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International audience; In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

Codification of the Criminal Law

Sandhoff disease, a GM2 gangliosidosis caused by a deficiency in β-hexosaminidase, is characterized by progressive neurodegeneration. Although loss of neurons in association with lysosomal storage of glycosphingolipids occurs in patients with this disease, the molecular pathways that lead to the accompanying neurological defects are unclear. Using an authentic murine model of GM2 gangliosidosis, we examined the pattern of neuronal loss in the central nervous system and investigated the effects of gene transfer using recombinant adeno-associated viral vectors expressing β-hexosaminidase subunits (rAAV2/1-Hex). In 4-month-old Sandhoff mice with neurological deficits, cells staining positively for the apoptotic signature in the TUNEL reaction were found in the ventroposterior medial and ventroposterior lateral (VPM/VPL) nuclei of the thalamus. There was progressive loss of neuronal density in this region with age. Comparable loss of neuronal density was identified in the lateral vestibular nucleus of the brainstem and a small but statistically significant loss was present in the ventral spinal cord. Loss of neurons was not detected in other regions that were analysed. Administration of rAAV2/1-Hex into the brain of Sandhoff mice prevented the decline in neuronal density in the VPM/VPL. Preservation of neurons in the VPM/VPL was variable at the humane endpoint in treated animals, but correlated directly with increased lifespan. Loss of neurons was localized to only a few regions in the Sandhoff brain and was prevented by rAAV-mediated transfer of β-hexosaminidase gene function at considerable distances from the site of vector administration.

By the action of N-bromosuccinimide the side-chain of an alkyl-naphthalene is brominated on the α-carbon atom (allyl system). Removal of hydrogen bromide gives an olefin which is easily oxidised to the naphthoic acid.

Background: Pregnancy outcomes following in utero exposure to antiepileptic drugs (AEDs) are uncertain, limiting an evidenced-based approach. Objective: To determine if fetal outcomes vary as a function of different in utero AED exposures. Methods: This ongoing prospective observational study across 25 epilepsy centers in the USA and UK enrolled pregnant women with epilepsy from October 1999 to February 2004 to determine if differential long-term cognitive and behavioral neurodevelopmental effects exist across the four most commonly used AEDs. This initial report focuses on the incidence of serious adverse outcomes including major congenital malformations (which could be attributable to AEDs) or fetal death. A total of 333 mother/child pairs were analyzed for monotherapy exposures: carbamazepine (n = 110), lamotrigine (n = 98), phenytoin (n = 56), and valproate (n = 69). Results: Response frequencies of pregnancies resulting in serious adverse outcomes for each AED were as follows: carbamazepine 8.2%, lamotrigine 1.0%, phenytoin 10.7%, and valproate 20.3%. Distribution of serious adverse outcomes differed significantly across AEDs and was not explained by factors other than in utero AED exposure. Valproate exhibited a dose-dependent effect. Conclusions: More adverse outcomes were observed in pregnancies with in utero valproate exposure vs the other antiepileptic drugs (AEDs). These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus. For women who fail other AEDs and require valproate, the dose should be limited if possible.

Helen A Lane, Jamie C Smith, J Stephen DaviesDepartment of Endocrinology, University of Wales College of Medicine, Heath Park, Cardiff, Wales, UKAbstract: Initially considered as a semipermeable barrier separating lumen from vessel wall, the endothelium is now recognised as a complex endocrine organ responsible for a variety of physiological processes vital for vascular homeostasis. These include the regulation of vascular tone, luminal diameter, and blood flow; hemostasis and thrombolysis; platelet and leucocyte vessel-wall interactions; the regulation of vascular permeability; and tissue growth and remodelling. The endothelium modulates arterial stiffness, which precedes overt atherosclerosis and is an independent predictor of cardiovascular events. Unsurprisingly, dysfunction of the endothelium may be considered as an early and potentially reversible step in the process of atherogenesis and numerous methods have been developed to assess endothelial status and large artery stiffness. Methodology includes flow-mediated dilatation of the brachial artery, assessment of coronary flow reserve, carotid intimamedia thickness, pulse wave analysis, pulse wave velocity, and plethysmography. This review outlines the various modalities, indications, and limitations of available methods to assess arterial dysfunction and vascular risk.Keywords: endothelial function, vascular risk, vascular stiffness

In patients with cancer, adrenal enlargement due to either metastatic disease or diffuse non-metastatic hyperplasia is increasingly recognized with modern imaging techniques. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, characterized by non-suppressible hypercortisolism, has also been described in neoplasia in the absence of ectopic adrenocorticotrophic hormone (ACTH) production. In the majority of cases of malignancy-associated hypercortisolism, it might be expected that the presence of malignant disease would be clinically apparent, thus rendering a detailed endocrinological evaluation of the HPA axis unnecessary. However, in the present case we describe a patient with occult malignancy presenting with bilateral adrenocortical enlargement and non-suppressible hypercortisolism that was not due to the ectopic ACTH syndrome. There were no clinical Cushingoid features other than hypertension and new-onset diabetes mellitus. Detailed diagnostic investigations for the possibility of Cushing's syndrome were performed before the underlying diagnosis of gastric adenocarcinoma eventually became apparent. Characteristics and potential mechanisms of non-suppressible hypercortisolism in cancer are discussed. We believe that this scenario will occur with greater frequency in the future, given the increasing early use of sophisticated high-resolution imaging for the evaluation of suspected intra-abdominal pathology.

Objective Tracheostomies in children are increasingly performed for chronic medical conditions. There are no published studies reporting the experience of children with a tracheostomy in school. Such information would be valuable in planning the care and education of these children. The aims of this study were to identify those children with a tracheostomy in Nottinghamshire schools and determine the support they were receiving. Design, setting and participants Questionnaire survey to families and school carers of 11 children with a tracheostomy. Results All children of school age were in full-time education (five mainstream, five special schools). One preschool child attended a Family Centre. Four had problems finding suitable carers, delaying return to school in three. Four parents were dissatisfied with aspects of the child's experience at school: two felt the teaching staff were unsupportive, one was unhappy with the care of the tracheostomy, and one had problems funding a carer. Ten out of 11 school carers were satisfied with their training; 10 would have liked regular update sessions. The amount of care required varied. Those with complex medical problems in a special school setting needed frequent care, and one had required admission to hospital from school. One child had time off school because of lack of carer availability. Those who were severely disabled had less time off school for ill health after the tracheostomy than before the tracheostomy. Conclusion Children with tracheostomies can successfully and safely achieve full-time education in both mainstream and special schools. A dedicated multidisciplinary team, including input from the parents, is essential to achieve this goal. Regular revision of skills and information sessions for the teaching staff would be beneficial.

Although GH deficiency may underlie the increased cardiovascular risk in adult hypopituitarism, other coexisting hormonal deficiencies and/or unphysiological hormone replacement may contribute. l-Deamino-8-d-arginine (DDAVP), when administered parenterally, potentiates hemostasis by increasing plasma procoagulant factors. We investigated whether chronic intranasal DDAVP therapy influences clotting factors (plasma fibrinogen, factor VIII, and von Willebrand factor antigen) and endothelial function (flow-mediated dilation of the brachial artery) in 30 GH-treated hypopituitary subjects, including both DDAVP-treated subjects (group A) (mean age, 46 ± 11 yr) and vasopressin-sufficient subjects (group B) (mean age, 47 ± 16 yr). Fifteen healthy controls (group C) (mean age, 48 ± 12 yr) were also studied. All hypopituitary patients were receiving stable GH replacement (median duration, 19 months). Comparing the three groups, concentrations of fibrinogen (mean ± sd) (A, 3.3 ± 1.0 g/liter vs. B, 3.5 ± 0.9 vs. C, 2.6 ± 0.8, P < 0.05), factor VIII (A, 130% ± 30% vs. B, 128% ± 30% vs. C, 104% ± 35%, P < 0.05) and von Willebrand factor antigen (A, 124% ± 35% vs. B, 134% ± 45% vs. C, 93% ± 36%, P < 0.05) were higher in hypopituitary subjects, compared with controls. However, there were no differences in clotting factors between groups A and B. Flow-mediated dilation did not differ significantly between the two hypopituitary groups (A, 5.9% ± 2.0% vs. B, 4.7% ± 1.6%) and was similar to that in the control group (C, 5.7% ± 2.1%). In conclusion, although endothelium-dependent vasodilation is intact in GH-treated hypopituitary adults, elevated concentrations of hemostatic markers suggest the persistence of a prothrombotic tendency and endothelial dysfunction. Intranasal DDAVP does not appear to influence this proatherogenic profile in hypopituitary adults with vasopressin deficiency.

Summary objectives Untreated growth hormone deficiency (GHD) is implicated in the increased cardiovascular risk associated with adult hypopituitarism. Oxidative stress, predisposing to lipid peroxidation, may be an important mediator of endothelial dysfunction, a pro-atherogenic state associated with adult GHD. design and patients In a randomized, double-blind, placebo-controlled study we investigated the effects of GH replacement on low-density lipoprotein (LDL) oxidation and neutrophil superoxide (O2−) generating capacity in 32 GHD adults (19 males, 13 females; age range 19–64 years) over 3 months. Thirty age- and sex-matched healthy controls were also studied. measurements Lipid hydroperoxides (HPOs) in plasma were measured using the ferrous oxidation with xylenol orange (FOX) assay. The susceptibility of LDL to oxidation was assessed by the copper-catalysed lag phase of LDL oxidation. Neutrophil O2−generating capacity was assessed by a lucigenin-based chemiluminescent assay of NADPH oxidase activity. Body composition was assessed using bioelectrical impedance analysis. results Compared to controls, GHD subjects had higher LDL cholesterol (4·0 ± 0·8 vs. 3·5 ± 0·9 mmol/l, P

OBJECTIVES Hypopituitary adults with growth hormone deficiency (GHD) have an increased cardiovascular mortality, although the mechanisms remain unclear. Endothelial dysfunction, characterized by reduced nitric oxide (NO) bioavailability, is a key early event in atherogenesis and is associated with increased vascular smooth muscle tone and arterial stiffening. DESIGN AND PATIENTS In a randomized, double-blind, placebo-controlled study, we investigated the effects of GH replacement on endothelial function and large-artery stiffness in 32 GHD adults (19 males, 13 females) (age range 19-64 years) over a 6-month period. Thirty-two age- and sex-matched healthy controls were also studied. MEASUREMENTS Endothelial function was assessed using ultrasonic wall tracking to measure flow-mediated dilatation (FMD) of the brachial artery. Large artery stiffness was assessed by pulse wave analysis of the radial artery pressure waveform, allowing determination of the corresponding central arterial pressure waveform and derivation of the augmentation index. Fasting lipid profiles, glucose and insulin were also measured. RESULTS At baseline, FMD (mean +/- SD) was impaired in GH-deficient subjects vs. controls (3.4 +/- 2.3 vs. 5.7 +/- 2.0%, P < 0.0001), although endothelium-independent dilatation was similar. The augmentation index was higher in GH-deficient subjects vs. controls (23 +/- 12 vs. 14 +/- 14%, P < 0.01). GH-deficient subjects had higher LDL cholesterol (4.1 +/- 0.8 vs. 3.5 +/- 0.8 mmol/l, P < 0.01) and lower HDL cholesterol (1.1 +/- 0.3 vs. 1.4 +/- 0.4 mmol/l, P < 0.01). In GH-deficient subjects, there were inverse correlations between LDL cholesterol and FMD (r = -0.40, P < 0.05) and between FMD and the augmentation index (r = - 0.58, P < 0.01). Regression analysis identified FMD as an independent predictor of the augmentation index (P < 0.0001). In comparison with baseline, GH replacement resulted in an increase in FMD (5.0 +/- 2.6 vs. 2.8 +/- 1.9%, P < 0.01). There were decreases in central aortic systolic pressure (117 +/- 15 vs. 123 +/- 17 mmHg, P < 0.01), diastolic pressure (82 +/- 10 vs. 86 +/- 8 mmHg, P < 0.01) and the augmentation index (22 +/- 8% vs. 26 +/- 10%, P < 0.05) despite unchanged brachial pressure indices. LDL cholesterol also decreased (3.5 +/- 0.8 vs. 4.2 +/- 0.8 mmol/l, P < 0.01). There were no significant changes in the placebo group. CONCLUSIONS Adult GHD is associated with endothelial dysfunction and increased large-artery stiffness. An improvement in endothelial function and a reduction in arterial stiffness following GH replacement suggests an important therapeutic role for GH in reducing cardiovascular risk associated with adult GHD.

Sex hormones appear to play a pivotal role in determining cardiovascular risk. Androgen deprivation therapy for males with prostate cancer results in a hypogonadal state that may have important, but as yet undetermined, effects on the vasculature. We studied the effects of androgen deprivation therapy on large artery stiffness in 22 prostate cancer patients (mean age, 67 +/- 8 yr) over a 6-month period. Arterial stiffness was assessed using pulse-wave analysis, a technique that measures peripheral arterial pressure waveforms and generates corresponding central aortic waveforms. This allows determination of the augmentation of central pressure resulting from wave reflection and the augmentation index, a measure of large artery stiffness. Body compositional changes were assessed using bioelectrical impedance analysis. Fasting lipids, glucose, insulin, testosterone, and estradiol were measured. After a 3-month treatment period, the augmentation index increased from 24 +/- 6% (mean +/- SD) at baseline to 29 +/- 9% (P = 0.003) despite no change in peripheral blood pressure. Timing of wave reflection was reduced from 137 +/- 7 to 129 +/- 10 msec (P = 0.003). Fat mass increased from 20.2 +/- 9.4 to 21.9 +/- 9.6 kg (P = 0.008), whereas lean body mass decreased from 63.2 +/- 6.8 to 61.5 +/- 6.0 kg (P = 0.016). There were no changes in lipids or glucose during treatment. Median serum insulin rose from 11.8 (range, 5.6-49.1) to 15.1 (range, 7.3-83.2) mU/liter at 1 month (P = 0.021) and to 19.3 (range, 0-85.0 mU/liter by 3 months (P = 0.020). There was a correlation between the changes in fat mass and insulin concentration over the 3-month period (r = 0.56; P = 0.013). In a subgroup of patients whose treatment was discontinued after 3 months, the augmentation index decreased from 31 +/- 7% at 3 months to 29 +/- 5% by 6 months, in contrast to patients receiving continuing treatment in whom the augmentation index remained elevated at 6 months compared with baseline (P = 0.043). These data indicate that induced hypogonadism in males with prostate cancer results in a rise in the augmentation of central arterial pressure, suggesting large artery stiffening. Adverse body compositional changes associated with rising insulin concentrations suggest reduced insulin sensitivity. These adverse hemodynamic and metabolic effects may increase cardiovascular risk in this patient group.

Primary hyperparathyroidism (PHPT) is associated with increased cardiovascular risk, although the mechanisms involved remain unclear. Recent evidence has shown increased pulse pressure to be a powerful predictor of cardiovascular events. As increases in pulse pressure are due largely to arterial stiffening, we measured arterial stiffness in 21 subjects with PHPT (18 women and 3 men; 46-71 yr old) and 21 age- and sex-matched healthy controls using pulse wave analysis, a technique that measures peripheral arterial pressure waveforms and generates corresponding central aortic waveforms. This allows determination of the augmentation of central pressure resulting from wave reflection and augmentation index, a measure of vessel stiffness. Metabolic parameters were also measured. The serum calcium level among PHPT subjects was (mean +/- SD) 2.74+/-0.14 mmol/L. pulse wave analysis showed that both augmentation and the augmentation index were significantly higher in the PHPT group vs. controls [16+/-5 vs. 10+/-4 mm Hg (P < 0.001) and 36+/-9% vs. 25+/-6% (P < 0.001)] despite comparable brachial systolic pressures between groups (136+/-13 vs. 134+/-18 mm Hg). Patients with PHPT had higher fasting serum insulin levels [median (range), 15.8 (7.4-39.4) vs. 11.6 (5.1-23) mU/L; P < 0.05] and triglyceride (1.6+/-0.6 vs. 1.2+/-0.4 mmol/L; P < 0.05), but lower high density lipoprotein cholesterol (1.4+/-0.4 vs. 1.6+/-0.3 mmol/L; P < 0.05). These data indicate that subjects with mild PHPT (calcium

The purpose of the present work was to examine effects of the Cu–Fe interaction on intestinal β-carotene 15,15′-dioxygenase activity when a wide range of dietary Fe (deficiency to excess) was used in relation to Cu status of rats. The effect of dietary carbohydrates was also examined since they play a role in the Cu–Fe interactionin vivo. Weanling male Sprague-Dawley rats (n72) were divided into twelve dietary groups, which were fed on either low-, normal-, or high-Fe levels (0·9, 9·0, and 90·0 mmol Fe/kg diet respectively) combined with Cu-adequate or -deficient levels (0·94 and 0·09 mmol Cu/kg diet respectively) and with starch or fructose in the diets. The data showed that both Fe concentration and β-carotene 15,15′-dioxygenase activity in small intestinal mucosa were enhanced with increasing dietary Fe and with Cu deficiencyv. Cu adequacy. Dietary fructose did not aggravate the Fe-enhancement, related to Cu deficiency, in the small intestine; however, fructose increased the intestinal dioxygenase activity in rats fed on normal- or high-Fe diets when compared with starch controls. Thus, the highest intestinal dioxygenase activity associated with the lowest hepatic retinol (total) concentration was found in rats fed on the Cu-deficient, high-Fe, fructose-based diet. Finally, a positive linear relationship was found between the dioxygenase activity and Fe concentration in intestinal mucosa. In conclusion, the data indicate that β-carotene 15,15′-dioxygenase activity requires Fe as cofactorin vivoand the enzyme is modulated by the three dietary components: Cu, Fe, and fructose.

Aims: The primary objective was to estimate prevalence of malnutrition on admission to four hospitals. Secondary objectives included assessing the relationship between nutritional status and length of hospital stay, numbers of new prescriptions, new infections and disease severity. Methods: We entered eligible patients according to predefined quotas for elective and emergency admissions to 23 specialities. We measured height, weight, Body Mass Index and anthropometrics, and recorded history of unintentional weight loss. Patients who had lost ≧10% of their body weight, had a Body Mass Index ⪡20, or had a Body Mass Index ⪡20 with one anthropometric measurement ⪡15th centile were considered malnourished. Results: Of 1611 eligible patients, 761 did not participate; 269 were too ill; 256 could not be weighed; and 236 refused consent. Eight hundred and fifty were subsequently evaluated. Prevalence of malnutrition on admission was 20%. Length of stay, new prescriptions and infections and disease severity were significantly higher in the malnourished. Conclusions: One patient in every five admitted to hospital is malnourished. Although this figure is unacceptably high, it may underestimate true prevalence. Malnutrition was associated with increased length of stay, new prescriptions and infections. Malnutrition may also have contributed to disease severity.

The objective of this study was to assess daily self-selected mineral intake of free-living African-American adults using the duplicate portion collection technique coupled with direct chemical analysis. A duplicate sample of every food and beverage consumed was collected by each subject. The collection period was for 3 days (Sunday, Tuesday, and Thursday) of 1 week in 1986. The chemical analysis included calcium, phosphorus, magnesium, sodium, potassium, manganese, iron, copper, zinc, and phytate. Forty adult African-Americans (20 females and 20 males) living in the Washington, DC area volunteered to participate. They were apparently healthy, ranging in age from 21 to 65 years, with a median age of 38.5 years. The analytical data from the daily food and beverage intake were compared with the Recommended Dietary Allowances (RDA)/ Estimated Safe and Adequate Daily Dietary Intakes (ESADDI). The results were also compared with data from the National Health and Nutrition Examination Survey (NHANES) III and USDA's Continuing Survey of Food Intakes by Individuals(USDA-CSFII 1989–91). Compared with the RDA/ESADDI, for women, the median intakes of less than two-thirds the recommendations were : calcium (54%), magnesium (65%), iron (61%), copper(60%), zinc (61%), and potassium (50%) as determined by chemical analysis. For the men, applying the same criteria, the minerals and percentages are: calcium (64%), magnesium (56%), copper (60%), zinc (61%), and potassium (58%). The phytate:zinc and phytate × Ca:Zn molar ratios suggested no general inhibition of zinc bioavailability despite some higher than suggested limiting molar ratios found in a few individual daily diets. Although limited in scope, these results suggest that African-American adults are selecting diets that are frequently low in specific minerals. Some of these essential nutrients have been implicated in chronic health problems prevalent in this ethnic group; e.g., hypertension and cardiovascular diseases. Therefore, nutritionists and other health professionals should emphasize the need for a wider selection of foods to prevent specific mineral deficits. These foods might include acceptable dairy products, meats/seafood, and mineral-fortified cereals/breads and juices.

Congestive heart failure occurring in unoperated patients with otherwise uncomplicated tetralogy of Fallot (TF) is rare. We report the case of a boy who was first diagnosed as having TF when he presented at age 3 years with hypoxia and heart failure. Heart failure improved following an aortopulmonary shunt. We attributed his heart failure to cardiomyopathy associated with severe hypoxia. We believe that this report is the first one that attributes heart failure to hypoxia in an unoperated patient with tetralogy of Fallot.

Facial cooling (FC) elicits a marked bradycardia at rest that appears to be reduced during exercise. This study was done to delineate the effects of exercise mediated central command from those of muscle afferent feedback and sympathetic stimulation on the attenuation of the bradycardic effect of FC during the onset of exercise. Ten healthy subjects (26 +/- 2 yr) were exposed to FC under five different conditions: 1) seated rest on the cycle ergometer, 2) onset of mild exercise (resting HR + 20 beats.min-1), 3) onset of moderate exercise (resting HR + 50 beats.min-1), 4) seated rest on the ergometer during electrical stimulation, and 5) seated rest on the ergometer during a cold immersion test (CT) (one hand immersed in an ice slurry at 0 degree C). The two exercise intensities were presumed to provide different degrees of central command. Electrical stimulation of the quadriceps was assumed to provide isolated muscle afferent feedback, while the CT served as a sympathetic stimulus. Beat-by-beat data were recorded for HR and mean arterial blood pressure for the duration of each test (50 s), and a rating of perceived pain was taken after each FC. FC elicited significant increases in mean arterial pressure during mild and moderate exercise compared with resting control (P0.05) and during moderate exercise compared to exercise without FC (P0.05). Mean decreases in HR during FC were similar for resting control (-12 +/- 3 beats.min-1), electrical stimulation (-10 +/- 3 beats.min-1), and CT (-9 +/- 3 beats.min-1). The HR response to FC during mild exercise (-7 +/- 2 beats.min-1) was significantly different (P0.05) from the rest condition; however, there was no significant bradycardia (-2 +/- 2 beats.min-1; P0.05) during onset of moderate exercise. These findings suggest that the magnitude of cold face-induced bradycardia may be attenuated at exercise onset by neural signals related to the higher levels of central motor command associated with heavier exercise.

Although two thirds or more of patients with microprolactinoma achieve normal serum prolactin levels over the long term after withdrawal of dopamine agonist therapy, there is no agreement on the appropriate duration of treatment, and treatment is not always interrupted. In this retrospective analysis of 89 patients, 84 women and 5 men with a mean age of 33 years, remissions were analyzed in 67 patients treated with 0.5 to 3 mg cabergoline weekly and 22 others given 2.5 to 10 mg bromocriptine daily. The mean duration of therapy was 3.1 years, and patients were followed for at least 1 year after treatment ended. None of the patients received medication other than a dopamine agonist. Seven women discontinued treatment when they became pregnant. All patients were symptomatic and hyperprolactinemic when first seen. Among 57 patients (64%) who had a recurrence after treatment stopped were 46 (81%) who had recurrent symptomatic hyperprolactinemia within 12 months after stopping treatment. The average interval was 9.6 months. Thirty-two patients, 36% of the total, achieved remission after at least 1 year of follow up; the mean duration of remission was 3.6 years. Nearly 85% of these patients remained in remission for longer than 2 years. Four of them were asymptomatic despite being hyperprolactinemic. The 2 dopamine agonists were equally effective. The overall median duration before relapse after discontinuance of treatment was 12 months. Logistic regression analysis failed to demonstrate an association between the risk of recurrence and age at presentation, imaging of an adenoma, or the duration of treatment. When dopamine agonist therapy is abruptly withdrawn after 2 years or longer in patients with microprolactinoma, 30% to 40% achieve long-term remission without side effects. Because symptomatic hyperprolactinemia may develop more than 1 year after treatment stops, long-term follow up is essential.

Avian influenza (AI) is a highly contagious viral infection, which can affect all species of birds. Highly pathogenic avian influenza (HPAI) viruses can spread rapidly, causing serious disease with high mortality in many bird species. Wild birds are recognised as the reservoir for low-pathogenicity AI virus and have been shown to play a role in the long-distance transmission of HPAI viruses. In April 2006, H5N1 HPAI (Eurasian lineage) was detected in a dead Whooper swan ( Cygnus cygnus ) in Scotland, marking the first detection of H5N1 HPAI virus in Great Britain since 1959. At the time of the outbreak, risk tools were developed collaboratively between the Veterinary Laboratories Agency, the British Trust for Ornithology, the Wildfowl and Wetlands Trust and Defra to support assessments of the likelihood of the introduction and spread of H5N1 HPAI via wild bird migratory movements to and within Great Britain (Crick and others 2006). A risk-based surveillance model was developed to identify areas in which commercial poultry were at the greatest risk of incursion of H5N1 HPAI from wild birds (Snow and others 2007). The resulting risk map was used by government to prioritise AI surveillance activities including the testing of wild birds found dead for H5N1 HPAI as mandated within the EU AI surveillance framework (Hesterberg and others 2009). This geospatial risk modelling tool has recently been updated to provide revised estimates of these geographical areas and was used as part of the evidence base to assess the risk of incursion from wild …

To identify the most suitable method to continuously monitor antibiotic prescriptions in a United Kingdom hospital, a study was performed in three phases over four years between 1985 to 1989 in a Liverpool teaching hospital. The aim of the study was to perfect a method to collect and analyse hospital-wide antibiotic prescribing data. The emphasis was laid on identifying problems and practicalities and also to minimize manpower and resource requirements. The data were used to illustrate the effect of the hospital's antibiotic policy on prescribing trends. The policy recommendation that co-trimoxazole be substituted by trimelhoprim was only partially adhered to because Augmentin® was the other replacement antibiotic in a significant number of cases. Therefore, it is important to monitor the effects of target drug programmes on all antibiotics since certain sequelae may be unexpected. A total of 1,804, 2,526 and 3,226 antibiotic prescriptions were collected and analysed during phases I, II and III respectively. 72–73% of the prescriptions were for the treatment of infection which equated to 81–89% of the total antibiotic cost. Therefore, cost control campaigns need to concentrate on infection treatment as opposed to prophylaxis. Specifically, respiratory tract, septicaemia and pyrexias of unknown origin account for the bulk of antibiotic expenditure. The method for phases I and II was multidisciplinary and very time-consuming. Phase III was very fast in operation, with data collection and analysis being performed on a single computer dedicated for the task. The minimum staff required to monitor all antibiotic prescriptions is one full-time pharmacist and clerk. Continuous intensive antibiotic monitoring in United Kingdom hospitals will not be feasible until antibiotic prescription forms are introduced on all wards.

With the introduction of interventional procedures such as percutaneous mitral valvuloplasty and radiofrequency ablation of left-sided bypass tracts, there has been renewed interest in the technique of transseptal left heart catheterization. We review our experience with 1,279 transseptal catheterizations performed over the last 10 years. The most common indications for transseptal catheterization included direct measurement of left atrial pressure or access to the left ventricle in patients with prosthetic aortic or mitral valves, and in patients undergoing percutaneous mitral valvuloplasty. A total of 17 major complications occurred (1.3%), including cardiac tamponade (15 patients, 1.2%), systemic emboli (1 patient, 0.08%), and death secondary to aortic perforation (0.08%). We conclude that when performed by experienced operators, transseptal left heart catheterization is associated with low morbidity and mortality.

In an initial study of 20 fresh ovarian tumour samples, we compared the immunohistochemical positivity of staining of the p53 protein with the presence of missense mutations of the p53 gene. This revealed a prevalence of 50% with a perfect correlation between mutation and immunohistochemical staining. Detection of the p53 protein by immunohistochemistry was, therefore, used as a reliable indicator for the presence of P53 mutation, and was applied to a study of an archival series of 93 ovarian tumours. Positive immunostaining of the p53 protein was observed in 47% of this series. Cox regression was used to assess whether various clinical variables and P53 mutation were related to survival. As a result, it was found that positive staining of the p53 protein was independent of age, tumour differentiation, tumour type, though possibly not stage. There was some evidence that p53 positivity was associated with reduced survival after adjusting for other variables, but the result was not statistically significant.

Three studies were performed to evaluate the effects of jet lag on factors associated with sport performance. In Study 1, members of the USA Women's Soccer Team traveled to Taiwan; in Study 2, North American students and faculty traveled to Western Europe; and in Study 3, European students traveled to North America. After travel, there was disruption of mood state and a reduction in dynamic strength; peak 5-s power and 30-s work capacity were reduced for 2 days (5-s power: 9.8 vs. 9.0 vs. 9.0 W∙kg−1; 30-s work capacity: 213 vs. 199 vs. 201 J∙kg−1). In these studies, mood state, anaerobic power and capacity, and dynamic strength were affected by rapid transmeridianal travel, and even highly trained athletes suffered from jet lag. However, effects of travel on the variables tested were essentially eliminated after 3 or 4 days. Key words: circadian rhythm, anaerobic power, anaerobic capacity, mood, travel

Previous surveys suggested that young children in Northeast Thailand may benefit from vitamin A and/or zinc supplementation. One hundred thirty-three children aged 6-13 y with marginal plasma retinol (less than 1.05 mumol/L) and Zn (less than 12.2 mumol/L) concentrations participated in a double-blind study. They were randomly assigned and supplemented with either zinc (25 mg/d), vitamin A (1500 RE/d), zinc plus vitamin A, or placebo for 6 mo. Biochemical indices of vitamin A (plasma vitamin A, retinol-binding protein) and zinc status (plasma zinc, alkaline phosphatase) increased significantly. The children had adequate liver stores of vitamin A (relative dose response less than 20%). Zinc supplementation resulted in an improvement in vision restoration time (VRT) in dim light (dark adaptometry). Vitamin A and zinc synergistically normalized conjunctival epithelium as measured by conjunctival impression cytology (CIC). Both functional indices, VRT and CIC, showed significant correlations with plasma zinc and vitamin A, respectively. The data suggest that functional improvements in populations with suboptimal vitamin A and zinc nutriture can be accomplished by supplementation with less than two times the recommended dietary allowance of these nutrients.

ABSTRACI’ We determined serial changes in four major plasma carotenoid fractions (a-carotene, /3-carotene, lutein/ zeaxanthin, and lycopene) in 30 men consuming defined daily doses of carotenoids from foods (broccoli, carrots, or tomato juice) or from purified /3-carotene in capsules (12 or 30 mg) for 6 wk while fed a controlled diet. Compared with baseline, /3carotene increased in the 30- and 12-mg-capsule and carrot groups whereas a-carotene increased in the carrot group and lutein increased in the broccoli group. Lower lutein concentrations in recipients of/3-carotene capsules suggested an interaction between these two carotenoids. Lycopene declined in all groups except the tomato-juice group. Total carotenoid concentration changes only reflected the large increases in /3-carotene concentrations and not the smaller changes observed in other individual carotenoids. Overall, purified /3-carotene produced a greater plasma response than did similar quantities ofcarotenoids from foods sources. However, some foods increased plasma concentrations of certain carotenoids. Am J C/in Nutr l992;55

1. Pulmonary arterial hypertension was demonstrated in a series of rats that had been kept for 24–31 days in an environment of compressed air, having a barometric pressure of 3040 mm. Hg. The partial pressure of oxygen was 635 mm. Hg, which is equivalent to an 83.6 per cent oxygen mixture at normal barometric pressure. 2. Sclerosing changes in the pulmonary arterioles have been observed which precede the development of demonstrable hypertension in the pulmonary circulation. These vessels showed histological changes that were indicative of injury after 3 days of exposure. There was a thickening of the walls which stained more intensely with eosin, as well as marked perivascular edema and often a narrowing of the lumina. Progressive thickening, narrowing, and hyalinization of the pulmonary arterioles occurred later, after the disappearance of perivascular edema. These changes appeared very similar to the renal arterial lesions seen at autopsy in patients dying from malignant hypertension. 3. Pathological examination did not reveal significant or constant changes from normal in any organs except the lungs and heart. The blood vessels of the systemic circulation showed no pathological change. 4. The walls of the large pulmonary arteries increased in thickness rapidly after the 3rd day of exposure. This change was due to the progressive formation and condensation of fibrous tissue outside of the media and to a lesser extent to thickening of the alternate layers of elastic tissue and smooth muscle in the arterial wall. 5. Marked dilatation of the right ventricle and conus arteriosus as well as small areas of scar tissue formation in the right ventricle were present on prolonged exposure. A few hearts showed larger areas of fibrosis that were visible on macroscopic examination. 6. The systemic arterial blood pressure of a small series of rats exposed to compressed air for 38 days and examined 7 to 10 days after decompression was in each instance less than one-half the average normal pressure. 7. The findings in this study are consistent with the clinical and pathological signs of pulmonary hypertension in man. 8. The anatomical alterations observed in the alveolar units of the lungs were essentially the same as those previously described (1). 9. A method has been devised whereby pulmonary arterial hypertension, accompanied by important sclerotic changes in the arteries of the pulmonary circulation can be induced for investigation.

The rate of movement of chromium (III) chloride through the gastrointestinal tract of rats was investigated. In the first experiment 85% of rats intubated with 51 CrCl 3 had more than 1% of the administered 51 Cr below the cecum after four hours. In the second study, most 51 Cr recovered in the small intestine reached the ileum one hour after initiation of feeding 2 g diet containing 51 CrCl 3 . In the third experiment, the intestine was ligated in situ; ligation blocked 51 Cr transit. 51 Chromium appeared to be associated with the fluid portion of the ingesta which may negate the use of CrCl 3 as a marker for rate of passage of dietary components.

Data are accumulating that support the hy- pothesis that inadequate zinc nutriture will result in an impair- ment of vitamin A utilization. Therefore, zinc and vitamin A status were assessed in 283 schoolchildren aged 7-1 3 y in Northeast Thailand. More than one-fourth had serum vitamin A concentrations < 0.86 �mol/L, with a mean (± SD) concen- tration of 1.06 ± 0.31 �cmol/L compared with 1.26 ± 0.02 zmol/L for US children of similar age. Seventy percent had low serum zinc concentrations, < 10.7 �mol/L. Twenty-three percent ofthe children exhibited both low serum zinc and vita- mm A concentrations. The mean concentration of retinol- binding protein (RBP)was bower for children in this study com- pared with healthy Thai children in Bangkok, 22.5 ± 6.6 vs 25.3 ± 6.0 mg/L, respectively. Serum zinc and RBP were sig- nificantly correlated (p < 0.001) whereas vitamin A and zinc were not correlated. These data suggest that a high proportion ofrural schoolchildren in Northeast Thailand are at risk of in- adequate zinc and/or vitamin A nutriture. Am J Clin Mar 1990;52:564-7.

In the 1950s, Puerto Rico began an active industrialization program. We used data from the 1982 Puerto Rico Fertility and Family Planning Assessment to describe the trend in the incidence of breastfeeding in Puerto Rico over time and to ascertain some of its determinants. From 1946 through 1982, 5,884 infants were born among this statistically representative sample of reproductive-aged women. The proportion of infants who had ever been breastfed was 59 percent for births before 1960 (mean duration = 7.8 months), dropped to 25 percent for infants born from 1970 to 1974 (mean duration = 4.9), and rose to 38 percent for births delivered from 1980 to 1982 (mean duration = 3.4). Prior breastfeeding experience was an important determinant of breastfeeding a newborn. Infants of mothers who had breastfed a previous baby were 7.3 times more likely to be breastfed (95% confidence interval = 6.6, 8.0) compared with infants of mothers who had not previously breastfed. The 38 percent of infants who were breastfed in Puerto Rico in the early 1980s is below the 74 percent to 97 percent reported in Latin America and below the 54 percent reported in the United States for the same period. This study provides baseline data for any future intervention strategies.

Background Anabolic androgenic steroids are used by some bodybuilders to enhance performance. While the cardiovascular implications of supraphysiological androgen levels requires further clarification, use is associated with sudden death, left ventricular hypertrophy, thrombo-embolism and cerebro-vascular events. Materials and methods To further understand the effect of androgenic anabolic steroid abuse on vascular function, this study assessed vascular stiffness (pulse-wave analysis) and cardiovascular risk factors in 28 male, bodybuilding subjects, of whom ten were actively receiving anabolic agents (group A; 26·4 ± 7·2 years) and eight had undergone a 3-month ‘wash-out’ period (group B; 32·1 ± 7·1 years). The remaining ten bodybuilding subjects (group C; 24·4 ± 4·4 years) denied any past use of anabolic steroids or other performance enhancing drugs. Comparisons were made with ten sedentary male controls (group D, 29·3 ± 4·7 years). Results Endothelial independent dilatation in response to glycerol trinitrate was significantly impaired in the group currently using anabolic steroids (group A) compared with the other three groups [A (5·63 ± 3·24%) versus; B (11·10 ± 4·91%), C (17·88 ± 9·2%) and D (14·46 ± 3·9%), P < 0·0005, respectively], whereas no significant differences in endothelial-dependant dilatation were detected between the groups [A (5·0 ± 3·0%), B (7·4 ± 3·4%), C (9·6 ± 4·5%) and D (8·2 ± 3·3%), P < 0·059, respectively]. Conclusions Previous studies described a decline in vascular reactivity occurring in bodybuilding subjects which is independent of anabolic steroid use and may result from smooth muscle hypertrophy with increased vascular stiffness. This study revealed impaired vascular reactivity associated with anabolic agents and that improvement in vascular function may occur following their discontinuation.

We report a breast-fed infant with clinical evidence of rickets and with dilated cardiomyopathy who responded well to supplemental calcium and vitamin D. We believe that this is the first report of such an association in an American child.

Acromegaly is associated with increased cardiovascular risk. Although conventional risk factors such as glucose intolerance, hypertension, and dyslipidemia probably contribute, there may also be direct effects of GH/IGF-I excess on the vasculature. To study the effects of GH excess on the vasculature, we have assessed arterial stiffness in acromegalic subjects with and without active disease and have investigated the effects of Sandostatin LAR (OCT-LAR) on vascular function. Sixteen normotensive subjects with acromegaly (10 males and 6 females) and 8 healthy controls were studied. Of the acromegalic subjects, eight had active disease (group A), and eight were cured (GH2.5 mU/liter; group B). The three groups were age, sex, and blood pressure matched. Group A subjects were restudied after 3 and 6 months of OCT-LAR therapy. Arterial stiffness was assessed by analyzing central arterial pressure waveforms derived from measured radial artery waveforms. This allowed determination of the augmentation of central pressure and the augmentation index. Lipids, glucose, and IGF-I were also measured. Comparing the three groups (ANOVA; mean +/- SD), the augmentation index was higher in group A (28 +/- 12 vs. 12 +/- 13%; P0.01) but not in group B (22 +/- 7 vs. 12 +/- 13%; P = 0.60), compared with controls. IGF-I was higher in group A (50.3 +/- 21.2 nmol/liter; P0.01), compared with group B (22.5 +/- 8.9 nmol/liter) and controls (19.5 +/- 5.3 nmol/liter). On regression analysis, IGF-I concentration was identified as a strong independent predictor of the augmentation index (beta = 0.50; P = 0.007). There were no significant differences in aortic systolic pressure, aortic diastolic pressure, lipids, or glucose. Compared with baseline, OCT-LAR treatment resulted in a lowering of augmentation index at 3 months (20 +/- 15 vs. 28 +/- 12%; P0.05), but at 6 months (24 +/- 16%; P = 0.21) there was no significant change. IGF-I was reduced from 50.3 +/- 21.2 nmol/liter at baseline to 31.4 +/- 13.2 nmol/liter at 3 months (P0.05) and 26.6 +/- 15.8 nmol/liter at 6 months (P0.05). In conclusion, acromegaly is associated with changes in the central arterial pressure waveform, suggesting large artery stiffening. This may have important implications for cardiac morphology and performance in acromegaly as well as increasing the susceptibility to atheromatous disease. Large artery stiffness is reduced in cured acromegaly and partially reversed after pharmacological treatment of active disease.

Malnutrition is common in sick elderly people on admission to hospital and in the community. We conducted a randomised controlled trial to determine if nutritional supplementation after discharge from hospital improved nutritional status and functional outcomes, or reduced health-care costs.Elderly malnourished subjects were randomised to 8 weeks of supplementation or no supplementation post discharge, and followed up for 24 weeks. Weight, body mass index, anthropometrics, handgrip strength, quality of life and requirements for health-care professionals' services and social services were measured throughout the study.Nutritional status improved significantly from baseline to week 24 in the intervention group (P0.05), but not in the control group. There was no significant difference in nutritional status between groups at week 24. Handgrip strength improved significantly in the intervention group during supplementation, and was significantly different from that of the control group at week 8, but decreased thereafter. There was no significant difference in quality of life or health economic outcomes between groups at week 24.In already malnourished elderly subjects, it may be too late to expect to improve function or quality of life or to reduce health-care costs simply by providing nutritional supplements after hospitalisation. Prevention is key. All elderly patients should be nutritionally assessed as part of their routine care, and appropriate intervention initiated early.

Hypothyroidism is associated with cardiovascular dysfunction. It is increasingly apparent that stiffening of central arteries may lead to increased afterload and cardiac dysfunction. We noninvasively studied the peripheral and central pressure waveforms in 12 untreated hypothyroid patients as well as in 12 age-, sex-, and body mass index-matched controls using the technique of pulse wave analysis from recordings at the radial artery. Indexes of arterial stiffness, augmentation index (AI) and augmentation of central arterial pressure (AG), were derived as well as time of travel of the reflected wave (TR), a direct estimate of aortic pulse wave velocity. At baseline, there were no significant differences between the 2 groups in brachial and aortic blood pressures. Hypothyroid patients had significantly higher AI than controls (mean +/- SEM[SCAP], 32.0 +/- 3.4% vs. 17.0 +/- 2.4%; P0.0005) even when corrected for heart rate (AI(C); 28.0 +/- 3.2% vs. 17.0 +/- 2.4%; P0.006) and AG (13.0 +/- 2.2 vs. 7.0 +/- 2.1 mm Hg; P0.03) together with a lower TR (132.0 +/- 4.1 vs. 142.0 +/- 1.5 msec; P0.03). After 6 months of therapy with T(4), all patients were euthyroid. AI(C) had decreased in the patient group (23.0 +/- 3.2% vs. 28.0 +/- 3.2%; P0.01) as had AG (9.0 +/- 1.5 vs. 13.0 +/- 2.2 mm Hg; P0.008), but TR was significantly higher (142.0 +/- 3.0 vs. 132.0 +/- 4.1 msec; P0.008). AI correlated with age in all groups (hypothyroid group: r = 0.937; P0.0005; control group: r = 0.804; P0.0005), but correlated with TSH level only among controls (r = 0.591; P0.05). This study confirms that hypothyroidism is associated with increased cardiovascular risk, as evidenced by increased augmentation of central aortic pressures and central arterial stiffness. Furthermore, these abnormalities are reversed after adequate T(4) replacement.

One candidate for an endogenous mesoderm-inducing factor in Xenopus is derrière, a member of the TGFβ family closely related to Vg1. In this paper we first show that derrière is able to exert long-range effects in the early Xenopus embryo, reinforcing the view that it functions as a secreted factor required for proper formation of posterior structures. Analysis of the derrière promoter shows that expression of the gene is controlled through a complex inductive network involving VegT and TGFβ-related molecules and also, perhaps, FGF family members. The work confirms that derrière plays an important role in mesoderm formation and it illustrates the complex regulation to which inducing factors are subject.

Cushing’s syndrome is a heterogeneous disorder characterized by numerous physical, psychological and metabolic abnormalities associated with glucocorticoid excess. Left untreated, the condition is associated with considerable morbidity and mortality. 1 The importance of accurate diagnosis and treatment can be inferred from the improved outcome following intervention. However, some individuals do not conform to traditional investigative approaches, presenting a diagnostic trap for the unwary. During the last

A 39-year-old man presented with lower limb muscle pains and weakness which had progressed rapidly over the preceding 2 weeks. Immediately prior to hospital admission he was unable to stand unaided. There had been no disturbance of bulbar, sensory or sphincter function and he reported no recent gastrointestinal symptoms. Medical history included colitis, which was quiescent. His only regular medication was olsalazine. On examination, he was normotensive (and remained so throughout his admission). There was no rash. Cardiovascular, respiratory and abdominal examinations were normal. Neurological examination revealed generalised weakness in all four limbs, most marked proximally. Tendon reflexes were preserved. Plantar response was flexor. Examination of cranial nerves was normal. Laboratory investigations revealed a serum potassium of 1.8 mmol/l. Serum sodium, urea and creatinine were within normal limits. Creatine kinase was 10 719 IU/l. A quadriceps muscle biopsy was performed and the histology is shown in figure 1. Further investigations included an abdominal ultrasound scan, following which computed tomography (CT) of the abdomen was performed (figure 2). A 24-hour urine collection for catecholamines was undertaken (table). View this table: Table Levels of free …

To determine whether supplementation of vitamin A and/or zinc (Zn) improved serum levels of these nutrients and/or height and weight gains in preschool children, 22 to 66 months, living in Belize, Central America.Subjects received either Zn, vitamin A, Zn and vitamin A or a placebo, (70 mg Zn and/or 3030 RE vitamin A, once per week) for 6 months in a 2x2 factorial design. Forty-three children, from a population of 104 prescreened, completed the study; they were selected, prior to treatment, for low/marginal serum concentrations of these micronutrients.Serum Zn levels were greater (16%, p0.001) for those who received Zn. In contrast, after vitamin A treatment there were no differences in serum vitamin A among groups. Although increases in height (+4.4 cm, p0.001) and weight (+0.79 kg, p0.001), compared with baseline values, were numerically greatest for children who received both supplements, only the vitamin A supplementation effect was significant, resulting in increased height (+1.4 cm, p0.002) and greater weight gain (+0.15 kg, p0.03) compared to those receiving no vitamin A. Vitamin A supplementation alone significantly increased (p0.001) hemoglobin concentration.The results suggest that the preschool children in this study, prescreened for low/marginal serum concentrations from a larger population prior to treatment, were enduring inadequate vitamin A and, to a lesser degree, Zn nutriture. Height and weight gain were significantly increased in the subjects who received a single weekly supplement 3030 RE of vitamin A.