Effect of tailored practice and patient care plans on secondary prevention of heart disease in general practice: cluster randomised controlled trial

Objective: To test the effectiveness of a complex intervention designed, within a theoretical framework, to improve outcomes for patients with coronary heart disease. Design: Cluster randomised controlled multicentre trial. Setting: General practices in Northern Ireland and the Republic of Ireland, regions with different healthcare systems. Participants: 903 patients with established coronary heart disease registered with one of 48 practices. Intervention: Tailored care plans for practices (practice based training in prescribing and behaviour change, administrative support, quarterly newsletter), and tailored care plans for patients (motivational interviewing, goal identification, and target setting for lifestyle change) with reviews every four months at the practices. Control practices provided usual care. Main outcome measures: The proportion of patients at 18 month follow-up above target levels for blood pressure and total cholesterol concentration, and those admitted to hospital, and changes in physical and mental health status (SF-12). Results: At baseline the numbers (proportions) of patients above the recommended limits were: systolic blood pressure greater than 140 mm Hg (305/899; 33.9%, 95% confidence interval 30.8% to 33.9%), diastolic blood pressure greater than 90 mm Hg (111/901; 12.3%, 10.2% to 14.5%), and total cholesterol concentration greater than 5 mmol/l (188/860; 20.8%, 19.1% to 24.6%). At the 18 month follow-up there were no significant differences between intervention and control groups in the numbers (proportions) of patients above the recommended limits: systolic blood pressure, intervention 98/360 (27.2%) v control, 133/405 (32.8%), odds ratio 1.51 (95% confidence interval 0.99 to 2.30; P=0.06); diastolic blood pressure, intervention 32/360 (8.9%) v control, 40/405 (9.9%), 1.40 (0.75 to 2.64; P=0.29); and total cholesterol concentration, intervention 52/342 (15.2%) v control, 64/391 (16.4%), 1.13 (0.63 to 2.03; P=0.65). The number of patients admitted to hospital over the 18 month study period significantly decreased in the intervention group compared with the control group: 107/415 (25.8%) v 148/435 (34.0%), 1.56 (1.53 to 2.60; P=0.03). Conclusions: Admissions to hospital were significantly reduced after an intensive 18 month intervention to improve outcomes for patients with coronary heart disease, but no other clinical benefits were shown, possibly because of a ceiling effect related to improved management of the disease. Trial registration: Current Controlled Trials ISRCTN24081411.

Neutrophil Elastase Increases Airway Epithelial Nonheme Iron Levels

Alpha-1-antitrypsin (A1AT) deficiency is characterized by increased neutrophil elastase (NE) activity and oxidative stress in the lung. We hypothesized that NE exposure generates reactive oxygen species by increasing lung nonheme iron. To test this hypothesis, we measured bronchoalveolar lavage (BAL) iron and ferritin levels, using inductively coupled plasma (ICP) optical emission spectroscopy and an ELISA, respectively, in A1AT-deficient patients and healthy subjects. To confirm the role of NE in regulating lung iron homeostasis, we administered intratracheally NE or control buffer to rats and measured BAL and lung iron and ferritin. Our results demonstrated that A1AT-deficient patients and rats postelastase exposure have elevated levels of iron and ferritin in the BAL. To investigate the mechanism of NE-induced increased iron levels, we exposed normal human airway epithelial cells to either NE or control vehicle in the presence or absence of ferritin, and quantified intracellular iron uptake using calcein fluorescence and ICP mass spectroscopy. We also tested whether NE degraded ferritin in vitro using ELISA and western analysis. We demonstrated in vitro that NE increased intracellular nonheme iron levels and degraded ferritin. Our results suggest that NE digests ferritin increasing the extracellular iron pool available for cellular uptake.

Oral Resveratrol Reduces Neuronal Damage in a Model of Multiple Sclerosis

Background: Neuronal loss in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), correlates with permanent neurological dysfunction. Current MS therapies have limited the ability to prevent neuronal damage. Methods: We examined whether oral therapy with SRT501, a pharmaceutical grade formulation of resveratrol, reduces neuronal loss during relapsing-remitting EAE. Resveratrol activates SIRT1, an NAD-dependent deacetylase that promotes mitochondrial function. Results: Oral SRT501 prevented neuronal loss during optic neuritis, an inflammatory optic nerve lesion in MS and EAE. SRT501 also suppressed neurological dysfunction during EAE remission, and spinal cords from SRT501-treated mice had significantly higher axonal density than vehicle-treated mice. Similar neuroprotection was mediated by SRT1720, another SIRT1-activating compound; and sirtinol, an SIRT1 inhibitor, attenuated SRT501 neuroprotective effects. SIRT1 activators did not prevent inflammation. Conclusions: These studies demonstrate that SRT501 attenuates neuronal damage and neurological dysfunction in EAE by a mechanism involving SIRT1 activation. SIRT1 activators are a potential oral therapy in MS. © 2010 by North American Neuro-Ophthalmology Society.

Convergence of partial-wave expansions for energies, scattering amplitudes and positron annihilation rates

We use many-body theory to find the asymptotic behaviour of second-order correlation corrections to the energies and positron annihilation rates in many- electron systems with respect to the angular momenta l of the single-particle orbitals included. The energy corrections decrease as 1/(l+1/2)4, in agreement with the result of Schwartz, whereas the positron annihilation rate has a slower 1/(l+1/2)2 convergence rate. We illustrate these results by numerical calculations of the energies of Ne and Kr and by examining results from extensive con?guration-interaction calculations of PsH binding and annihilation.

Fasciola hepatica: Disruption of the vitelline cells in vitro by the sulphoxide metabolite of triclabendazole

The effects of the active sulphoxide metabolite of the fasciolicide triclabendazole (Fasinex, Ciba-Geigy) on the vitelline cells of Fusciola hepatica were determined in vitro by transmission electron microscopy using both intact flukes and tissue-slice material. At a triclabendazole concentration of 15 mu g/ml the vitelline cells of intact flukes showed ultrastructural changes only after prolonged incubation periods (12-24 h). The changes observed were a swelling of the granular endoplasmic reticulum (GER) cisternae with decreased ribosomal covering in the intermediate-type cells and condensation of chromatin and disappearance of the nucleolus in the nucleus of the stem cell. Similar changes were evident more quickly (by 6 h) in whole flukes treated at the higher concentration of 50 mu g/ml. The shell globule clusters were loosely packed in the intermediate type-2 cells, and the number of intermediate type-1 cells declined with more prolonged incubation. Disruption of the nurse-cell cytoplasm was also observed from 12 h onwards. After only 6 h incubation of tissue-slice material at 50 mu g/ml, intermediate type-1 cells were absent, shell globule clusters in mature cells were loosely packed and the nurses cell cytoplasm was badly disrupted. By 12 h the vitelline cells were vacuolated and grossly abnormal. The results are discussed in relation to postulated actions of triclabendazole against the microtubule component of the cytoskeleton and against protein synthesis in the fluke.

Learning Not to Curse: Swearing, Testimony, and Truth in Olaudah Equiano’s The Interesting Narrative

This article addresses swearing and testimony in Olaudah Equiano’s The Interesting Narrative (1789) by reading the work in the context of a broader contemporary discourse concerning profane swearing and cursing. Acts of profane enunciation inform a number of key episodes in Equiano’s life, and bear particular significance for his spiritual development and abolitionist witnessing. Within the Narrative, swearing is cast as a failure of piety, civility, and humanity, and shown to be actively avenged by a retributive deity. In Britain, profane swearing was also thought to undermine the validity of legal testimony; while, in the British West Indies, slaves were denied recourse to such testimony against their oppressors. By disavowing profane swearing and cursing, the essay argues, Equiano sought to assert both the validity of his oath and the truth of his testimony against the iniquities of the British slave trade.

Measuring inconsistency in network intrusion rules

In this preliminary case study, we investigate how inconsistency in a network intrusion detection rule set can be measured. To achieve this, we first examine the structure of these rules which incorporate regular expression (Regex) pattern matching. We then identify primitive elements in these rules in order to translate the rules into their (equivalent) logical forms and to establish connections between them. Additional rules from background knowledge are also introduced to make the correlations among rules more explicit. Finally, we measure the degree of inconsistency in formulae of such a rule set (using the Scoring function, Shapley inconsistency values and Blame measure for prioritized knowledge) and compare the informativeness of these measures. We conclude that such measures are useful for the network intrusion domain assuming that incorporating domain knowledge for correlation of rules is feasible.

Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage.

Cdk2 and cdk1 are individually dispensable for cell-cycle progression in cancer cell lines because they are able to compensate for one another. However, shRNA-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated S phase cell-cycle arrest and the phosphorylation of a subset of ATR/ATM targets after DNA damage. Loss of DNA damage-induced checkpoint control was caused by a reduction in formation of BRCA1-containing foci. Mutation of BRCA1 at S1497 and S1189/S1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of BRCA1-containing foci. Abrogation of checkpoint control after cdk1 depletion or inhibition in non-small-cell lung cancer cells sensitized them to DNA-damaging agents. Conversely, reduced cdk1 activity caused more potent G2/M arrest in nontransformed cells and antagonized the response to subsequent DNA damage. Cdk1 inhibition may therefore selectively sensitize BRCA1-proficient cancer cells to DNA-damaging treatments by disrupting BRCA1 function.