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Objectives: The potential for undesirable systemic effects related to constitutive expression of certain therapeutic transgenes may be limited through the development of transcriptionally targeted disease- and cell-type-specific vectors. The objective of this study was to analyse the canine matrix metalloproteinase-9 (MMP-9) promoter and deletion constructs for its ability to drive expression in response to pro-inflammatory cytokines (interleukin-1beta and tumour necrosis factor-alpha)., Methods: Initial analysis of MMP-9 deletion constructs was made using a luciferase reporter system. The promoter was subsequently engineered to incorporate multiple NF-kappaB sites. In parallel experiments we used the mouse collagen type XI promoter to study cell-type-specific promoter activity in chondrocyte-specific cells (SW1353) and undifferentiated chondroprogenitor cells (ATDC5)., Results: Incorporation of multiple NF-kappaB sites into the MMP-9 promoter enhanced activity while maintaining disease specificity. Further, manipulation of the mouse collagen type XI (mColXI) promoter by the incorporation of SOX9 enhancer sites downstream of a reporter gene, increased gene activity while maintaining cell type specificity., Conclusions: Manipulation of promoter and enhancer regions can improve transcriptionally targeted genes. A combination of these systems, in the context of the canine model, has the potential to improve the safety of osteoarthritis gene therapy vectors.

Background: The aim of the study was to review systematically the literature measuring the accuracy of routine UK hospital statistics that classify patients on discharge., Methods: A systematic review was carried out of studies comparing routine discharge statistics about an episode of hospital care with the original medical record. Dual quality assessment and extraction was completed for included studies. Qualitative and descriptive analyses were undertaken. Additional comparisons of factors that could potentially introduce systematic variation in coding accuracy were also undertaken., Results: Thirty studies were identified, of which 21 were included in the review. Twelve of these were conducted in England and Wales, and nine in Scotland. The majority assessed the accuracy of a single diagnosis, or selection of diagnoses in a limited range of hospital settings. The median coding accuracy rates were 91 per cent for diagnostic codes and 69.5 per cent for operation or procedure codes in studies in England or Wales; 82 per cent for diagnostic codes and 98 per cent for operation or procedure codes in Scottish studies. There were no significant differences in coding accuracy over time or in the type or rarity of the codes being assessed. Accuracy rates were higher for ICD7 codes (median 96.5 per cent) than for ICD8 (median 87 per cent) or ICD9 (median 77 per cent)., Conclusions: Coding accuracy on average is high in the United Kingdom, especially for operations and procedures. However, policy-makers, planners and researchers need to recognize and account for the degree of inaccuracy in routine hospital information statistics. Further research is needed into methods of improving and maintaining coding accuracy.

Objective: The effectiveness of activities to promote routine prophylaxis to prevent thromboembolism is difficult to assess because information about the prevalence of prophylaxis is sparse. The aim of this study was to assess the prevalence of deep vein thrombosis (DVT) prophylaxis for patients at risk in general medicine, general surgery, orthopaedics and gynaecology in Scotland and the North of England., Design: Retrospective case note review of a random sample of episodes of care in a stratified random sample of directorates in Scotland and a convenience sample in England., Setting: Twenty acute hospital directorates in Scotland and eight in the North of England., Participants: Case notes of patients at risk of thrombosis and discharged from the selected directorates in a 12-month period (n = 742)., Main Outcome Measures: The proportion of patients receiving prophylaxis in each directorate., Results: Overall, 469/526 (89%) of patients in Scotland and 199/216 (92%) in England received prophylaxis. The proportion varied from 71% in general medicine to 100% in orthopaedics. The frequency of use of different forms of prophylaxis varied between directorates. Approximately 60% of the patients who received prophylaxis received more than one form., Conclusions: Prophylaxis for DVT is well established for procedures and conditions that are known to increase the risk of thrombosis and for which there are no contraindications. Additional efforts to promote prophylaxis for these conditions are unlikely to be cost effective. Further research is needed to establish whether rates are equally high in other conditions, and whether the high prophylaxis rates are due to clinical effectiveness initiatives.

Symptomatic heart failure is accompanied by diastolic ventricular dysfunction due largely to an extensive reactive and reparative fibrosis. Experimental evidence suggests a clear association between myocardial fibrosis and chronic inappropriate elevations in circulating angiotensin II (Ang II) and/or aldosterone. Although not entirely elucidated, injury follows Ang II-associated release of adrenal medullary catecholamines and aldosterone-induced myocardial potassium depletion. Increasing evidence indicates locally produced cardiac Ang II plays an important role in tissue repair that may underlie myocardial remodelling, the fibrous tissue accumulation both at and remote to the site of myocardial infarction (MI). Angiotensin converting enzyme (ACE) binding density markedly increases at these fibrous tissue sites after experimental MI, indicating an involvement in wound healing regardless of the cause and location of fibrosis; cells expressing Ang II receptors are primarily myofibroblasts. Therapy with ACE inhibitors and aldosterone receptor antagonist have each been shown to attenuate development of fibrosis.

To evaluate gender-related differences in left ventricular (LV) structure and function in aortic stenosis, LV biplane cineangiography, micromanometry and endomyocardial biopsies were carried out in 56 patients with aortic stenosis and normal coronary arteries. Patients were divided into males (M: n = 35), and females (F: n = 21). Sixteen normal subjects 8 M, 8 F) served as haemodynamic controls. Control biopsy data were obtained from six pre-transplantation donor hearts (3 M and 3 F). LV systolic function was evaluated by ejection fraction and its relationship to mean systolic circumferential wall stress, diastolic function by the time constant of LV pressure decay, peak filling rates and passive myocardial stiffness constant. Biopsy samples were evaluated for interstitial fibrosis, muscle fibre diameter and volume fraction of myofibrils. In a subset of 27 consecutive patients, biopsy samples were evaluated with a morphometric-morphological method, for total collagen volume fraction, endocardial fibrosis and the extension and thickness of orthogonal collagen fibres (cross-hatching). In patients with aortic stenosis, aortic valve area, aortic valve resistance and mean aortic pressure gradient were comparable in males and females, whereas end-systolic and end-diastolic volumes were larger in males than females. Ejection fraction was lower (56%) in males than females (64%) (P < 0.05); 20 of 35 males and four of 21 females had depressed systolic contractility when assessed with regard to the relationship ejection fraction-mean systolic stress (P < 0.01). Myocardial stiffness constant was higher in males than in females (P < 0.01). Nine of 14 males and two of 13 females had endocardial fibrosis (P < 0.009), whereas increased cross-hatching (> 1.5 grade) was present in 11 males and four females with aortic stenosis (P < 0.01). An abnormal collagen architecture was present in 13/14 males and 5/13 females (P < 0.002). In aortic stenosis, males have a depressed systolic function and abnormal passive elastic properties when compared to females with valve lesions of similar severity. Changes in collagen architecture may account, at least in part, for these differences.

In both humans and experimental animals, mineralocorticoid (MC)-induced hypertension is associated with myocardial fibrosis. We have shown that this fibrous tissue response includes a reactive interstitial fibrosis not initiated by parenchymal cell loss, and a reparative fibrosis or scarring, occurring in response to cardiac myocyte necrosis. The reactive fibrosis is thought to be related to MC excess, while cell loss and microscopic scarring may be secondary to enhanced potassium excretion or a cytotoxic effect of aldosterone. This histologic study was undertaken to determine whether or not the potassium sparing diuretic amiloride would be effective in preventing the appearance of either form of fibrosis. Uninephrectomized male Sprague Dawley rats received either aldosterone (AL; 0.75 microgram/h), amiloride (AMC; 1 mg/kg/day), aldosterone+amiloride (ALAM), or vehicle (ALC) alone via subcutaneous osmotic minipumps for 8 weeks. All rats received 1% NaCl in their drinking water. Hearts were recovered, immersion-fixed, and tissue sections from both left and right ventricles stained with the collagen specific stain Sirius Red F3BA were morphometrically analyzed. The interstitial collagen volume fraction was elevated in AL and ALAM groups compared to ALC and AMC, but did not differ between AL and ALAM. Microscopic scarring, found in both ventricles, was evident in AL animals, but was not found in the ALAM, AMC, or ALC groups. These data suggest that chronic elevations in plasma aldosterone, relative to dietary sodium intake, do not have a direct cytotoxic effect on cardiac myocytes, but they are associated with a reactive interstitial fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)