with strain-gauge plethysmography. Genistein (10 to 300 nmol/min, each dose for 6 minutes) produced a dose-dependent increase in forearm blood flow from 3.4±0.3 to 9.6±1.3 mL · min−1 · 100 mL forearm−1 (mean±SEM) in men (n=9, P<0.0001 by ANOVA). The mean forearm venous concentration of genistein during infusion of the highest dose was 1.8±0.3 μmol/L in 6 additional men. Genistein produced a similar increase in blood flow in premenopausal women. Daidzein, another phytoestrogen, was ineffective, but equimolar concentrations of 17β-estradiol caused similar vasodilation to genistein. Responses ...

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TL;DR: Changes in maternal physiology during pregnancy influence pharmacokinetics, and this may have important sequelae for drug dosing, especially for drugs for which adverse effects occur at concentrations within, or just above, the therapeutic range.
Abstract: Pharmacokinetics describes the handling of a drug by the body - how the drug is absorbed, distributed and eliminated and how these processes determine plasma concentrations of the drug. Changes in maternal physiology during pregnancy influence pharmacokinetics, and this may have important sequelae for drug dosing, especially for drugs for which adverse effects occur at concentrations within, or just above, the therapeutic range. For many drugs absorption is decreased and elimination increased, thus tending to reduce plasma concentrations. There are, however, relatively few specific data on pharmacokinetics in pregnancy, compared to the non-gravid state, because of the obvious ethical issues surrounding studies during pregnancy. Most therapeutic guidelines are thus based on observational studies and basic principles.