Non-invasive in vivo measurement of cardiac output in C57BL/6 mice using high frequency transthoracic ultrasound: evaluation of gender and body weight effects

Even though mice are being increasingly used as models for human cardiovascular diseases, non-invasive monitoring of cardiovascular parameters such as cardiac output (CO) in this species is challenging. In most cases, the effects of gender and body weight (BW) on these parameters have not been studied. The objective of this study was to provide normal reference values for CO in C57BL/6 mice, and to describe possible gender and/or BW associated differences between them. We used 30-MHz transthoracic Doppler ultrasound to measure hemodynamic parameters in the ascending aorta [heart rate (HR), stroke volume (SV), stroke index (SI), CO, and cardiac index (CI)] in ten anesthetized mice of either sex. No differences were found for HR, SV, and CO. Both SI and CI were statistically lower in males. However, after normalization for BW, these differences disappeared. These results suggest that if comparisons of cardiovascular parameters are to be made between male and female mice, values should be standardized for BW.     

Soluble adhesion molecules and angiotensin-converting enzyme in dementia

We aimed to determine plasma and cerebrospinal fluid (CSF) levels of angiotensin-converting enzyme (ACE) and the soluble forms of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1) and platelet endothelial cell adhesion molecule-1 (sPECAM-1) as surrogate markers for endothelial cell activation in clinically diagnosed patients with Alzheimer's disease (AD, n=260), dementia with Lewy bodies (DLB, n=39) and non-demented controls (n=34). Plasma sICAM-1 and sPECAM-1 were higher and CSF sVCAM-1 were lower in AD and DLB patients than in controls (p<0.001). DLB patients had higher CSF sICAM-1, but lower CSF sVCAM-1 (p<0.001). No difference in ACE levels was found between the dementia groups and controls. In controls and AD patients CSF sICAM and sVCAM-1 strongly correlated with each other and with blood barrier permeability whereas in DLB group these correlations were weaker. The observed patterns in adhesion molecules may reflect distinctions in the pathophysiological basis of their generation in dementia patients.     

Analysis of patient selection and external validity in the Swedish contribution to the COLOR trial

Objective  The colon cancer laparoscopic or open resection (COLOR) trial is an international, randomised controlled trial comparing outcomes of open and laparoscopic surgery for colon cancer. The main purpose of this study was to determine representability by comparing included and nonincluded patients in the participating Swedish centres. Design  At eight centres, which included 391 of the 422 Swedish patients, a local database search was performed to identify retrospectively all patients (n = 2,384) who underwent surgery for colon cancer during the inclusion period, and data was retrieved from medical records. Results  Four hundred fifty-six patients were randomised, 65 of whom were excluded post randomisation (group 2), leaving 391 patients in the study (group 1). For 1,566 patients, valid exclusion criteria were found (group 3). Thus, 362 patients were eligible but not included (group 4). Relative to group 1, patients in group 4 had a significantly higher American Society of Anaesthesiologists (ASA) score, more advanced tumour stage and difference regarding the resections performed. Results showed that 1470 patients (62%) could be calculated as feasible for laparoscopic colon resection (LCR) in a clinical, nontrial situation. Conclusions  The study population in the Swedish part of the COLOR trial was representative of the eligible population with the exception of comorbidity, where those actually included had less severe comorbidity than the nonincluded but eligible patients. In Sweden, 50–60% of colon cancer patients can be operated on by laparoscopy. This work was supported by grants from the Swedish Cancer Society (Project Number 4287-B01-03XCC and Project Number 1921-B03-21XCC), the County Council of Stockholm, Assar Gabrielsson’s Foundation for Clinical Research, Jubileumskliniken Research Foundation, Sahlgrenska University Hospital and the Swedish Society of Medicine. A preliminary version of this paper was previously published in an academic thesis; “Laparoscopic and open surgery for colon cancer. Studies on costs and health related quality of life” by Martin Janson, Karolinska Institutet 2006, ISBN 91-7140-782-0.     

MRI with diffusion tensor imaging post-mortem at 3.0 T in a patient with frontotemporal dementia

The formalin-fixed brain of a patient with clinically diagnosed frontotemporal dementia (FTD) was examined post-mortem using magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) at 3.0 T. Frontotemporal atrophy as well as bilateral frontal white matter abnormalities were seen. The white matter changes were slightly more extensive on DTI than on conventional MRI. Correlation with histopathology of the corresponding regions revealed typical frontal lobe degeneration of non-Alzheimer type, with mild frontotemporal degeneration in the outer cortical layers and a moderate frontal white matter gliosis with demyelination. Post-mortem MRI/DTI with histopathologic correlation will enhance our understanding of the basis of white matter changes observed in dementia patients and may improve the in vivo MRI/DTI diagnostic assessment in FTD.     

Resequencing and association analysis of arylalkylamine N‐acetyltransferase (AANAT) gene and its contribution to major depression susceptibility

Abstract: Circadian rhythms disruptions, including abnormalities of circadian phase position and melatonin secretion, have been described in major depression (MD). Arylalkylamine N‐acetyltransferase (AANAT) is a key enzyme of the melatonin pathway involved in circadian oscillations of melatonin levels. We assessed the contribution of AANAT gene variability to susceptibility to MD considering common and rare genetic variations through a sequential sequencing and single nucleotide polymorphism (SNP)‐based genotyping approach in a sample of 445 unrelated patients with MD (257 unipolar MD, 188 bipolar depression) and 440 community‐based screened control subjects. We identified 17 sequence changes, thirteen of which represented novel sequence variations. We did not observe an over‐representation of patients carrying rare variants compared with the healthy controls. Common variants (MAF > 2%) were included in a case–control association analysis that showed significant association after multiple testing correction of two SNPs located in the promoter region of AANAT with MD: rs3760138 (P = 0.00006) and rs4238989 (P = 0.005). Multimarker analysis found significant associations between two three‐marker protective haplotypes and a susceptibility three‐marker haplotype containing the rare alleles of rs3760138‐rs4238989‐rs8150 and MD. We present evidence of the association of genetic variability in the AANAT gene with susceptibility to MD. Our results support the hypothesis that the melatonin‐signaling pathway and circadian clock mechanisms may contribute to the pathophysiology of MD.     

Test–retest variability for standard automated perimetry and short‐wavelength automated perimetry in diabetic patients

Purpose: To assess limits for significant improvement or deterioration of visual fields in diabetic patients based on short‐term test–retest variability in subjects with different degrees of retinopathy. Methods: Fifty patients with diabetic retinopathy ranging from level 10 to 75 [according to the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale] were tested repeatedly with both standard automated perimetry (SAP) and short‐wavelength automated perimetry (SWAP) with short intervals. The association between visual field loss and degree of retinopathy outside fovea was analysed. Test–retest variability of global and local visual field indices and prediction limits for significant change were calculated. Results: The amount of visual field loss was significantly associated to the degree of retinopathy, with a correlation coefficient of ?0.51 for SAP (P = 0.0003) and ?0.45 for SWAP (P = 0.002). Global test–retest variability was smaller with SAP than with SWAP (P < 0.0001). For both SAP and SWAP, local test–retest variability was considerably smaller at test points with normal sensitivity than at test points with reduced sensitivity (P < 0.0001). Paracentral test points within 10° of eccentricity had less variability than peripheral points (P < 0.0001), implying that smaller change is required to reach statistically significant improvement or deterioration at initially normal and paracentral points than at depressed points and peripherally located test points. Conclusion: Our results propose that SAP, as well as SWAP, can be useful for monitoring visual function outside fovea in diabetic patients with various degrees of retinopathy. We report a preference for SAP because of less variability generally. Limits for significant improvement or deterioration have been assessed but need future validation in a longitudinal study.     

An affibody in complex with a target protein: structure and coupled folding

Combinatorial protein engineering provides powerful means for functional selection of novel binding proteins. One class of engineered binding proteins, denoted affibodies, is based on the three-helix scaffold of the Z domain derived from staphylococcal protein A. The Z(SPA-1) affibody has been selected from a phage-displayed library as a binder to protein A. Z(SPA-1) also binds with micromolar affinity to its own ancestor, the Z domain. We have characterized the Z(SPA-1) affibody in its uncomplexed state and determined the solution structure of a Z:Z(SPA-1) protein-protein complex. Uncomplexed Z(SPA-1) behaves as an aggregation-prone molten globule, but folding occurs on binding, and the original (Z) three-helix bundle scaffold is fully formed in the complex. The structural basis for selection and strong binding is a large interaction interface with tight steric and polar/nonpolar complementarity that directly involves 10 of 13 mutated amino acid residues on Z(SPA-1). We also note similarities in how the surface of the Z domain responds by induced fit to binding of Z(SPA-1) and Ig Fc, respectively, suggesting that the Z(SPA-1) affibody is capable of mimicking the morphology of the natural binding partner for the Z domain.     

Equity and health systems reform in Latin America

The aim of any health care system is to help improve the people's health, and to do so as efficiently as possible. In order to improve the efficiency and equity of health services provision, many countries around the world have implemented reforms, including several Latin American nations. However similar the objectives may appear, the various ways societies implement such reforms reflect different values and concepts. This article analyzes the egalitarian and neoliberal values underlying different concepts of equity in health care. The authors develop criteria to interpret selected health services funding and provision strategies in Latin American health system reforms. These criteria are then applied to health care financing and delivery policies under the reforms currently being implemented in Colombia and Costa Rica.     

Cardiac valvular abnormalities are frequent in systemic lupus erythematosus patients with manifest arterial disease

The objective of this study was to study cardiac valve morphology and function and ventricular function in systemic lupus erythematosus (SLE) patients with and without co-existing cardiovascular disease (CVD) and in population controls. Twenty-six women (52 +/- 8.2 years) with SLE (SLE cases) and a history of CVD (angina pectoris, myocardial infarction, cerebral infarction or intermittent claudication) were compared with 26age-matched women with SLE but without manifest CVD (SLE controls) and 26 age-matched control women (population controls). Echocardiographywas performed to assess valvular abnormalities and manifestations of ischaemic heart disease. Thirteen of the 26 SLE cases but only one of the SLE controls and one of the population controls had cardiac valvular abnormalities. Three of the SLE cases had already undergone valve replacement and another had significant aortic insufficiency; the other nine had thickening of mainly mitral leaflets without hemodynamic significance. Among SLE cases, patients with valvular abnormalities had higher homocysteine (P < 0.001) and triglyceride (P = 0.02) concentrations than patients without valvular disease. In contrast atherosclerosis as determined by IMT, oxidized LDL as measured by the monoclonal antibody E06, autoantibodies against epitopes of OxLDL (aOxLDL) or phospholipids (aPL), disease duration or activity, or acute phase reactants did not differ between SLE cases with or without valvular abnormalities. Valvular abnormalities were not more common in SLE cases with stroke as compared to those with myocardial infarction, angina or claudication. In conclusion, valvular abnormalities are strongly associated with CVD in SLE. Raised levels of homocysteine and triglycerides characterize patients with cardiac valve abnormalities.