Prevalence of vitamin D insufficiency in children with forearm fractures.

PURPOSE: This study aimed to determine whether children with distal radius impaction fractures have increased prevalence of 25-hydroxyvitamin D (25(OH) D) insufficiency compared with healthy controls. PATIENTS AND METHODS: This is a prospective controlled study. The 30 children who were diagnosed with forearm fracture at the orthopaedic emergency clinic were included in the study and 30 healthy children from the routine paediatric outpatient unit were included as the control group. Peripheric venous 25(OH) D, calcium (Ca), magnesium (Mg), phosphor (P), alkaline phosphatase (ALP) and parathyroid hormone (PTH) of both groups were recorded. The sample size was estimated based on the effect size for a type I error of 5% and power of 80%. RESULTS: Demographic characteristics of the two groups did not differ in terms of weekly physical activity levels and breast milk intake. The mean whole body BMI was similar in both groups of patients. History of previous fracture and 25(OH) D level were significantly lower in the patient group than the control group. CONCLUSION: In the present study, the prevalence of vitamin D insufficiency or deficiency was higher in patients with forearm impaction type fractures than healthy controls and the baseline levels reported in the literature. In addition, there were no significant differences in serum Ca, Mg, P, ALP and PTH levels between the healthy controls and the patient group.

PP032. Unique features of long-term cardiovascular phenotype in young women with early-onset pre-eclampsia.

INTRODUCTION: Early-onset preeclampsia is associated with a greater risk of cardiovascular disease than late-onset preeclampsia. OBJECTIVES: We tested the hypothesis that young women, with previous early-onset preeclampsia, have unique differences in long term cardiovascular phenotype compared to late-onset preeclampsia or normal pregnancy. METHODS: 140 women (mean age 40 yrs) were followed up 6-13years following pregnancy. 90 had had preeclampsia (45 early onset (before 34 weeks of gestation), 45 late onset) and 50 had normotensive uncomplicated pregnancies. Women with cardiovascular risk factors present before pregnancy were excluded. Fasting lipids, glucose, insulin and circulating cytokines were measured. Central blood pressure (BP) and arterial stiffness (pulse wave velocity (PWV)/augmentation index (AI)) were assessed by applanation tonometry, common carotid intima media thickness (cIMT) by ultrasound and cutaneous capillary density by intravital microscopy. 46 women returned for assessment of cardiac structure and function by magnetic resonance and echocardiography as well as ambulatory blood pressure monitoring. RESULTS: All women with a previous history of preeclampsia had 5-10mmHg higher peripheral and central BP (P<0.001) as well as elevated total: HDL cholesterol (P<0.003), insulin resistance (P<0.04) and circulating TNFα (P<0.007). They also had increased arterial stiffness (P<0.04) and cIMT (P<0.005). Cardiac size and systolic function were preserved but there was evidence of abnormal diastolic relaxation (E/E' -P<0.04). In contrast early-onset preeclampsia was associated with characteristic differences in peri-pregnancy blood pressure, long term ambulatory measures and microvascular function. CONCLUSION: Early onset preeclampsia is associated with unique features in long term cardiovascular phenotype. Pregnancy disease characteristics may identify women at greatest potential benefit from monitoring and primary prevention.

Urban trench fever presenting as culture-negative endocarditis.

A young Russian man presented with increasing shortness of breath and signs of worsening aortic regurgitation. A diagnosis of infective endocarditis was made before emergency valve replacement. The infective cause was not discovered by routine culture but was suggested by electron microscopy and confirmed by serology and PCR testing.

Chronic treatment with tetrahydrobiopterin reverses endothelial dysfunction and oxidative stress in hypercholesterolaemia.

BACKGROUND: Reduced availability of tetrahydrobiopterin (BH(4)), an essential cofactor of nitric oxide (NO) synthase (NOS), decreases NO production and increases reactive oxygen species. Both mechanisms contribute to atherosclerotic vascular disease. Although acute supplementation of BH(4) improves endothelial dysfunction, the effect of chronic BH(4) in humans is unknown. OBJECTIVE: To investigate the effect of chronic BH(4) supplementation on endothelial function and oxidative stress in hypercholesterolaemia. DESIGN: Randomised double-blind, placebo-controlled trial. SETTING: University Hospital. PATIENTS: 22 hypercholesterolaemic patients (low-density lipoprotein (LDL) >4.5 mmol/l) were randomised to 4 weeks of oral BH(4) (400 mg twice daily) or placebo. Age-matched healthy volunteers served as controls. MAIN OUTCOME MEASURES: Endothelium-dependent and -independent vasodilatation was assessed by venous occlusion plethysmography. To elucidate the mechanisms of BH(4) effect, NO release and superoxide anion (O(2)(-)) production were measured in human aortic endothelial cells exposed to native LDL (2.6 mmol cholesterol/l). RESULTS: BH(4) plasma levels were significantly increased by oral supplementation. NO-mediated vasodilatation to acetylcholine was reduced in patients compared with controls and restored by BH(4). No effect of BH(4) on endothelium-independent vasodilatation was seen. Furthermore, 8-F(2 )isoprostane plasma levels, a marker of vascular oxidative stress, were reduced by BH(4). In LDL-treated endothelial cells, BH(4) levels and NO release were reduced and O(2)(-) production increased compared with control cells. Exogenous BH(4) normalised NO and O(2)(-) production. CONCLUSIONS: In hypercholesterolaemia, endothelial dysfunction and oxidative stress can be reversed by chronic oral treatment with BH(4). Thus, BH(4) availability is essential for maintaining NO synthesis and low O(2)(-) production by endothelial NOS in vivo, and may provide a rational therapeutic approach to prevent cardiovascular disease.

Severe endothelial dysfunction in the aorta of a mouse model of Fabry disease; partial prevention by N-butyldeoxynojirimycin treatment.

OBJECTIVE: Fabry disease results from alpha-gala-ctosidase A deficiency and is characterized by the lysosomal accumulation of globotriaosylceramide. Globotriaosylceramide storage predominantly affects endothelial cells, altering vascular wall morphology and vasomotor function. Our objective was to investigate aortic globotriaosylceramide levels, morphology and function in a mouse model of Fabry disease, and the effect of substrate reduction therapy, using the glycosphingolipid biosynthesis inhibitor N-butyldeoxynojirimycin. METHODS AND RESULTS: Mice used were C57BL/6J and alpha-galactosidase A knockout (Fabry). We show progressive accumulation of aortic globotriaosylceramide throughout the lifespan of untreated Fabry mice (55-fold elevation at 2 months increasing to 187-fold by 19 months), localized to endothelial and vascular smooth-muscle cells; there was no effect on vascular wall morphology in young Fabry mice. In old mice, storage resulted in intimal thickening. Endothelial function declined with age in Fabry mouse aorta. Aortae from N-butyldeoxynojirimycin-treated Fabry mice at 19 months of age had reduced endothelial globotriaosylceramide storage, fewer morphological abnormalities and less severe vasomotor dysfunction compared with untreated littermates. CONCLUSION: We provide evidence of a novel vascular phenotype in the Fabry mouse that has relevance to vascular disease in Fabry patients. N-Butyldeoxynojirimycin treatment partially prevented the phenotype in the Fabry mouse by reducing endothelial globotriaosylceramide storage.

Relationships between nitric oxide-mediated endothelial function, eNOS coupling and blood pressure revealed by eNOS-GTP cyclohydrolase 1 double transgenic mice.

Endothelium-dependent relaxation in conduit vessels is mediated largely by nitric oxide (NO), produced by the enzyme endothelial nitric oxide synthase (eNOS) in the presence of the cofactor tetrahydrobiopterin (BH4) and mediated through a cGMP-dependent downstream signalling cascade. Endothelial NOS regulates blood pressure in vivo, and impaired endothelial NO bioactivity in vascular disease states may contribute to systemic hypertension. In the absence of sufficient levels of the cofactor BH4, NO becomes uncoupled from arginine oxidation and eNOS produces superoxide rather than NO. The enzymatic uncoupling of eNOS is an important feature of vascular disease states associated with increased oxidative stress. However, whether eNOS coupling, rather than overall eNOS activity, has specific effects on endothelium-dependent vasorelaxation in vitro, or on blood pressure regulation in vivo, remains unclear. In this study, we evaluate the relationships between blood pressure and endothelial function in models of eNOS uncoupling, using mice with endothelium-targeted transgenic eNOS overexpression (eNOS-Tg), in comparison with littermates in which eNOS coupling was rescued by additional endothelium-targeted overexpression of GTP cyclohydrolase 1 (eNOS/GCH-Tg) to increase endothelial BH4 levels. Despite the previously characterized differences in eNOS-dependent superoxide production between these animals, we find that blood pressure is equally reduced in both genotypes, compared with wild-type animals. Furthermore, both eNOS-Tg and eNOS/GCH-Tg mice exhibit similarly impaired endothelium-dependent vasorelaxation. We show that reduced vasorelaxation responses result from desensitization of cGMP-mediated signalling and are associated with increased NO production rather than changes in superoxide production.

Endothelial nitric oxide synthase dysfunction in diabetic mice: importance of tetrahydrobiopterin in eNOS dimerisation.

AIMS/HYPOTHESIS: Impaired nitric oxide (NO) bioactivity and increased superoxide (SO) production are characteristics of vascular endothelial dysfunction in diabetes. The underlying mechanisms remain unknown. In this regard, we investigated the role of tetrahydrobiopterin (BH4) bioavailability in regulating endothelial nitric oxide synthase (eNOS) activity, dimerisation and SO production in streptozotocin-induced diabetic mice. METHODS: Mouse aortas were used for assays of the following: (1) aortic function by isometric tension; (2) NO by electronic paramagnetic resonance; (3) SO by lucigenin-enhanced chemiluminescence and dihydroethidine fluorescence; (4) total biopterin and BH4 by high-performance liquid chromatography; and (5) eNOS protein expression and dimerisation by immunoblotting. RESULTS: In diabetic mouse aortas, relaxations to acetylcholine and NO levels were significantly decreased, but SO production was increased, in association with reductions in total biopterins and BH4. Although total eNOS levels were increased in diabetes, the protein mainly existed in monomeric form. Conversely, specifically augmented BH4 in diabetic endothelium preserved eNOS dimerisation, but the expression remained unchanged. CONCLUSIONS/INTERPRETATION: Our results demonstrate that BH4 plays an important role in regulating eNOS activity and its functional protein structure, suggesting that increasing endothelial BH4 and/or protecting it from oxidation may be a rational therapeutic strategy to restore eNOS function in diabetes.

Candida prosthetic valve endocarditis cured by caspofungin therapy without valve replacement.

A 64-year-old woman with a mechanical mitral valve prosthesis developed late-onset Candida endocarditis. Blood cultures grew Candida glabrata and Candida krusei. Transesophageal echocardiography demonstrated vegetations on the valve. The patient was not medically fit for valve replacement, but her condition was successfully treated with 6 weeks of intravenous caspofungin therapy.

A rapid troponin-I-based protocol for assessing acute chest pain.

In a prospective randomized open trial with 30-day follow-up, we compared a troponin-I-based protocol to 'standard management' for the diagnosis and risk stratification of patients with acute non-ST-elevation chest pain. Patients with acute chest pain (n=400) were randomized to standard diagnostic tests and management, or a protocol based on the admission ECG and the troponin-I result 6 h after onset of chest pain. Low-risk patients were discharged early from CCU; high-risk patients were treated with medical therapy or referred for in-patient angiography as appropriate. We measured length of CCU stay, and followed all patients for major adverse cardiac events (MACE) of death, non-fatal myocardial infarction (MI), or urgent revascularization during the admission and for 30 days post-discharge. The troponin protocol allowed earlier discharge in the low-risk group (10 vs. 30 h, p<0.001) with no excess of adverse events compared to standard management (3% vs. 5%, p=0.32). It identified a group of patients at moderate risk of cardiac events (15% MACE rate during admission and 30-day follow-up), and a high-risk group (75% MACE rate) more accurately than did standard management. The prognostic power of troponin testing in combination with the admission ECG was higher than with either test used alone. The protocol improved the efficiency of low-risk patient management, and improved patient risk stratification. This study adds to the evidence favouring troponin evaluation as part of the management of acute coronary syndromes.

Randomised comparison of antero-lateral versus antero-posterior paddle positions for DC cardioversion of persistent atrial fibrillation.

We designed a prospective, randomised, single-blind trial to compare the relative efficacy of antero-lateral versus antero-posterior paddle positions for DC cardioversion of persistent atrial fibrillation. A total of 59 patients were randomised to cardioversion using standard gel pads placed either in the antero-lateral (AL) or antero-posterior (AP) positions. The first synchronised shock was given at 360 J; if this was unsuccessful, a second shock of 360 J was given in the alternative position. We compared cardioversion success rate and energy requirements with each strategy. With the first 360 J DC shock, a significantly greater proportion of patients were restored to sinus rhythm from the antero-lateral position (18/30) compared to the antero-posterior position (10/29) (P=0.048). For those patients remaining in atrial fibrillation, there was no difference in the proportions cardioverted from the antero-lateral position (4/19) compared to the antero-posterior position (5/12) with the second 360 J DC shock (P=0. 22). The total cardioversion success rate was 23/30 (77%) for antero-lateral followed by antero-posterior shocks compared to a success rate of 14/29 (48%) for antero-posterior followed by antero-lateral shocks, and this difference was significant (P=0.024). There was no significant difference in the mean energy delivered for patients randomised to an initial antero-lateral shock (504 J), compared to patients given an initial antero-posterior shock (583 J) (P=0.1). We conclude that the antero-lateral paddle position appears more effective for DC cardioversion of persistent atrial fibrillation.

Randomised double blind trial of oral versus intravenous flecainide for the cardioversion of acute atrial fibrillation.

OBJECTIVE: To investigate whether an oral loading dose of flecainide is as safe and effective as intravenous flecainide for the cardioversion of acute atrial fibrillation. DESIGN: Prospective, randomised, double blind, double placebo study. SETTING: Cardiac care unit of a large district general hospital in the UK. PATIENTS AND METHODS: 79 patients presenting with symptomatic acute atrial fibrillation: patients were given either intravenous flecainide (n = 39) or a solution of oral flecainide (n = 40), with appropriate placebos. All patients were heparinised during the study. PRIMARY OUTCOME MEASURES: Safety; mean time to cardioversion; proportion of patients restored to sinus rhythm at two hours and eight hours after treatment. Analysis was by intention to treat. RESULTS: There were no differences in baseline characteristics between the oral and intravenous groups. Both forms of flecainide were well tolerated, with no adverse clinical events during the study. The mean time to cardioversion was 110 minutes in the oral group and 52 minutes in the intravenous group (p = 0.002). Two hours after treatment, 27 of the 40 patients in the oral group (68%) and 25 of the 39 in the intravenous group (64%) had reverted to sinus rhythm (p = 0.74). Eight hours after treatment, 30 patients in the oral group (75%) and 28 in the intravenous group (72%) had reverted to sinus rhythm (p = 0.76). CONCLUSIONS: Intravenous flecainide restored sinus rhythm more rapidly than oral flecainide, but at two hours and eight hours after treatment there was no difference in the proportion of patients cardioverted by the two approaches. These results suggest a role for oral loading doses of flecainide in the treatment of acute or symptomatic paroxysmal atrial fibrillation.

The evaluation of normal corneal topography in emmetropic eyes with computer-assisted videokeratography.

PURPOSE: By defining the topographic features of normal corneas, corneal surface abnormalities and their relation to visual function may be better understood. In our study, we have defined the corneal topographic features of emmetropic eyes to evaluate the relationship between topographic patterns and visual acuity. METHODS: Topographic pattern of 114 normal corneas of 114 emmetropic subjects with a keratometric astigmatism of 0.5 D or less were analyzed by computer-assisted videokeratography. Thetopographic maps were grouped into the following patterns: round, oval, symmetric bow tie, asymmetric bow tie, and irregular. RESULTS: Asymmetric bow tie was the most common topographic pattern in our study population (33%), followed by symmetric bow tie (29%), round (14%), irregular (12%), and oval (11%) patterns. There were significant differences in the astigmatic values obtained by keratometry versus videokeratography for aspheric patterns, while the values among the spheric patterns were more in agreement. Mean corneal astigmatism calculated from videokeratographic data was 0.24 D for round, 0.61 D for oval, 1.05 D for symmetric bow tie, 0.85 D for asymmetric bow tie, and 0.76 D for irregular patterns. CONCLUSION: We conclude that: the topographic configuration may not be a good predictor of visual function; an emmetropic eye may have an aspheric topographic pattern, such as asymmetric or symmetric bow tie; and the reconstruction algorithm used for providing topographic maps may not be accurate enough to determine the true shape of the corneal surface for interpretation.

Vertical transmission of human immunodeficiency virus.

We discuss the interactions between mother and infant that influence the transmission of HIV. Potential routes of infection are identified, and maternal and infant risk factors for transmission are explored. The role of the immune system in controlling HIV infection in the infant is discussed. Finally, preventive measures for reducing vertical transmission are proposed and evaluated.

An HLA-B35-restricted epitope modified at an anchor residue results in an antagonist peptide.

Peptides associated with HLA-B35 commonly have a proline or occasionally a serine residue in the P2 anchor position of the peptide, with a tyrosine at the C terminus. Based on this motif, we identified an octamer epitope from influenza A matrix protein which is presented by HLA-B35. The requirements for MHC binding and T cell receptor contact have been analyzed using analogs of this peptide with substitutions at positions 1, 2, 4, 7 and 8. The natural epitope contains a serine residue at P2 of the peptide. Substitution of this residue with proline (the favored amino acid in this position in B35-associated peptides) considerably enhances binding to HLA-B35 in the T2-B35 cell line, but the peptide is not recognized by the majority of CTL clones and can antagonize recognition of the index peptide. This suggests that a conservative substitution at the P2 anchor position results in a conformational change in the peptide-MHC surface exposed to the T cell receptor.