Showing papers by "St Thomas' Hospital published in 2003"

Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial.

Abstract: Context The expression and release of tissue factor is a major trigger for the activation of coagulation in patients with sepsis. Tissue factor pathway inhibitor (TFPI) forms a complex with tissue factor and blood protease factors leading to inhibition of thrombin generation and fibrin formation. Objectives To determine if administration of tifacogin (recombinant TFPI) provides mortality benefit in patients with severe sepsis and elevated international normalized ratio (INR) and to assess tifacogin safety in severe sepsis, including patients with low INR. Design and Setting A randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial conducted from March 21, 2000, through September 27, 2001, in 245 hospitals in 17 countries in North America, Europe, and Israel. Patients The primary efficacy population consisted of 1754 patients (≥18 years) with severe sepsis and a high INR (≥1.2) randomly assigned to intravenous infusion of either tifacogin (0.025 mg/kg per hour for 96 hours, n = 880) or placebo (arginine citrate buffer, n = 874), and 201 patients with a low INR ( Main Outcome Measure All-cause 28-day mortality. Results Overall mortality at 28 days in the tifacogin-treated group (n = 880) vs the placebo group (n = 874) for high INR was 34.2% vs 33.9%, respectively ( P = .88, Pearson χ 2 test; P = .75, logistic regression model). None of the protocol-specified secondary end points differed between the tifacogin vs placebo groups. An analysis on the first 722 patients demonstrated a mortality rate of 38.9% for placebo vs 29.1% for tifacogin ( P = .006, Pearson χ 2 test). Tifacogin significantly attenuated prothrombin fragment 1.2 and thrombin:antithrombin complex levels ( P t test) in patients with high and low INR. Overall mortality was lower in the tifacogin response in patients with low INR (12%; n = 83) vs placebo (22.9%; n = 118) ( P =.051, Pearson χ 2 test; P = .03, logistic regression model). There was an increase in serious adverse events with bleeding in the tifacogin group in both cohorts (6.5% tifacogin and 4.8% placebo for high INR; 6.0% tifacogin and 3.3% placebo for low INR). Conclusions Treatment with tifacogin had no effect on all-cause mortality in patients with severe sepsis and high INR. Tifacogin administration was associated with an increase in risk of bleeding, irrespective of baseline INR.

A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference.

Abstract: Study objectives To investigate the link between extreme diurnal preference, delayed sleep phase syndrome, and a length polymorphism in Per3. Design Subjects were genotyped using polymerase chain reaction. Patients or participants Subjects with defined diurnal preference as determined by the Horne-Ostberg questionnaire and patients with delayed sleep phase syndrome. Measurements and results The Per3 polymorphism correlated significantly with extreme diurnal preference, the longer allele associating with morningness and the shorter allele with eveningness. The shorter allele was strongly associated with the delayed sleep phase syndrome patients, 75% of whom were homozygous. Conclusion The length of the Per3 repeat region identifies a potential genetic marker for extreme diurnal preference.

Magnesium Metabolism and its Disorders

Abstract: Magnesium is the fourth most abundant cation in the body and plays an important physiological role in many of its functions. Magnesium balance is maintained by renal regulation of magnesium reabsorption. The exact mechanism of the renal regulation is not fully understood. Magnesium deficiency is a common problem in hospital patients, with a prevalence of about 10%. There are no readily available and easy methods to assess magnesium status. Serum magnesium and the magnesium tolerance test are the most widely used. Measurement of ionised magnesium may become more widely available with the availability of ion selective electrodes. Magnesium deficiency and hypomagnesaemia can result from a variety of causes including gastrointestinal and renal losses. Magnesium deficiency can cause a wide variety of features including hypocalcaemia, hypokalaemia and cardiac and neurological manifestations. Chronic low magnesium state has been associated with a number of chronic diseases including diabetes, hypertension, coronary heart disease, and osteoporosis. The use of magnesium as a therapeutic agent in asthma, myocardial infarction, and pre-eclampsia is also discussed. Hypermagnesaemia is less frequent than hypomagnesaemia and results from failure of excretion or increased intake. Hypermagnesaemia can lead to hypotension and other cardiovascular effects as well as neuromuscular manifestations. Causes and management of hypermagnesaemia are discussed.

Mutations in SOX2 cause anophthalmia

Abstract: A submicroscopic deletion containing SOX2 was identified at the 3q breakpoint in a child with t(3;11)(q26.3;p11.2) associated with bilateral anophthalmia. Subsequent SOX2 mutation analysis identified de novo truncating mutations of SOX2 in 4 of 35 (11%) individuals with anophthalmia. Both eyes were affected in all cases with an identified mutation.

Major and minor salivary gland tumors

Abstract: Malignant salivary gland tumors are rare. The most common tumor site is the parotid. Aetiologic factors are not clear. Nutrition may be a risk factor, as well as irradiation or a long-standing histologically benign tumor that occurs at youth. Painless swelling of a salivary gland should always be considered as suspicious, especially if no sign of inflammation is present. Signs and symptoms related to major salivary gland tumors differ from those concerning minor salivary gland tumors, as they depend on the different location of the salivary gland. Surgical excision represents the standard option in the treatment of resectable tumors of both major and minor salivary glands. Neutron, heavy ions or proton radiotherapy may be a treatment option for inoperable locoregional disease. Surgery, irradiation or re-irradiation are treatment options for local relapse, whereas radical neck dissection is indicated for regional relapses. Metastatic disease may be either treated with radiotherapy or palliative chemotherapy, depending on the site of metastases. For highly selected patients the employment of anti-androgen therapy is indicated.

Erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator

Abstract: Erectile dysfunction (ED) is a common condition and studies predict that it will become even more common in the future. There is increasing evidence to suggest that it is predominantly a vascular disease and may even be a marker for occult cardiovascular disease. The common pathological process is at the level of the endothelium, and cardiovascular risk factor control may be the key to preventing ED. Many men with established cardiovascular disease have ED. Specific guidelines for the management of ED in these patients have been produced by an expert panel. Cardiovascular risk stratification is an important initial step in managing such patients. In cardiac patients considered to have low cardiovascular risk, the management of ED can be safe and effective.

Gender-Linked Hypertension in Offspring of Lard-Fed Pregnant Rats

Abstract: Epidemiological studies suggest an association between maternal nutrition and offspring cardiovascular disease. We previously demonstrated endothelial dysfunction and abnormal aortic fatty acid composition in adult female offspring of rats fed animal lard during pregnancy. We have now further investigated this model. Female Sprague-Dawley rats were fed a control breeding diet (5.3% fat) or a diet rich in lard (25.7% fat) 10 days before and throughout pregnancy and lactation. Male and female offspring were implanted with radiotelemeters for recording of blood pressure, heart rate, and activity at 80, 180, and 360 days of age. Reactivity to acetylcholine and to nitric oxide were assessed in isolated small mesenteric arteries from 80- and 180-day-old littermates. Systolic blood pressure (awake phase) was raised in female offspring (180 days: offspring of control, 130.7±1.6 mm Hg, n=5, versus offspring of lard-fed, 138.1±2.9, n=5, P=0.029; 360 days: offspring of control, 129.7±3.7 mm Hg, n=6, versus offspring of lard-fed, 142.1±3.2, n=6, P=0.005). Diastolic blood pressure was also raised at 180 days (offspring of control, 87.6±1.0 mm Hg, n=5, versus offspring of lard-fed, 94.7±2.6, n=5, P=0.011). Blood pressure was not raised in male offspring. Endothelium-dependent relaxation to acetylcholine was blunted in male and female offspring of lard-fed dams (80 and 180 days). Feeding a diet rich in lard to pregnant rats leads to gender-related cardiovascular dysfunction in normally fed offspring.

Sex-differences in heritability of BMI: A comparative study of results from Twin Studies in Eight Countries

Abstract: Body mass index (BMI), a simple anthropometric measure, is the most frequently used measure of adiposity and has been instrumental in documenting the worldwide increase in the prevalence of obesity witnessed during the last decades. Although this increase in overweight and obesity is thought to be mainly due to environmental changes, i.e., sedentary lifestyles and high caloric diets, consistent evidence from twin studies demonstrates high heritability and the importance of genetic differences for normal variation in BMI. We analysed self-reported data on BMI from approximately 37,000 complete twin pairs (including opposite sex pairs) aged 20-29 and 30-39 from eight different twin registries participating in the GenomEUtwin project. Quantitative genetic analyses were conducted and sex differences were explored. Variation in BMI was greater for women than for men, and in both sexes was primarily explained by additive genetic variance in all countries. Sex differences in the variance components were consistently significant. Results from analyses of opposite sex pairs also showed evidence of sex-specific genetic effects suggesting there may be some differences between men and women in the genetic factors that influence variation in BMI. These results encourage the continued search for genes of importance to the body composition and the development of obesity. Furthermore, they suggest that strategies to identify predisposing genes may benefit from taking into account potential sex specific effects.

Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome

Abstract: Kindler syndrome is an autosomal recessive disorder characterized by neonatal blistering, sun sensitivity, atrophy, abnormal pigmentation, and fragility of the skin. Linkage and homozygosity analysis in an isolated Panamanian cohort and in additional inbred families mapped the gene to 20p12.3. Loss-of-function mutations were identified in the FLJ20116 gene (renamed “KIND1” [encoding kindlin-1]). Kindlin-1 is a human homolog of the Caenorhabditis elegans protein UNC-112, a membrane-associated structural/signaling protein that has been implicated in linking the actin cytoskeleton to the extracellular matrix (ECM). Thus, Kindler syndrome is, to our knowledge, the first skin fragility disorder caused by a defect in actin-ECM linkage, rather than keratin-ECM linkage.

Dietary silicon intake is positively associated with bone mineral density in men and premenopausal women of the Framingham Offspring cohort.

Abstract: The role of dietary silicon in bone health in humans is not known. In a cross-sectional, population-based study (2847 participants), associations between dietary silicon intake and BMD were investigated. Dietary silicon correlated positively and significantly with BMD at all hip sites in men and premenopausal women, but not in postmenopausal women, suggesting that increased silicon intake is associated with increased cortical BMD in these populations. Introduction: Osteoporosis is a burgeoning health and economic issue. Agents that promote bone formation are widely sought. Animal and cellular data suggest that the orthosilicate anion (i.e., dietary silicon) is involved in bone formation. The intake of silicon (Si, ∼30 mg/day) is among the highest for trace elements in humans, but its contribution to bone health is not known. Materials and Methods: In a cross-sectional, population-based study, we examined the association between silicon intake and bone mineral density (BMD) in 1251 men and 1596 pre- and postmenopausal women in the Framingham Offspring cohort (age, 30–87 years) at four hip sites and lumbar spine, adjusting for all potential confounding factors known to influence BMD and nutrient intake. Results: Silicon intake correlated positively with adjusted BMD at four hip sites in men and premenopausal women, but not in postmenopausal women. No significant association was observed at the lumbar spine in any group. Categorical analysis by Si intake, or energy-adjusted Si intake, supported these findings, and showed large differences in BMD (up to 10%) between the highest (>40 mg Si/day) and lowest (<14 mg Si/day) quintiles of silicon intake. A significant association at the lumbar spine in men was also observed. Further analyses indicated that some of the effects seen for moderate consumption of alcoholic beverages on BMD might be attributed to Si intake. Conclusions: These findings suggest that higher dietary silicon intake in men and younger women may have salutary effects on skeletal health, especially cortical bone health, that has not been previously recognized. Confirmation of these results is being sought in a longitudinal study and by assessment of the influence of silicon intake on bone markers in this cohort.

Cause of Stroke Recurrence Is Multifactorial Patterns, Risk Factors, and Outcomes of Stroke Recurrence in the South London Stroke Register

Abstract: Background and Purpose— This article examines stroke recurrence and whether the subtype of the initial stroke influences the risk and subtypes of further strokes. The proportion of recurrences attributable to conventional risk factors is quantified. Methods— From January 1995 to August 2000, all first-in-a-lifetime strokes (n=1626) were identified and prospectively followed up in a defined multiethnic inner city population of 234 533. Twelve overlapping referral sources and face-to-face follow-up at 3 months and 1 and 3 years were used to attain complete registration of stroke recurrence. Index and recurrent stroke were classified according to the Oxford Community Stroke Project classification. Results— In 2744 person-years of follow-up, 153 recurrences were observed. At 5 years, the cumulative risk of first stroke recurrence was 16.6% (95% CI, 13.5 to 20.4), and the combined risk of death or stroke recurrence was 65.3% (95% CI, 61.9 to 68.6). Ethnicity and subtype of index stroke were not associated with...

Guidelines for the management of pemphigus vulgaris

Abstract: These guidelines for management of pemphigus vulgaris have been prepared for dermatologists on behalf of the British Association of Dermatologists. They present evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation.

Is methicillin-resistant Staphylococcus aureus more virulent than methicillin-susceptible S. aureus? A comparative cohort study of British patients with nosocomial infection and bacteremia.

Abstract: Staphylococcus aureus is the most common cause of hospital-acquired bacteremia. From 1995 through 2000, data on age, sex, patient specialty at time of first bacteremia, primary and secondary sites of infection, delay in initiating antimicrobial therapy, and patient outcome were prospectively recorded for 815 patients with nosocomial S. aureus bacteremia. The proportion of patients whose death was attributable to methicillin-resistant S. aureus (MRSA) was significantly higher than that for methicillin-susceptible S. aureus (MSSA) (11.8% vs. 5.1%; odds ratio [OR], 2.49; 95% confidence interval [CI], 1.46–4.24; P < .001). After adjustment for host variables, the OR decreased to 1.72 (95% CI, 0.92–3.20; P = .09). There was no significant difference between rates of disseminated infection (7.1% vs. 6.2% for MRSA-infected patients and MSSA-infected patients, respectively; P = .63), though the rate of death due to disseminated infection was significantly higher than death due to uncomplicated infection (37% vs. 10% for MRSA-infected patients [P < .001] and 37% vs. 3% for MSSA-infected patients [P < .001]). There was a strong statistical trend toward death due to nosocomial MRSA infection and bacteremia, compared with MSSA.

Cytotoxic/natural killer cell cutaneous lymphomas. Report of EORTC Cutaneous Lymphoma Task Force Workshop.

Abstract: BACKGROUND: Cutaneous lymphomas expressing a cytotoxic or natural killer (NK) cell phenotype represent a group of lymphoproliferative disorders for which there is currently much confusion and little consensus regarding the best nomenclature and classification METHODS: This study analyzes 48 cases of primary cutaneous lymphoma expressing cytotoxic proteins and/or the NK cell marker, CD56 These cases were collected for a workshop of the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Task Force, to better clarify the clinical, morphologic, and phenotypic features of these uncommon tumors RESULTS: Several categories with different clinical and pathologic features were delineated: 1) aggressive, CD8+, epidermotropic, cytotoxic T-cell lymphoma; 2) mycosis fungoides, cytotoxic immunophenotype variant; 3) subcutaneous panniculitis-like T-cell lymphoma; 4) NK/T-cell lymphoma, nasal type; 5) CD4+, NK cell lymphoma; 6) blastoid NK cell lymphoma; (7) intravascular NK-like lymphoma; and 8) cytotoxic, peripheral T-cell lymphoma CONCLUSIONS: Our data show that primary cutaneous cytotoxic/NK cell lymphomas include distinct groups of diseases, clinically, histologically, and biologically Because the finding of a cytotoxic phenotype often has prognostic significance, the routine use of cytotoxic markers in the diagnosis and classification of cutaneous lymphomas should be expanded

Blood culture negative endocarditis: analysis of 63 cases presenting over 25 years

Abstract: Objective: To analyse cases of blood culture negative endocarditis (BCNE) seen at St Thomas’ Hospital, London, between 1975 and 2000. Methods: Data on all episodes of endocarditis with negative blood cultures seen at St Thomas’ Hospital between 1975 and 2000 were collected prospectively and analysed retrospectively. Results: Sixty three patients with BCNE were seen during the study period: 48 (76%) with native and 15 (24%) prosthetic valve infection. BCNE accounted for 12.2% of the 516 cases of endocarditis seen at St Thomas’ Hospital. The diagnosis of endocarditis was clinically definite by the Duke criteria in only 21% (7 of 34) of cases of pathologically proven native valve endocarditis but in 62% (21 of 34) of cases by the St Thomas’ modifications of the criteria. Comparable figures for the 11 cases of pathologically proven prosthetic valve endocarditis were 45% and 73%. Despite negative blood cultures a causative organism was identified in 31 (49%) of the 63 cases: in 15 by serology (8 Coxiella burnetii , 6 Bartonella species, and 1 Chlamydia psittaci ); in 9 cases by culture of the excised valve; in 3 by microscopy of the excised valve, on which large numbers of Gram positive cocci were seen although the culture was sterile; and in the other 4 by isolation from a site other than the excised valve (2 respiratory specimens, 1 from the pacemaker tip, and 1 from an excised embolus). In addition 5 of the 6 cases of Bartonella infection were confirmed by polymerase chain reaction study of the excised valve. Two thirds of the 32 patients for whom no pathogen was identified had received antibiotics before blood was cultured. Thus truly “negative” endocarditis was very uncommon (6% of the cases). Conclusion: If blood cultures are negative in definite or suspected endocarditis, serum should be analysed for Bartonella , Coxiella , and Chlamydia species antibodies, and the excised valve or (rarely) embolus should be analysed by microscopy, culture, histology, and relevant polymerase chain reaction. Other specimens may be relevant. The Duke criteria performed poorly in BCNE; St Thomas’ additional minor criteria gave more definite diagnoses.

Dissolution of different forms of partially porous silicon wafers under simulated physiological conditions

Abstract: Silicon (Si) in the form of orthosilicic acid (Si(OH) 4 ) is vital for normal bone and connective tissue homeostasis. Porous Si films release Si(OH) 4 in aqueous solutions in the physiological pH range. This study investigates the release of Si(OH) 4 from porous Si films under physiological conditions with the aim of developing a bioavailable form of Si. Using a standardised technique, porous Si films released increasing Si with time. Dissolution was significant at pH 7 and above, and at a temperature of 37 °C. Higher porosity generally promoted dissolution, however multiple layer films did not show enhanced solubility over corresponding single layer controls. These properties will be used to optimise Si nanostructures that slowly deliver orthosilicic acid in the digestive tract.

Joint British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous T-cell lymphomas

Abstract: These guidelines were commissioned by the British Association of Dermatologists guidelines and therapeutics subcommittee. Members of the committee are N.H.Cox (Chairman), A.S.Highet, D.Mehta, R.H.Meyrick Thomas, A.D.Ormerod, J.K.Schofield, C.H.Smith and J.C.Sterling. Members of the U.K. Cutaneous Lymphoma Group who have contributed include C.Benton, R.Cowan, C.Deardon, B.Hancock, H.Lucraft and D.Slater. Disclaimer These guidelines have been prepared for dermatologists on behalf of the British Association of Dermatologists and the U.K. Cutaneous Lymphoma Group (UKCLG) and reflect the best data available at the time the report was prepared. Caution should be exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations in this report. It may be necessary or even desirable to depart from the guidelines in special circumstances. Just as adherence to guidelines may not constitute defence against a claim of negligence, so deviation from them should not be necessarily deemed negligent. Summary These guidelines for the management of cutaneous T-cell lymphoma have been prepared for dermatologists on behalf of the British Association of Dermatologists and the U.K. Cutaneous Lymphoma Group. They present evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation.

Integrin-specific signaling pathways controlling focal adhesion formation and cell migration

Abstract: The fibronectin (FN)-binding integrins α4β1 and α5β1 confer different cell adhesive properties, particularly with respect to focal adhesion formation and migration. After analyses of α4+/α5+ A375-SM melanoma cell adhesion to fragments of FN that interact selectively with α4β1 and α5β1, we now report two differences in the signals transduced by each receptor that underpin their specific adhesive properties. First, α5β1 and α4β1 have a differential requirement for cell surface proteoglycan engagement for focal adhesion formation and migration; α5β1 requires a proteoglycan coreceptor (syndecan-4), and α4β1 does not. Second, adhesion via α5β1 caused an eightfold increase in protein kinase Cα (PKCα) activation, but only basal PKCα activity was observed after adhesion via α4β1. Pharmacological inhibition of PKCα and transient expression of dominant-negative PKCα, but not dominant-negative PKCδ or PKCζ constructs, suppressed focal adhesion formation and cell migration mediated by α5β1, but had no effect on α4β1. These findings demonstrate that different integrins can signal to induce focal adhesion formation and migration by different mechanisms, and they identify PKCα signaling as central to the functional differences between α4β1 and α5β1.

Seronegative antiphospholipid syndrome

Abstract: History repeats itself The antiphospholipid syndrome (APS; Hughes syndrome) is now 20 years old.1,2 The clinical features are well defined, and include the tendency to both arterial and venous thrombosis, to recurrent miscarriages, and to occasional thrombocytopenia. So too are the features which give the syndrome such a distinctive flavour, setting it apart from other coagulopathies—the severity of the headaches and migraine, the memory loss, the “atypical multiple sclerosis”, the prominence of the livedo reticularis, the heart valve involvement.3 Traditionally, raised levels of antiphospholipid antibodies (aPL), especially IgG aPL, are associated with the increased thrombotic risk characteristic of the syndrome. However, as always in real clinical practice, there are often discrepancies between antibody levels and clinical disease expression. As awareness increases, and the number of patients with APS grows, it comes …

How sensitive to clinical change are ETDRS logMAR visual acuity measurements

Abstract: Purpose: To determine the sensitivity to change and specificity achieved when published test–retest variability (TRV) data are used to determine whether measured changes in ETDRS logarithm of the minimum angle of resolution (logMAR) visual acuity reflect true clinical change or are attributable to measurement error alone. Methods: Various degrees of change in visual acuity were simulated in a group of normal subjects by adjusting test difficulty through manipulation of viewing distance. Sensitivity to simulated change and specificity were determined with change criteria derived from published Bland-Altman 95% ranges for TRV. Results: The relationship between viewing distance and measured acuity was as predicted theoretically. Simulated acuity change of 0.2 logMAR (two lines of letters) or greater can be reliably distinguished from no change (both sensitivity and specificity >95%) with the ETDRS chart, but a change of 0.1 logMAR or less cannot. Conclusions: The use of 95% ranges for TRV to establish the smallest measured visual acuity change that can be reliably detected ensures a high specificity but does not take account of sensitivity. Use of change criteria derived from published 95% ranges results in a sensitivity of approximately 50% (assuming identical levels of TRV). Sensitivity may be improved by using a change criterion that is smaller than the minimum change sought, providing the change criterion is still at least as large as the 95% range for TRV, so that specificity is maintained. Reducing TRV allows smaller changes in acuity to be reliably detected.

Relation of erectile dysfunction to angiographic coronary artery disease

Abstract: I t is estimated that over 152 million men worldwide experience erectile dysfunction (ED).1 Although the incidence and severity of ED increases with age, the most common pathologic risk factor for organic ED is believed to be diabetes. Other vascular diseases are also known to cause ED; the main link is insult to the vascular endothelium, which plays a major role in the regulation of arterial patency. Hyperlipidemia, smoking, hypertension, and diabetes cause endothelial cell dysfunction, which precedes the formation of atherosclerotic plaques. This study assesses the prevalence and severity of ED in a cohort of men who underwent coronary angiography and identifies any correlaton of ED and the severity of plaque burden found on coronary angiography. • • • The study received ethical committee approval and recruited 132 men attending day case coronary angiography, who agreed and consented to take part in the study. Baseline demographic data were determined with an emphasis on cardiovascular risk factors (Table 1). All men were asked to complete the International Index of Erectile Function-5 (IIEF) questionnaire to ascertain erectile performance. In addition, they were specifically asked about the temporal relation of their ED to their date of onset of cardiovascular symptoms. The diagnosis of coronary artery disease was defined either by a history of myocardial infarction (48%), percutaneous coronary angioplasty (12%), coronary artery bypass grafting (7%), or by angiographic results. Stenosis of 50% in a coronary artery on angiography was considered significant. Formal stratification of plaque burden was assessed by calculation of a Gensini score2 for each angiogram. The relation between the number of coronary arteries with significant stenosis and IIEF score was assessed by chi-square test. Linear regression analysis was performed to ascertain the relation between plaque burden as quantified by the Gensini score and IIEF score. Multiple regression analysis was used to investigate the association between IIEF score and established cardiovascular risk factors and drug therapies. Symptoms of ED were volunteered by 45% (n 59) of all men who admitted to having ED, although 65% (n 86) scored 21 on the IIEF, suggesting a diagnosis of ED. Of those 59 men who subjectively admitted to having ED, 58% (n 34) admitted to experiencing ED before their diagnosis of coronary artery disease. Angiography was performed for progression of disease in 44% (n 58) and established a diagnosis in 41% (n 54). Coronary angiographic findings demonstrated that 30% (n 39) had singlevessel disease, 21% (n 28) had 2-vessel disease, and 27% (n 36) had 3-vessel disease. The median Gensini score (median 34, range 0 to 192) showed an inverse correlation with IIEF score (r 0.17; p 0.05), although there were no significant differences between the number of diseased arteries observed and the incidence of ED (p 0.34). Backward stepwise multiple regression analysis demonstrated an inverse correlation of IIEF score with cardiovascular risk factors (r 0.54; p 0.001) and identified age ( 0.51; p 0.001) and smoking ( 3.13; p 0.05) as the principal risk factors. Further analysis showed that IIEF score correlated (r 0.44; p 0.001) with Gensini score ( 0.06; p 0.04), aspirin use ( 6.57; p 0.04), or clopidogrel therapy ( 7.34; p 0.07). No correlation was observed with any other drug therapy, including diuretics or blockers. • • • ED is a common symptom in men and is often attributed to the presence of diabetes or therapy with drugs used to treat cardiovascular risk, such as blockers or thiazide diuretics. It is not often recognized that ED shares the same determinants as atheroFrom the Departments of Cardiology and Chemical Pathology, St. Thomas’ Hospital, London, United Kingdom. Dr. Wierzbicki’s address is: Department of Chemical Pathology, St. Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom. E-mail: Anthony. Wierzbicki@kcl.ac.uk. Manuscript received May 21, 2002; revised manuscript received and accepted August 28, 2002. TABLE 1 Baseline Characteristics of Patients Who Underwent Angiography

The association of body mass index and osteoarthritis of the knee joint: an examination of genetic and environmental influences.

Abstract: Objective To examine the genetic and environmental influences on the known association between body mass index (BMI) and knee osteoarthritis (OA), using adult twin data. Methods Bilateral knee radiographs were obtained from 785 pairs of healthy female twins (mean age 54.5 ± 7.8 years) from the St. Thomas' Hospital Adult Twin Registry (261 monozygotic [MZ] and 524 dizygotic [DZ] twin pairs). Tibiofemoral knee OA was graded according to the Kellgren and Lawrence (K/L) scoring system on an ordinal scale of 0–4. Presence of knee OA was defined as a K/L grade of ≥2 on either side of the knee joint. Body weight and height were measured and the subjects were stratified into quartiles of BMI. Cross-trait cross-twin association of BMI and knee OA was assessed by logistic regression, to assess whether genetic or environmental influences explain the BMI–knee OA link. The genetic (heritability) and environmental contributions to each of the measures were estimated using path modeling. Results A strong association was found between high BMI and the presence of knee OA (odds ratio 3.90 for highest versus lowest quartile of BMI; P = 0.0001). The heritability of knee OA was 50.4% (95% confidence interval [95% CI] 34–62%) and that of BMI was 55.7% (95% CI 35–72%). However, cross-trait cross-twin associations were not significantly different from unity in either the MZ or DZ twin pairs, indicating that shared genetic influences were unlikely to explain the association. Path modeling showed that the model containing additive genetic factors, common environmental factors, and unique environmental factors had the best fit to the data overall. The shared genetic path between BMI and knee OA could be dropped without deterioration in the fit of the model. Conclusion The strong association between high BMI and knee OA is not likely to be mediated by shared genetic factors. The results imply that environmental modification of BMI can influence knee OA.

The role of the growth hormone-insulin-like growth factor axis in glucose homeostasis

Abstract: Homeostatic mechanisms normally maintain the plasma glucose concentration within narrow limits despite major fluctuations in supply and demand. There is increasing evidence that the growth hormone (GH)-insulin-like growth factor (IGF) axis may play an important role in glucose metabolism. GH has potent effects on intermediary metabolism, some of which antagonize the actions of insulin. In contrast, IGF-I has insulin-like actions, which are, in the case of glucose metabolism, opposite to those of GH. There is often deranged glucose metabolism in situations where GH is deficient or in excess. The clinical administration of GH or IGF-I results in altered glucose metabolism and changes in insulin resistance. Despite these observations, the precise role of GH and IGF-I and their interactions with insulin in controlling normal glucose homeostasis are unknown. In diabetes, GH secretion is abnormally increased as a result of reduced portal insulin resulting in impaired hepatic IGF-I generation. Evidence suggests that this may contribute to the development of diabetic microvascular complications. IGF-I 'replacement' in diabetes is under investigation and new methods of delivering IGF-I as a complex with IGFBP-3 offer exciting new prospects.