Zinc Gluconate Induces Potentially Cancer Chemopreventive Activity in Barrett's Esophagus: A Phase 1 Pilot Study.

BACKGROUND: Chemopreventive effects of zinc for esophageal cancer have been well documented in animal models. This prospective study explores if a similar, potentially chemopreventive action can be seen in Barrett's esophagus (BE) in humans. AIMS: To determine if molecular evidence can be obtained potentially indicating zinc's chemopreventive action in Barrett's metaplasia. METHODS: Patients with a prior BE diagnosis were placed on oral zinc gluconate (14 days of 26.4 mg zinc BID) or a sodium gluconate placebo, prior to their surveillance endoscopy procedure. Biopsies of Barrett's mucosa were then obtained for miRNA and mRNA microarrays, or protein analyses. RESULTS: Zinc-induced mRNA changes were observed for a large number of transcripts. These included downregulation of transcripts encoding proinflammatory proteins (IL32, IL1ß, IL15, IL7R, IL2R, IL15R, IL3R), upregulation of anti-inflammatory mediators (IL1RA), downregulation of transcripts mediating epithelial-to-mesenchymal transition (EMT) (LIF, MYB, LYN, MTA1, SRC, SNAIL1, and TWIST1), and upregulation of transcripts that oppose EMT (BMP7, MTSS1, TRIB3, GRHL1). miRNA arrays showed significant upregulation of seven miRs with tumor suppressor activity (-125b-5P, -132-3P, -548z, -551a, -504, -518, and -34a-5P). Of proteins analyzed by Western blot, increased expression of the pro-apoptotic protein, BAX, and the tight junctional protein, CLAUDIN-7, along with decreased expression of BCL-2 and VEGF-R2 were noteworthy. CONCLUSIONS: When these mRNA, miRNA, and protein molecular data are considered collectively, a cancer chemopreventive action by zinc in Barrett's metaplasia may be possible for this precancerous esophageal tissue. These results and the extensive prior animal model studies argue for a future prospective clinical trial for this safe, easily-administered, and inexpensive micronutrient, that could determine if a chemopreventive action truly exists.

The short-term cost of falls, poisonings and scalds occurring at home in children under 5†years old in England: multicentre longitudinal study.

BACKGROUND: Childhood falls, poisonings and scalds, occurring predominantly in the home, are an important public health problem, yet there is limited evidence on the costs of these injuries to individuals and society. OBJECTIVES: To estimate National Health Service (NHS) and child and family costs of falls, poisonings and scalds. METHODS: We undertook a multicentre longitudinal study of falls, poisonings and scalds in children under 5 years old, set in acute NHS Trusts across four UK study centres. Data from parental self-reported questionnaires on health service resource use, family costs and expenditure were combined with unit cost data from published sources to calculate average cost for participants and injury mechanism. RESULTS: 344 parents completed resource use questionnaires until their child recovered from their injury or until 12 months, whichever came soonest. Most injuries were minor, with >95% recovering within 2 weeks, and 99% within 1 month of the injury. 61% emergency department (ED) attendees were not admitted, 35% admitted for ≤1 day and 4% admitted for ≥2 days. The typical healthcare cost of an admission for ≥2 days was estimated at £2000-3000, for an admission for ≤1 day was £700-1000 and for an ED attendance without admission was £100-180. Family costs were considerable and varied across injury mechanisms. Of all injuries, scalds accrued highest healthcare and family costs. CONCLUSIONS: Falls, poisonings and scalds incur considerable short-term healthcare and family costs. These data can inform injury prevention policy and commissioning of preventive services.

Risk and protective factors for falls on one level in young children: multicentre case-control study.

BACKGROUND: Childhood falls are an important global public health problem, but there is lack of evidence about their prevention. Falls on one level result in considerable morbidity and they are costly to health services. OBJECTIVE: To estimate ORs for falls on one level in children aged 0-4 years for a range of safety behaviours, safety equipment use and home hazards. DESIGN, SETTING AND PARTICIPANTS: Multicentre case-control study at hospitals, minor injury units and general practices in and around four UK study centres. Participants included 582 children less than 5 years of age with a medically attended fall injury occurring at home and 2460 controls matched on age, sex, calendar time and study centre. MAIN OUTCOME MEASURE: Fall on one level. RESULTS: Cases' most common injuries were bangs on the head (52%), cuts or grazes not needing stitches (29%) or cuts or grazes needing stitches (17%). Comparing cases to community controls in the adjusted analyses, significant findings were observed for only two exposures. Injured children were significantly less likely to live in a household without furniture corner covers (adjusted OR (AOR) 0.72, 95% CI 0.55 to 0.95), or without rugs and carpets firmly fixed to the floor (AOR 0.76, 95% CI 0.59 to 0.98). CONCLUSIONS: We did not find any safety practices, use of safety equipment or home hazards associated with a reduced risk of fall on one level. Our findings do not provide evidence to support changes to current injury prevention practice.

Outcomes from chemoradiotherapy for patients with esophageal cancer.

Chemoradiotherapy is a widely used alternative treatment to surgical resection in certain patient groups with early esophageal cancer. The aim of this study was to retrospectively assess toxicity and outcome of patients treated with definitive chemoradiotherapy for early esophageal cancer at one institution. A retrospective analysis of all patients treated with chemoradiotherapy between February 2000 and December 2008 at a single tertiary center was performed with documentation of treatment given, toxicities recorded, and follow-up and outcome data. Sixty-two patients received chemoradiotherapy for esophageal cancer. There were 20 males and 42 female patients with an average age of 68 years. Histology revealed adenocarcinoma in 28 patients and squamous cell carcinoma in 34 patients. All patients were staged with a computerized tomography scan, endoscopic ultrasound and positron emission tomography scan. Selection criteria for chemoradiotherapy were unfit for surgery, upper esophageal squamous carcinoma, unresectable primary tumor, or patient choice. The majority of the patients received a combination of cisplatin and 5-fluorouracil chemotherapy with 55 Gy in 25 fractions of radiotherapy. Grade 3 toxicities were recorded in 11% of the patients. Eleven patients suffered from local recurrence and a stent was required in nine patients. Radiation strictures occurred in 10 patients requiring dilation in four. Five patients required a radiologically inserted feeding gastrostomy. The median overall survival was 21 months. Patients with adenocarcinomas and those with squamous cell carcinoma had a similar median survival. Overall survival was 70% at 1 year, 48% at 2 years, and 26% at 3 years. This case series of patients treated with chemoradiation for localized esophageal cancer suggest a generally well-tolerated treatment with survival rates after chemoradiotherapy comparable with those seen with surgery.

Early childhood wheezing symptoms in relation to plasma selenium in pregnant mothers and neonates.

OBJECTIVE: Reduced dietary selenium intake has been linked to the development of asthma. We have investigated whether childhood wheezing symptoms, and asthma up to the age of 5 years are associated with plasma selenium and erythrocyte glutathione peroxidase (GPx) concentrations in pregnant mothers and neonates. METHODS: Two thousand pregnant women were recruited and their 1924 singleton children followed up. Plasma selenium and erythrocyte GPx concentrations were measured in maternal blood during early pregnancy (12 weeks gestation) and in neonatal cord blood. Cohort children were followed up at 1, 2 and 5 years using a respiratory symptom questionnaire and at 5 years children were also invited for spirometry and skin-prick test (SPT). Maternal and neonatal plasma selenium and erythrocyte GPx were related to the childhood outcomes of wheezing, and asthma. RESULTS: At 2 years 1282 children were followed up. At 5 years symptom data were available for 1167 children, 700 children were SPT tested, and forced expiratory volume in 1 s (FEV(1)) was measured in 478. Maternal plasma selenium concentration during early pregnancy was inversely associated with wheezing (odds ratio per 10 microg/kg plasma selenium 0.86, 95% confidence interval 0.76-0.97), and consulting a doctor because of wheeze (0.79, 0.69-0.93) in the second year of life. Cord plasma selenium was also inversely associated with wheezing (0.67, 0.47-0.96), and consulting a doctor because of wheeze (0.62, 0.41-0.93) in the second year of life. By age 5 these associations had disappeared. Maternal and neonatal erythrocyte GPx concentrations were not associated with any childhood outcomes at 2 or 5 years. CONCLUSION: The selenium status of mothers during early pregnancy, and neonates is associated with early childhood wheezing but not asthma or atopic sensitization, furthermore, this association is absent by the age of 5 years.

Radiotherapy for a pulmonary aspergilloma complicating p-ANCA positive small vessel vasculitis.

Life-threatening haemoptysis may complicate aspergillomas within pre-existing lung cavities. Treatment options have included lung resection, pulmonary or bronchial artery embolisation and antifungal therapy administered either systemically or by endobronchial or percutaneous instillation. We present a case of aspergilloma complicating small vessel vasculitis, and its successful treatment using radiotherapy.

Optimizing dynamic T2* MR imaging for measurement of cerebral blood flow using infusions for cerebral blood volume.

We describe an approach to measuring cerebral blood flow (CBF) based on independent measurements of cerebral blood volume (CBV) and mean transit time (MTT) with calculation of CBF by using the central volume theorem: CBF = CBV / MTT. This permits optimization of the individual acquisitions and analyses. In particular, measurement of CBV during contrast infusion, rather than simultaneously with MTT from a single bolus, yields values more consistent with those of other methods.

Copper absorption from foods labelled intrinsically and extrinsically with Cu-65 stable isotope.

OBJECTIVE: To determine copper absorption from copper containing foods labelled either intrinsically or extrinsically with a highly enriched Cu-65 stable isotope label. DESIGN: A longitudinal cross-over study. SETTING: The study was conducted at the Institute of Food Research, Human Nutrition Unit, Norwich, UK. SUBJECTS: Subjects were recruited locally via advertisements placed around the Norwich Research Park. A total of 10 volunteers (nine female, one male) took part in the study, but not all volunteers completed each of the test meals. INTERVENTIONS: A highly enriched Cu-65 stable isotope label was administered to volunteers in the form of a reference dose or in breakfast test meals consisting of red wine, soya beans, mushrooms or sunflower seeds. Faecal monitoring and mass spectrometry techniques were used to estimate the relative quantities of copper absorbed from the different test meals. RESULTS: True copper absorption from the reference dose (54%) was similar to extrinsically labelled red wine (49%) and intrinsically labelled sunflower seeds (52%), but significantly higher than extrinsically labelled mushrooms (35%), intrinsically (29%) and extrinsically (15%) labelled soya beans and extrinsically labelled sunflower seed (32%) test meals. CONCLUSIONS: The use of Cu-65 extrinsic labels in copper absorption studies requires validation according to the food being examined; intrinsic and extrinsic labelling produced significantly different results for sunflower seeds.

Cerebral blood volume measurements by T*2-weighted MRI and contrast infusion.

A reliable, accurate, and accessible method for measuring cerebral blood volume (CBV) has been developed based on T(*) (2)-weighted MRI and a 1-min infusion of gadolinium instead of a bolus. Computer simulations predict that this infusion CBV method will have a signal-to-noise ratio (SNR) 3-5 times greater than that obtained by area-under-the-curve (AUC) methods, with high accuracy over a wide range of arterial, tissue, and MRI conditions. In six healthy controls, the CBV was 1.87 +/- 0.44 in white matter (WM), 3.40 +/- 0.44 in deep gray matter (DGM), and 3.84 +/- 1.87 ml blood/100 g tissue in cortical GM (CGM). The mean GM/WM ratio was 1.94. In five patients with bilateral carotid disease, the corresponding values were 2.63 +/- 0.33, 4.72 +/- 0.33, and 5.27 +/- 2.40 ml blood/100 g tissue, all of which were significantly different from controls. AUC values were generally higher and failed to demonstrate differences between controls and patients. The infusion method shows great potential for providing reliable, accurate, and accessible CBV values with the ability to discriminate physiologic or pathological volume changes under a wide range of conditions.

Scanning electron microscopic examination of bacterial immobilisation in a carboxymethyl cellulose (AQUACEL) and alginate dressings.

Dressings have been applied to open wounds for centuries. Traditionally they have been absorbent, permeable materials, i.e. gauze that could adhere to desiccated wound surfaces, inducing trauma on removal. With the advent of modern wound care products many dressings are now capable of absorbing large volumes of exudate whilst still continuing to provide a moist wound healing environment. Equally important is their ability to lock exudate in the dressing (i.e. bacterial retention within the dressing matrix) such that upon removal from a wound surface bacterial dispersion is minimised. In these studies detailed scanning electron microscopy techniques have demonstrated the fluid controlling properties of alginate wound dressings and a carboxymethylated cellulose wound dressing (AQUACEL) Hydrofiber) dressing (CMCH)). It was demonstrated that following hydration of the latter wound dressing, the subsequent formation of a cohesive gel was effective in encapsulating large populations of potentially pathogenic bacteria such as Psuedomonas aeruginosa and Staphylococcus aureus under the gelled surface, as well as being immobilised within the swollen fibres. In contrast, hydrated alginate wound dressings did not form a uniform, cohesive gel structure, with the result that fewer bacteria were immobilised within the gel matrix. Many bacteria were trapped on individual, non-hydrated fibres. The unique absorbent gelling properties of the CMCH dressing appears to provide an ideal environment for immobilising bacteria.

Fluid-attenuated inversion recovery and diffusion- and perfusion-weighted MRI abnormalities in 117 consecutive patients with stroke symptoms.

BACKGROUND AND PURPOSE: Diffusion-weighted MRI (DWI) is highly sensitive to early cerebral ischemia, but its dependence on lesion location, acuity, and etiology remains unknown. Furthermore, although a marked perfusion-weighted MRI (PWI)-DWI mismatch may exist in a subset of acute strokes, the frequency and distribution of these mismatches have never been methodically characterized in an unselected population. To address these 2 issues, we evaluated echo-planar imaging in 117 consecutive patients with signs and symptoms of acute stroke. METHODS: Clinical diagnoses were determined by chart review. Fluid-attenuated inversion recovery (FLAIR), DWI, and PWI sequences were scored for lesion acuity, neuroanatomy, and vascular territory. Lesion and PWI-DWI mismatch volumes were determined by image analysis. RESULTS: DWI was more sensitive than was FLAIR for the detection of stroke for all subtypes in all anatomic distributions and at all tested time intervals. Although DWI exhibited its greatest benefit over FLAIR during the first 6 hours, it was still superior to FLAIR even after 24 hours. PWI abnormalities were detected in 49% of patients with DWI abnormalities. In the majority of these cases, the PWI-DWI mismatch was substantially larger than the DWI lesion itself. Both the largest DWI lesion volumes and the largest mismatch volumes occurred in patients with carotid disease. CONCLUSIONS: DWI nearly doubles the likelihood of detecting acute ischemic stroke lesions compared with FLAIR for all etiologies and in all anatomic locations. In the hyperacute period (0 to 6 hours), DWI more than triples the likelihood of acute-stroke detection over FLAIR. PWI reveals a measurable mismatch compared with DWI nearly 50% of the time; and in more than half of these patients, the ratio of the volume of the PWI lesion to the DWI lesion is several times larger than the core ischemic lesion itself. In the final analysis, approximately one fourth of all stroke patients present with a large volume of potentially salvageable tissue at risk for infarction.

Critical analysis of supracostal access for percutaneous renal surgery.

PURPOSE: Percutaneous renal surgery is currently performed for complex renal calculi as well as for various other endourological indications. In many patients an upper pole nephrostomy tract allows direct access to most of the intrarenal collecting system. Upper pole percutaneous access may be obtained via the supracostal or subcostal approach. The preferred route depends on the location and size of the specific stone or lesion. Previously others have cautioned against the supracostal approach above the 12th rib and many have discouraged an approach above the 11th rib due to concern about the increased risk of intrathoracic complications. We retrospectively assessed the morbidity associated with supracostal percutaneous renal surgery and compared and analyzed the morbidity of the supracostal and subcostal approaches. MATERIALS AND METHODS: The records of all patients who underwent upper pole percutaneous renal surgery between November 1993 and July 1999 were retrospectively reviewed. A total of 240 patients underwent percutaneous renal procedures, including 225 for managing symptomatic renal or ureteral stones, that is nonstaghorn calculi in 157, staghorn calculi in 41, proximal ureteral calculi in 12, calculi within a caliceal diverticulum in 6, calculi associated with primary ureteropelvic junction obstruction in 5 and calculi associated with a retained ureteral stent in 4. An additional 15 procedures were done for ureteropelvic junction obstruction (7), intrarenal collecting system tumors (5), a caliceal diverticulum without stones (1), a retained ureteral stent (1) and a ureteral stricture (1). RESULTS: A total of 300 nephrostomy tracts were placed to obtain access to the intrarenal collecting system via the supracostal approach in 98 (32.7%) cases and the subcostal approach in 202 (67.3%). Of the supracostal approaches 72 (73.5%) tracts were above the 12th and 26 (26.5%) were above the 11th rib. The overall complication rate irrespective of percutaneous approach was 8.3% (16.3% for supracostal and 4.5% for subcostal access). Complications included blood transfusion in 7 patients, intraoperative hemothorax/hydrothorax in 5, sepsis/bacteremia in 3, atrial fibrillation in 2, delayed nephropleural fistula in 2, renal artery pseudoaneurysm in 2, deep venous thrombosis/pulmonary embolus in 2, pneumothorax in 1 and subcapsular hematoma in 1. Seven of 8 intrathoracic complications (87.5%) developed in supracostal cases. CONCLUSIONS: Percutaneous renal surgery remains an important option for managing complex renal calculi and other upper urinary tract lesions. In our experience it is generally associated with low morbidity. The supracostal approach is often preferred for obtaining intrarenal access to complex renal and proximal ureteral pathology. Because supracostal access tracts are associated with significantly higher intrathoracic and overall complication rates compared to subcostal access tracts, this approach must be used with caution when no other alternatives are available.

In vitro bond strengths of resin modified glass ionomer cements and composite resin self-cure adhesives: introduction of an adhesive system with increased bond strength and inhibition of decalcification.

This study evaluated the shear bond strength and adhesive remnant index of 5 self-cure adhesives to comparatively evaluate a new adhesive system. Extracted human incisors were randomly divided into 7 test groups of 20 each. Incisor mesh-backed brackets were bonded to the tooth specimens in each group with their respective adhesive according to the manufacturer's instructions. The specimens were thermocycled for 2 weeks at temperatures from 5 degrees to 55 degrees C to simulate oral conditions and debonded using an Instron machine. Acceptable bond strength parameters were present with the Contacto No-Mix (composite resin containing glass ionomer 8.75 MPa) and Fuji Ortho SC with acid conditioning (6.98 MPa). Contacto No-Mix had a higher bond strength (11.2 MPa) when microetching and Megabond were employed than when these adjuncts were not employed. When FUJI Ortho SC specimens were conditioned with polyacrylic acid, they showed a higher bond strength (6.98 MPa) than when bonded to unetched teeth (5.41 MPa). In test 3, EXPT-fluoride adhesive (AF) demonstrated a higher bond strength (13.44 MPa) than both resin composite Contacto No-Mix (8.8 MPa, GAC 7.4 MPa) and FUJI Ortho SC (5.41 MPa). Expt AF (Test 3) and Concise had equal bond strengths, however, the former can potentially release fluoride from the glass ionomer. Although the Ex

A dose of 75 microg/kg/d of i.v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura.

Treatment with 75 microg/kg/d intravenous (i.v.) anti-D was compared with 50 microg/kg/d in a prospective randomized study of 27 RhD-positive, human immunodeficiency virus-negative, adult, acute, non-splenectomized patients with immune thrombocytopenic purpura (ITP) and platelet counts < or = 30 x 109/l. The higher dose resulted in greater median d 1 (43 x 109/l vs. 7.5 x 109/l; P = 0.012) and d 7 (153 x 109/l vs. 64.5 x 109/l; P = 0.001) platelet increases despite no greater haemoglobin decrease. Children with acute ITP receiving 75 microg/kg/d had overnight platelet increases in seven out of nine cases. The duration of effect at the 75 microg/kg/d dose was 46 d vs. 21 d (P = 0.03). Adverse events were mild to moderate and ameliorated with prednisone and acetaminophen premedication.

Comparative assessment of light-cured resin-modified glass ionomer and composite resin adhesives: in vitro study of a new adhesive system.

The ideal adhesive system is one that prevents decalcifications and has sufficient bond strength to withstand untimely impact forces on bonded brackets. The purpose of this investigation was to study and compare the bond strengths and adhesive remnant indexes of light-cured resin-modified glass ionomer and conventional resin adhesives. A new light-cured resin-modified glass ionomer adhesive was compared with the conventional adhesive systems. The effects of the new adhesive, with a system of etching and using adhesive promoters on the tooth enamel, as well as microetching the brackets, were analyzed. Comparisons were made (analysis of variance and the Tukey method) between this and other adhesive systems. The new adhesive system is indicated where prevention of decalcification and increased bond strength in noncompliant patients are indicated.

Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry.

We present a simple yet powerful method for the isolation and analysis of exosomes released by antigen-presenting cells (APC). Exosomes are small vesicles (40-90 nm) released by APC, and may have an immuno-regulatory function in vivo. Such exosomes originate from MHC class II peptide loading compartments and, as such, express high levels of MHC Class II. We have utilised magnetic beads, coated with monoclonal antibodies specific for HLA DP, DQ, DR for the specific isolation of exosomes from cell-free supernatants. Beads coated with exosomes are subsequently stained with conjugated antibodies, and analysed by flow cytometry. Characterisation of exosomes by this method demonstrated that exosomes derived from B-lymphocytes express abundant MHC Class I and II molecules. Other immunologically important molecules detected included the co-stimulatory molecules B7.1 (CD80) and B7.2 (CD86). The adhesion molecule ICAM-1 (CD54) was also detected. These exosomes also expressed the B cell marker CD20, and the complement inhibitory protein CD59. The expression of CD63, a lysosomal marker, was variable, and there was no detectable expression of transferrin receptor (CD71). Monocyte derived dendritic cells (cultured for 7 days in GM-CSF/IL-4), demonstrated an immature phenotype, and secreted exosomes with a similar phenotype, with abundant MHC molecules. The expression of CD63 was consistently strong, and the MHC Class I-like molecule CD1a was also present, suggesting a possible function in the presentation of lipid antigens. Again CD59 was expressed suggesting a possible role for APC exosomes in complement regulation. There was no detectable CD71, CD40, CD14, CD20 or CD83. Modification of the extraction protocol allowed a comparative analysis of exosome secretion under various conditions. Treatment of cells with calcium ionophore, or phorbol ester resulted in apparent increases in exosome release, while the phosphatidyl inositol 3-kinase inhibitor, wortmannin, reduced exosome secretion. The immuno-magnetic isolation and analysis of exosomes is a versatile and rapid tool for the analysis of APC exosomes, and may prove a valuable tool for the study of exosome biology.