Relationship between changes in insulin sensitivity and associated cardiovascular disease risk factors in thiazolidinedione-treated, insulin-resistant, nondiabetic individuals: pioglitazone versus rosiglitazone

This study compared the effects of administering rosiglitazone (RSG) vs pioglitazone (PIO) oil cardiovascular disease risk factors in insulin-resistant. nondiabetic individuals with no apparent disease. Twenty-two nondiabetic, apparently healthy individuals, classified as being insulin resistant oil the basis of a steady-state plasma glucose concentration of at least 10 mmol/L during the insulin suppression test, were treated with either RSG or 1110 for 3 months. Measurements were made before and after drug treatment of weight; blood pressure; fasting and daylong glucose, insulin, and free fatty acid (FFA) levels; and lipid and lipoprotein concentrations. Insulin sensitivity (steady-state plasma glucose concentration) significantly improved in both treatment groups, associated with significant decreases in daylong plasma concentrations of glucose, insulin, and FFA. Diastolic blood pressure fell somewhat in both groups, and this change reached significance in those receiving PIO. Improvement in lipid metabolism was confined to the PIO-treated group, signified by a significant decrease in plasma triglyceride concentration, whereas triglyceride concentration did not decline in the RSG-treated group, and these individuals also had increases in total (P = .047) and low-density lipoprotein cholesterol (P = .07). In conclusion, RSG and PIO appear to have comparable abilities to improve insulin sensitivity and lower daylong glucose, insulin, and FFA concentrations in nondiabetic, insulin-resistant individuals. However, despite these similarities, their effects on lipoprotein metabolism seem to be quite different, with beneficial effects confined to PIO-treated individuals. (C) 2009 Elsevier Inc. All rights reserved.

Accuracy and cost- and time-effectiveness of digital clip versus videotape interpretation of echocardiograms in patients with valvular disease

Background. Although digital and videotaped images are known to be comparable for the evaluation of left ventricular function, their relative accuracy for assessment of more complex anatomy is unclear. We sought to compare reading time, storage costs, and concordance of video and digital interpretations across multiple observers and sites. Methods. One hundred one patients with valvular (90 mitral, 48 aortic, 80 tricuspid) disease were selected prospectively, and studies were stored according to video and standardized digital protocols. The same reviewer interpreted video and digital images independently and at different times with the use of a standard report form to evaluate 40 items (eg, severity of stenosis or regurgitation, leaflet thickening, and calcification) as normal or mildly, moderately, or severely abnormal Concordance between modalities was expressed at kappa Major discordance (difference of >1 level of severity) was ascribed to the modality that gave the lesser severity. CD-ROM was used to store digital data (20:1 lossy compression), and super-VHS video-tape was used to store video data The reading time and storage costs for each modality were compared Results. Measured parameters were highly concordant (ejection fraction was 52% +/- 13% by both). Major discordance was rare, and lesser values were reported with digital rather than video interpretation in the categories of aortic and mitral valve thicken ing (1% to 2%) and severity of mitral regurgitation (2%). Digital reading time was 6.8 +/- 2.4 minutes, 38% shorter than with video (11.0 +/- 3.0, range 8 to 22 minutes, P < .001). Compressed digital studies had an average size of 60 <plus/minus> 14 megabytes (range 26 to 96 megabytes). Storage cost for video was A$0.62 per patient (18 studies per tape, total cost A$11.20), compared with A$0.31 per patient for digital storage (8 studies per CD-ROM, total cost A$2.50). Conclusion. Digital and video interpretation were highly concordant; in the few cases of major discordance, the digital scores were lower, perhaps reflecting undersampling. Use of additional views and longer clips may be indicated to minimize discordance with video in patients with complex problems. Digital interpretation offers a significant reduction in reading times and the cost of archiving.

Applying statistical approaches in the dissection of genes versus environment for asthma and allergic disease

Now that some of the genes involved in asthma and allergy have been identified, interest is turning to how genetic predisposition interacts with exposure to environmental risk factors. These questions are best answered by studies in which both genotypes and other risk factors are measured, but even simpler studies, in which family history is used as a proxy for genotype, have made suggestive findings. For example, early breast feeding may increase the risk of allergic disease in genetically susceptible children, and decrease the risk of 'sporadic' allergy. This review also addresses the overall importance of genetic causes of allergic disease in the general population.

G551D CF mice display an abnormal host response and have impaired clearance of Pseudomonas lung disease

Several cystic fibrosis (CF) mouse models demonstrate an increased susceptibility to Pseudomonas aeruginosa lung infection, characterized by excessive inflammation and high rates of mortality. Here we developed a model of chronic P. aeruginosa lung disease in mice homozygous for the murine CF transmembrane conductance regulator G551D mutation that provides an excellent model for CF lung disease. After 3 days of infection with mucoid P. aeruginosa entrapped in agar beads, the G551D animals lost substantially more body weight than non-CF control animals and were less able to control the infection, harboring over 40-fold more bacteria in the lung. The airways of infected G551D animals contained altered concentrations of the inflammatory mediators tumor necrosis factor-alpha, KC/N51, and macrophage inflammatory protein-2 during the first 2 days of infection, suggesting that an ineffective inflammatory response is partly responsible for the clearance defect.

Differential effect of long versus short wavelength light exposure on pupillary re-dilation in patients with outer retinal disease.

BACKGROUND: In patients with outer retinal degeneration, a differential pupil response to long wavelength (red) versus short wavelength (blue) light stimulation has been previously observed. The goal of this study was to quantify differences in the pupillary re-dilation following exposure to red versus blue light in patients with outer retinal disease and compare them with patients with optic neuropathy and with healthy subjects. DESIGN: Prospective comparative cohort study. PARTICIPANTS: Twenty-three patients with outer retinal disease, 13 patients with optic neuropathy and 14 normal subjects. METHODS: Subjects were tested using continuous red and blue light stimulation at three intensities (1, 10 and 100 cd/m2) for 13 s per intensity. Pupillary re-dilation dynamics following the brightest intensity was analysed and compared between the three groups. MAIN OUTCOME MEASURES: The parameters of pupil re-dilation used in this study were: time to recover 90% of baseline size; mean pupil size at early and late phases of re-dilation; and differential re-dilation time for blue versus red light. RESULTS: Patients with outer retinal disease showed a pupil that tended to stay smaller after light termination and thus had a longer time to recovery. The differential re-dilation time was significantly greater in patients with outer retinal disease (median = 28.0 s, P < 0.0001) compared with controls and patients with optic neuropathy. CONCLUSIONS: A differential response of pupil re-dilation following red versus blue light stimulation is present in patients with outer retinal disease but is not found in normal eyes or among patients with visual loss from optic neuropathy.

Rendu-Osler disease: treatment with oestrogen/progestagen versus octreotide.

In Rendu-Osler disease, haemorrhages due to gastrointestinal vascular malformations are common. Surgical and endoscopic treatments for haemorrhage due to gastrointestinal vascular malformations are compromised when lesions are diffuse, escape identification or are inaccessible to treatment. Hormonal treatment with oestrogen and progestagens is still controversial based on contradictory results from two randomised clinical trials. Although somatostatin and its long-acting analogue, octreotide, have been reported to be beneficial in preventing rebleeding, there is no consensus on this type of treatment. This case report shows how the combination of ethinyloestradiol and norethisterone markedly reduced the need for blood transfusions with few side effects in one patient; in comparison, octreotide seems less effective but this could be related to a worsening of the disease.

Frequency of platelet type versus type 2B von Willebrand disease. An international registry-based study.

Less than 50 patients are reported with platelet type von Willebrand disease (PT-VWD) worldwide. Several reports have discussed the diagnostic challenge of this disease versus the closely similar disorder type 2B VWD. However, no systematic study has evaluated this dilemma globally. Over three years, a total of 110 samples/data from eight countries were analysed. A molecular approach was utilised, analysing exon 28 of the von Willebrand factor (VWF) gene, and in mutation negative cases the platelet GP1BA gene. Our results show that 48 cases initially diagnosed as putative type 2B/PT-VWD carried exon 28 mutations consistent with type 2B VWD, 17 carried GP1BA mutations consistent with a PT-VWD diagnosis, three had other VWD types (2A and 2M) and five expressed three non-previously published exon 28 mutations. Excluding 10 unaffected family members and one acquired VWD, 26 cases did not have mutations in either genes. Based on our study, the percentage of type 2B VWD diagnosis is 44% while the percentage of misdiagnosis of PT-VWD is 15%. This is the first large international study to investigate the occurrence of PT-VWD and type 2B VWD worldwide and to evaluate DNA analysis as a diagnostic tool for a large cohort of patients. The study highlights the diagnostic limitations due to unavailability/poor application of RIPA and related tests in some centres and proposes genetic analysis as a suitable tool for the discrimination of the two disorders worldwide. Cases that are negative for both VWF and GP1BA gene mutations require further evaluation for alternative diagnoses.

Cost evaluation of cardiovascular magnetic resonance versus coronary angiography for the diagnostic work-up of coronary artery disease: Application of the European Cardiovascular Magnetic Resonance registry data to the German, United Kingdom, Swiss, and United States health care systems.

ABSTRACT: BACKGROUND: Cardiovascular magnetic resonance (CMR) has favorable characteristics for diagnostic evaluation and risk stratification of patients with known or suspected CAD. CMR utilization in CAD detection is growing fast. However, data on its cost-effectiveness are scarce. The goal of this study is to compare the costs of two strategies for detection of significant coronary artery stenoses in patients with suspected coronary artery disease (CAD): 1) Performing CMR first to assess myocardial ischemia and/or infarct scar before referring positive patients (defined as presence of ischemia and/or infarct scar to coronary angiography (CXA) versus 2) a hypothetical CXA performed in all patients as a single test to detect CAD. METHODS: A subgroup of the European CMR pilot registry was used including 2,717 consecutive patients who underwent stress-CMR. From these patients, 21% were positive for CAD (ischemia and/or infarct scar), 73% negative, and 6% uncertain and underwent additional testing. The diagnostic costs were evaluated using invoicing costs of each test performed. Costs analysis was performed from a health care payer perspective in German, United Kingdom, Swiss, and United States health care settings. RESULTS: In the public sectors of the German, United Kingdom, and Swiss health care systems, cost savings from the CMR-driven strategy were 50%, 25% and 23%, respectively, versus outpatient CXA. If CXA was carried out as an inpatient procedure, cost savings were 46%, 50% and 48%, respectively. In the United States context, cost savings were 51% when compared with inpatient CXA, but higher for CMR by 8% versus outpatient CXA. CONCLUSION: This analysis suggests that from an economic perspective, the use of CMR should be encouraged as a management option for patients with suspected CAD.

Cost evaluation of cardiac magnetic resonance imaging versus coronary angiography for the work-up of coronary artery disease

Background: CMR has recently emerged as a robust and reliable technique to assess coronary artery disease (CAD). A negative perfusion CMR test predicts low event rates of 0.3-0.5%/year. Invasive coronary angiography (CA) remains the "gold standard" for the evaluation of CAD in many countries.Objective: Assessing the costs of the two strategies in the European CMR registry for the work-up of known or suspected CAD from a health care payer perspective. Strategy 1) a CA to all patients or 2) a CA only to patients who are diagnosed positive for ischemia in a prior CMR.Method and results: Using data of the European CMR registry (20 hospitals, 11'040 consecutive patients) we calculated the proportion of patients who were diagnosed positive (20.6%), uncertain (6.5%), and negative (72.9%) after the CMR test in patients with known or suspected CAD (n=2'717). No other medical test was performed to patients who were negative for ischemia. Positive diagnosed patients had a coronary angiography. Those with uncertain diagnosis had additional tests (84.7%: stress echocardiography, 13.1%: CCT, 2.3% SPECT), these costs were added to the CMR strategy costs. Information from costs for tests in Germany and Switzerland were used. A sensibility analysis was performed for inpatient CA. For costs see figure. Results - costs.Discussion: The CMR strategy costs less than the CA strategy for the health insurance systems both, in Germany and Switzerland. While lower in costs, the CMR strategy is a non-invasive one, does not expose to radiation, and yields additional information on cardiac function, viability, valves, and great vessels. Developing the use of CMR instead of CA might imply some reduction in costs together with superior patient safety and comfort, and a better utilization of resources at the hospital level. Document introduit le : 01.12.2011

Integration of Trypanosoma cruzi kDNA minicircle sequence in the host genome may be associated with autoimmune serum factors in Chagas disease patients

Integration of kDNA sequences within the genome of the host cell shown by PCR amplification with primers to the conserved Trypanosoma cruzi kDNA minicircle sequence was confirmed by Southern hybridization with specific probes. The cells containing the integrated kDNA sequences were then perpetuated as transfected macrophage subclonal lines. The kDNA transfected macrophages expressed membrane antigens that were recognized by antibodies in a panel of sera from ten patients with chronic Chagas disease. These antigens barely expressed in the membrane of uninfected, control macrophage clonal lines were recognized neither by factors in the control, non-chagasic subjects nor in the chagasic sera. This finding suggests the presence of an autoimmune antibody in the chagasic sera that recognizes auto-antigens in the membrane of T. cruzi kDNA transfected macrophage subclonal lines.

Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes.

TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell- specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n=39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n=41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P&lt; .001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P&lt; .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD(-)CD27(+) B cells (P= .019), benign lymphoproliferation (P&lt; .001), and autoimmune complications (P= .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation.

Highly pathogenic adapted HIV-1 strains limit host immunity and dictate rapid disease progression.

OBJECTIVE:: The study of HIV-1 rapid progressors has been limited to specific case reports. Nevertheless, identification and characterization of the viral and host factors involved in rapid progression are crucial when attempting to uncover the correlates of rapid disease outcome. DESIGN:: We carried out comparative functional analyses in rapid progressors (n = 46) and standard progressors (n = 46) early after HIV-1 seroconversion (≤1 year). The viral traits tested were viral replicative capacity, co-receptor usage, and genomic variation. Host CD8 T-cell responses, humoral activity, and HLA immunogenetic markers were also determined. RESULTS:: Our data demonstrate an unusual convergence of highly pathogenic HIV-1 strains in rapid progressors. Compared with standard progressors, rapid progressor viral strains show higher in-vitro replicative capacity (81.5 vs. 67.9%; P = 0.025) and greater X4/DM co-receptor usage (26.3 vs. 2.8%; P = 0.006) in early infection. Limited or absent functional HIV-1 CD8 T-cell responses and neutralizing activity were measured in rapid progressors. Moreover, the increase in common HLA allele-restricted CD8 T-cell escape mutations in rapid progressors acts as a signature of uncontrolled HIV-1 replication and early impairment of adaptive cellular responses. CONCLUSION:: Our data support a dominant role for viral factors in rapid progressors. Robust HIV-1 replication and intrinsic viral properties limit host adaptive immune responses, thus driving rapid disease progression.

Cellular and genetic mechanisms involved in the generation of protective and pathogenic immune responses in human Chagas disease

Perhaps one of the most intriguing aspects of human Chagas disease is the complex network of events that underlie the generation of protective versus pathogenic immune responses during the chronic phase of the disease. While most individuals do not develop patent disease, a large percentage may develop severe forms that eventually lead to death. Although many efforts have been devoted to deciphering these mechanisms, there is still much to be learned before we can fully understand the pathogenesis of Chagas disease. It is clear that the host's immune response is decisive in this process. While characteristics of the parasite influence the immune response, it is becoming evident that the host genetic background plays a fundamental role in the establishment of pathogenic versus protective responses. The involvement of three complex organisms, host, parasite and vector, is certainly one of the key aspects that calls for multidisciplinary approaches towards the understanding of Chagas disease. We believe that now, one hundred years after the discovery of Chagas disease, it is imperative to continue with highly interactive research in order to elucidate the immune response associated with disease evolution, which will be essential in designing prophylactic or therapeutic interventions.