Mutating the CX3C Motif in the G Protein Should Make a Live Respiratory Syncytial Virus Vaccine Safer and More Effective.

Respiratory syncytial virus (RSV) belongs to the family Paramyxoviridae and is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. Through a CX3C chemokine motif (182CWAIC186) in the G protein, RSV binds to the corresponding chemokine receptor, CX3CR1. Since RSV binding to CX3CR1 contributes to disease pathogenesis, we investigated whether a mutation in the CX3C motif by insertion of an alanine, A186, within the CX3C motif, mutating it to CX4C (182CWAIAC187), which is known to block binding to CX3CR1, might decrease disease. We studied the effect of the CX4C mutation in two strains of RSV (A2 and r19F) in a mouse challenge model. We included RSV r19F because it induces mucus production and airway resistance, two manifestations of RSV infection in humans, in mice. Compared to wild-type (wt) virus, mice infected with CX4C had a 0.7 to 1.2 log10-fold lower virus titer in the lung at 5 days postinfection (p.i.) and had markedly reduced weight loss, pulmonary inflammatory cell infiltration, mucus production, and airway resistance after challenge. This decrease in disease was not dependent on decrease in virus replication but did correspond to a decrease in pulmonary Th2 and inflammatory cytokines. Mice infected with CX4C viruses also had higher antibody titers and a Th1-biased T cell memory response at 75 days p.i. These results suggest that the CX4C mutation in the G protein could improve the safety and efficacy of a live attenuated RSV vaccine.IMPORTANCE RSV binds to the corresponding chemokine receptor, CX3CR1, through a CX3C chemokine motif (182CWAIC186) in the G protein. RSV binding to CX3CR1 contributes to disease pathogenesis; therefore, we investigated whether a mutation in the CX3C motif by insertion of an alanine, A186, within the CX3C motif, mutating it to CX4C (182CWAIAC187), known to block binding to CX3CR1, might decrease disease. The effect of this mutation and treatment with the F(ab')2 form of the anti-RSV G 131-2G monoclonal antibody (MAb) show that mutating the CX3C motif to CX4C blocks much of the disease and immune modulation associated with the G protein and should improve the safety and efficacy of a live attenuated RSV vaccine.

Status Report--Retracing the history of the early development of national chronic disease surveillance in Canada and the major role of the Laboratory Centre for Disease Control (LCDC) from 1972 to 2000.

TITRE: Rapport d'étape - Historique des débuts de la surveillance nationale des maladies chroniques au Canada et rôle majeur du Laboratoire de lutte contre la maladie (LLCM) de 1972 à 2000. INTRODUCTION: La surveillance de la santé consiste en l'utilisation systématique et continue de données sur la santé recueillies régulièrement en vue d'orienter les mesures de santé publique en temps opportun. Ce document décrit la création et l'essor des systèmes nationaux de surveillance au Canada et les répercussions de ces systèmes sur la prévention des maladies chroniques et des blessures. En 2008, les auteurs ont commencé à retracer l'historique des débuts de la surveillance nationale des maladies chroniques au Canada, en commençant à 1960, et ils ont poursuivi leur examen jusqu'en 2000. Une publication de 1967 a retracé l'historique de la création du Laboratoire d'hygiène de 1921 à 1967. Notre étude fait suite à cette publication et décrit l'historique de l'établissement de la surveillance nationale des maladies chroniques au Canada, à la fois avant et après la création du Laboratoire de lutte contre la maladie (LCDC).

Cardiac rehabilitation for people with heart disease: an overview of Cochrane systematic reviews.

INTRODUCTION: Overviews are a new approach to summarising evidence and synthesising results from related systematic reviews. OBJECTIVES: To conduct an overview of Cochrane systematic reviews to provide a contemporary review of the evidence for cardiac rehabilitation (CR), identify opportunities for merging or splitting existing Cochrane reviews, and identify current evidence gaps to inform new review titles. METHODS: The Cochrane Database of Systematic Reviews was searched to identify reviews that address the objectives of this overview. Data presentation is descriptive with tabular presentations of review- and trial-level characteristics and results. RESULTS: The six included Cochrane systematic reviews were of high methodological quality and included 148 randomised controlled trials in 97,486 participants. Compared to usual care alone, exercise-based CR reduces hospital admissions and improves patient health related quality of life (HRQL) in low to moderate risk heart failure and coronary heart disease (CHD) patients. At 12 months or more follow-up, there was evidence of some reduction in mortality in patients with CHD. Psychological- and education-based interventions appear to have little impact on mortality or morbidity but may improve HRQL. Home- and centre-based programmes are equally effective in improving HRQL at similar costs. Selected interventions can increase the uptake of CR programmes but evidence to support interventions that improve adherence is weak. CONCLUSIONS: This overview confirms that exercise-based CR is effective and safe in the management of clinically stable heart failure and post-MI and PCI patients. We discuss the implications of this overview on the future direction of the Cochrane CR reviews portfolio.

Effectiveness of enzyme replacement therapy in adults with late-onset Pompe disease: results from the NCS-LSD cohort study.

OBJECTIVES: To determine the effectiveness of enzyme replacement therapy (ERT) for adults with late-onset Pompe disease. DESIGN: A longitudinal cohort study including prospective and retrospective clinical outcome data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment. Untreated patients contributed natural history data. PARTICIPANTS: Consenting adults (N = 62) with a diagnosis of late-onset Pompe disease who attended a specialist treatment centre in England. This cohort represented 83 % of all patients in the UK with a confirmed diagnosis of this rare condition. At study entry, all but three patients were receiving ERT (range of treatment duration, 0 to 3.1 years). OUTCOME MEASURES: Percent predicted forced vital capacity (%FVC); ventilation dependency; mobility; 6 min walk test (6MWT); muscle strength and body mass index (BMI). RESULTS: An association was found between time on ERT and significant increases in the distance walked in the 6MWT (p < 0.001) and muscle strength scores (p < 0.001). Improvements in both these measures were seen over the first 2 years of treatment with ERT. No statistically significant relationship was found between time on ERT and respiratory function or in BMI. CONCLUSIONS: These data provide some further evidence of the effectiveness of ERT in adults with late-onset Pompe disease. SYNOPSIS: The results of this longitudinal cohort study of 62 adults with late-onset Pompe disease, provide further evidence on the effectiveness of ERT in this rare condition.

Long-term effectiveness of enzyme replacement therapy in Fabry disease: results from the NCS-LSD cohort study.

OBJECTIVES: To determine the effectiveness of enzyme replacement therapy (ERT) for adults and children with Fabry disease. DESIGN: Cohort study including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment and untreated patients contributed natural history data. PARTICIPANTS: Consenting adults (N = 289) and children (N = 22) with a confirmed diagnosis of Fabry disease attending a specialist Lysosomal Storage Disorder treatment centre in England. At recruitment 211 adults and seven children were on ERT (range of treatment duration, 0 to 9.7 and 0 to 4.2 years respectively). OUTCOME MEASURES: Clinical outcomes chosen to reflect disease progression included left ventricular mass index (LVMI); proteinuria; estimated glomerular filtration rate (eGFR); pain; hearing and transient ischaemic attacks (TIA)/stroke. RESULTS: We found evidence of a statistically significant association between time on ERT and a small linear decrease in LVMI (p = 0.01); a reduction in the risk of proteinuria after adjusting for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (p < 0.001) and a small increase in eGFR in men and women without pre-treatment proteinuria (p = 0.01 and p < 0.001 respectively). The same analyses in children provided no statistically significant results. No associations between time on ERT and pain, risk of needing a hearing aid, or risk of stroke or TIAs, were found. CONCLUSIONS: These data provide some further evidence on the long-term effectiveness of ERT in adults with Fabry disease, but evidence of effectiveness could not be demonstrated in children.

Long-term effectiveness of enzyme replacement therapy in children with Gaucher disease: results from the NCS-LSD cohort study.

OBJECTIVES: To determine the effectiveness of enzyme replacement therapies (ERT) for children with Gaucher disease (GD). DESIGN: A longitudinal cohort study including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Children on treatment contributed data before and during treatment. Children not on treatment contributed natural history data. PARTICIPANTS: Consenting children (N = 25, aged 1.1 to 15.6 years) with a diagnosis of GD (14 with GD1 and 11 with GD3) who attended a specialist treatment centre in England. At recruitment, 24 patients were receiving ERT (mean treatment duration, 5.57 years; range 0-13.7 years). OUTCOME MEASURES: Clinical outcomes chosen to reflect disease progression, included platelet count; haemoglobin and absence/presence of bone pain. RESULTS: Duration of ERT was associated with statistically significant improvements in platelet count (p < 0.001), haemoglobin (p < 0.001), and reported bone pain (p = 0.02). The magnitude of effect on haematological parameters was greater in children with GD3 than in those with GD1. CONCLUSIONS: These data provide further evidence of the long-term effectiveness of ERT in children with GD.

The NCS-LSD cohort study: a description of the methods and analyses used to assess the long-term effectiveness of enzyme replacement therapy and substrate reduction therapy in patients with lysosomal storage disorders.

Lysosomal storage disorders (LSDs) comprise more than 50 extremely rare, inherited metabolic diseases resulting from a deficiency of specific lysosomal enzymes required for normal macromolecular metabolism. The National Collaborative Study for Lysosomal Storage Disorders (NCS-LSD), was a longitudinal cohort study which collected prospective and retrospective clinical data, and patient-reported data from adults and children with a confirmed diagnosis of Gaucher disease, Fabry disease, mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II (MPS II), Pompe disease and Niemann Pick disease type C (NPC) in the UK. The study aimed to determine the natural history of these conditions and estimate the effectiveness and cost of therapies. Clinical outcomes were chosen to reflect disease progression. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment while untreated patients contributed natural history data. A total of 711 adults and children were recruited to this study from the seven LSD treatment centres in England. Data was collected from 2008 to 2011. This paper describes the methods used to collect and analyse clinical data for this study. The clinical findings are reported separately in a series of condition-specific articles in this issue.

Long-term effectiveness of enzyme replacement therapy in adults with Gaucher disease: results from the NCS-LSD cohort study.

OBJECTIVES: To determine the effectiveness of enzyme replacement therapies (ERT) for adults with Gaucher disease (GD). DESIGN: A longitudinal, multi-centre cohort study, including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment. Untreated patients contributed natural history data. PARTICIPANTS: Consenting adults (N = 150, aged 16 to 83 years) with a diagnosis of GD who attended a specialist treatment centre in England. At recruitment, 131 patients were receiving ERT (mean treatment duration, 10.8 years; range 0-18 years). OUTCOME MEASURES: Clinical outcomes chosen to reflect disease progression, included platelet count; haemoglobin; absence/presence of bone pain; spleen and liver volumes and AST levels. RESULTS: One hundred and fifty adults were recruited. Duration of ERT was associated with statistically significant improvements in platelet count (p < 0.001), haemoglobin (p < 0.001), liver and spleen volumes (p < 0.001) and AST levels (p = 0.02). CONCLUSIONS: These data provide further evidence of the long-term effectiveness of ERT in adults with GD.

Strategic priorities for respiratory syncytial virus (RSV) vaccine development.

Although RSV has been a high priority for vaccine development, efforts to develop a safe and effective vaccine have yet to lead to a licensed product. Clinical and epidemiologic features of RSV disease suggest there are at least 4 distinct target populations for vaccines, the RSV naïve young infant, the RSV naïve child ≥ 6 months of age, pregnant women (to provide passive protection to newborns), and the elderly. These target populations raise different safety and efficacy concerns and may require different vaccination strategies. The highest priority target population is the RSV naïve child. The occurrence of serious adverse events associated with the first vaccine candidate for young children, formalin inactivated RSV (FI-RSV), has focused vaccine development for the young RSV naïve child on live virus vaccines. Enhanced disease is not a concern for persons previously primed by a live virus infection. A variety of live-attenuated viruses have been developed with none yet achieving licensure. New live-attenuated RSV vaccines are being developed and evaluated that maybe sufficiently safe and efficacious to move to licensure. A variety of subunit vaccines are being developed and evaluated primarily for adults in whom enhanced disease is not a concern. An attenuated parainfluenza virus 3 vector expressing the RSV F protein was evaluated in RSV naïve children. Most of these candidate vaccines have used the RSV F protein in various vaccine platforms including virus-like particles, nanoparticles, formulated with adjuvants, and expressed by DNA or virus vectors. The other surface glycoprotein, the G protein, has also been used in candidate vaccines. We now have tools to make and evaluate a wide range of promising vaccines. Costly clinical trials in the target population are needed to evaluate and select candidate vaccines for advancement to efficacy trials. Better data on RSV-associated mortality in developing countries, better estimates of the risk of long term sequelae such as wheezing after infection, better measures of protection in target populations, and data on the costs and benefits of vaccines for target populations are needed to support and justify funding this process. Addressing these challenges and needs should improve the efficiency and speed of achieving a safe and effective, licensed RSV vaccine.

The use of DNA markers to map anthelmintic resistance loci in an intraspecific cross of Haemonchus contortus.

The use of DNA markers to track the development of anthelmintic resistance in parasites of livestock would allow informed choices for the management of this important problem. We describe a genetic mapping approach for the discovery of DNA markers for anthelmintic resistance in Haemonchus contortus. We crossed a multi-drug resistant field isolate of H. contortus with a well-characterized laboratory strain susceptible to 4 drug classes. The F2 were separately selected with 5 anthelmintics from 4 drug classes, producing drug-resistant populations carrying gene variants derived from both the field isolate and the laboratory strain. Individual F2 worms were analysed using amplicon length polymorphisms (ALPs). We looked for field isolate alleles over- or under-represented in F2 populations compared to the unselected F2 and/or the laboratory strain. The data we obtained suggest that marker association can be used to link neutral markers with resistance, but also that more markers and perhaps more inbred laboratory strains would make the procedure more likely to succeed.

Cardiac T2* magnetic resonance for prediction of cardiac complications in thalassemia major.

BACKGROUND: The goal of this study was to determine the predictive value of cardiac T2* magnetic resonance for heart failure and arrhythmia in thalassemia major. METHODS AND RESULTS: We analyzed cardiac and liver T2* magnetic resonance and serum ferritin in 652 thalassemia major patients from 21 UK centers with 1442 magnetic resonance scans. The relative risk for heart failure with cardiac T2* values <10 ms (compared with >10 ms) was 160 (95% confidence interval, 39 to 653). Heart failure occurred in 47% of patients within 1 year of a cardiac T2* <6 ms with a relative risk of 270 (95% confidence interval, 64 to 1129). The area under the receiver-operating characteristic curve for predicting heart failure was significantly greater for cardiac T2* (0.948) than for liver T2* (0.589; P<0.001) or serum ferritin (0.629; P<0.001). Cardiac T2* was <10 ms in 98% of scans in patients who developed heart failure. The relative risk for arrhythmia with cardiac T2* values <20 ms (compared with >20 ms) was 4.6 (95% confidence interval, 2.66 to 7.95). Arrhythmia occurred in 14% of patients within 1 year of a cardiac T2* of <6 ms. The area under the receiver-operating characteristic curve for predicting arrhythmia was significantly greater for cardiac T2* (0.747) than for liver T2* (0.514; P<0.001) or serum ferritin (0.518; P<0.001). The cardiac T2* was <20 ms in 83% of scans in patients who developed arrhythmia. CONCLUSIONS: Cardiac T2* magnetic resonance identifies patients at high risk of heart failure and arrhythmia from myocardial siderosis in thalassemia major and is superior to serum ferritin and liver iron. Using cardiac T2* for the early identification and treatment of patients at risk is a logical means of reducing the high burden of cardiac mortality in myocardial siderosis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00520559.

Genetic and phenotypic differences between isolates of Haemonchus contortus in Australia.

We believe this study is the first to consider the genetic and phenotypic divergence between isolates of Haemonchus contortus in Australia. Microsatellite markers have been used to investigate genetic divergence, whilst phenotypic divergence has been considered through individual worm morphology, isolate life history traits and the effect of isolates upon the host. The results are discussed in the context of the likely introduction of H. contortus to Australia, its recent isolation, and the characteristics of sheep and goat farming which might act to either isolate or distribute parasites. We conclude that there is significant observable genetic divergence between isolates of H. contortus in Australia. The divergence may have been under-estimated in this study due to a variety of factors. Phenotypic divergence is also observed, and potentially has significant implications for both economic losses due to haemonchosis on individual properties and for decisions regarding the regulation of stock movements in Australia.

Genetic variability of group A and B human respiratory syncytial viruses isolated from 3 provinces in China.

The genetic variability of HRSV in China was studied using nucleotide sequencing of the hypervariable C-terminal region of the G protein gene and phylogenetic analysis on 80 isolates obtained from three children's hospitals over a period of three epidemic seasons, 1990/1991, 2000/2001, and 2003/2004. The results showed that 76/80 of these isolates belonged to group A and 4/80 belonged to group B. Phylogenetic analysis revealed that most of the group A isolates were genotype GA2 (74/76 isolates), and the other two isolates were GA3 and GA5. All group B isolates clustered into genotype GB3. There was substantial variation among the GA2 isolates, with nucleotide sequence and amino acid homologies ranging from 88.1-100% and 78.4-100%, respectively, in the hypervariable C-terminal region of the G protein gene. One group B virus, HRSV/Beijing/B/04/11, contained a 60-nucleotide duplication in the C-terminal region of the G protein, which was similar to what has been reported previously for isolates in several countries. This is the first report on the genetic diversity of human respiratory syncytial virus isolated during epidemic periods from children in China. These data provided a preliminary evaluation of patterns of circulation and the genetic diversity of isolates associated with HRSV epidemics within China.

Trends in encephalitis-associated deaths in the United States.

The United States national mortality statistics and HIV/AIDS surveillance data were analysed to determine trends in encephalitis-associated deaths and to assess the impact of HIV infection on those deaths during 1979-1998, a period when ICD-9 codes were used for coding deaths in the United States. A total of 25125 encephalitis deaths were reported; 4779 of them (19%) had concurrent HIV infection. Overall encephalitis death rates remained stable, but they increased for groups where HIV infection was common and declined or remained unchanged for others. For persons without HIV infection, the rates declined in all demographic groups. Encephalitis deaths in HIV-infected persons followed general trends for HIV deaths in the United States. The rates in the HIV-infected population were several hundred- to thousand-fold higher than in the HIV-uninfected population. HIV infection was largely responsible for the lack of overall decline in the considerable mortality associated with encephalitis in the United States during 1979-1998.

Beyond viruses: clinical profiles and etiologies associated with encephalitis.

BACKGROUND: Encephalitis is a complex syndrome, and its etiology is often not identified. The California Encephalitis Project was initiated in 1998 to identify the causes and further describe the clinical and epidemiologic characteristics of encephalitis. METHODS: A standardized report form was used to collect demographic and clinical data. Serum, cerebrospinal fluid, and respiratory specimens were obtained prospectively and were tested for the presence of herpesviruses, arboviruses, enteroviruses, measles, respiratory viruses, Chlamydia species, and Mycoplasma pneumoniae. The association between an identified infection and encephalitis was defined using predetermined, organism-specific criteria for confirmed, probable, or possible causes. RESULTS: From 1998 through 2005, a total of 1570 patients were enrolled. Given the large number of patients, subgroups of patients with similar clinical characteristics and laboratory findings were identified. Ten clinical profiles were described. A confirmed or probable etiologic agent was identified for 16% of cases of encephalitis: 69% of these agents were viral; 20%, bacterial; 7%, prion; 3%, parasitic; and 1%, fungal. An additional 13% of cases had a possible etiology identified. Many of the agents classified as possible causes are suspected but have not yet been definitively demonstrated to cause encephalitis; these agents include M. pneumoniae (n=96), influenza virus (n=22), adenovirus (n=14), Chlamydia species (n=10), and human metapneumovirus (n=4). A noninfectious etiology was identified for 8% of cases, and no etiology was found for 63% of cases. CONCLUSIONS: Although the etiology of encephalitis remains unknown in most cases, the recognition of discrete clinical profiles among patients with encephalitis should help focus our efforts toward understanding the etiology, pathogenesis, course, and management of this complex syndrome.

Myocardial iron loading in patients with thalassemia major on deferoxamine chelation.

BACKGROUND: Heart failure secondary to myocardial iron loading remains the leading cause of death in thalassemia major (TM). We used cardiovascular magnetic resonance (CMR) to assess the prevalence of myocardial iron overload and ventricular dysfunction in a large cohort of TM patients maintained on conventional chelation treatment with deferoxamine. METHODS: A mobile CMR scanner was transported from London, UK, to Sardinia, Italy where 167 TM patients were assessed for myocardial iron loading, B-natriuretic peptide (BNP), and ferritin. In patients with myocardial iron loading CMR assessments of ventricular function were also made. RESULTS: Myocardial iron loading (T2* < 20 ms) was present in 108 (65%) patients, which was severe (T2* < 8 ms) in 22 (13%). Impaired (< 56%) left ventricular (LV) ejection fraction (EF) was present in 5%, 20% and 62% of patients with mild, moderate or severe iron loading. Increasing myocardial iron was related to impaired LVEF (Rs = 0.57, p < 0.001), weakly related to serum ferritin (Rs = -0.34, p < 0.001), and not related to liver iron (Rs = 0.11, p = 0.26). BNP was weakly related to myocardial iron (Rs = -0.35, p < 0.001) and was abnormal in only 5 patients. CONCLUSIONS: Myocardial siderosis was found in two-thirds of thalassemia major patients on maintenance deferoxamine treatment. This was combined with a high prevalence of impaired LV function, the severity of which tracked the severity of iron deposition. BNP was not useful to assess myocardial siderosis.

Canopy and environmental control of root dynamics in a long-term study of Concord grape.

Below-ground carbon allocation represents a substantial fraction of net photosynthesis in plants, yet timing of below-ground allocation and endogenous and exogenous factors controlling it are poorly understood. Minirhizotron techniques were used to examine root populations of Vitis labruscana Bailey cv. Concord under two levels of dormant-season canopy removal and irrigation. Root production, pigmentation, death and disappearance to a depth of 110 cm were determined over two wet and two dry years (1997-2000). There was continual root production and senescence, with peak root production rates occurring by midseason. Later in the season, when reproductive demands for carbon were highest and physical conditions limiting, few roots were produced, especially in dry years in nonirrigated vines. Root production under minimal canopy pruning was generally greater and occurred several weeks earlier than root production under heavy pruning, corresponding to earlier canopy development. Initial root production occurred in shallow soils, likely due to temperatures at shallow depths being warmer early in the season. Our study showed intricate relationships between internal carbon demands and environmental conditions regulating root allocation.

Active surveillance for respiratory virus infections in adults who have undergone bone marrow and peripheral blood stem cell transplantation.

Community-acquired respiratory virus (RV) infections are an important cause of disease in immunocompromised adults with cancer. To investigate the viral etiology, incidence, clinical presentation, and outcome of RV infections in an outpatient cohort of adult bone marrow or peripheral blood stem cell transplant (SCT) recipients, we monitored 62 outpatient volunteers from January 1 to April 30, 2001. A nasopharyngeal aspirate was collected from subjects when they reported new respiratory symptoms and tested for RV (influenza A, influenza B, human parainfluenza 1-3, adenovirus, and respiratory syncytial virus) by culture and reverse transcription polymerase chain reaction (RT-PCR) assay. Of 62 subjects enrolled, 27% had received allogeneic SCT and 45% were within 1 year of their transplant. In all, 35 participants (56%) reported 37 episodes of respiratory symptoms. Of the 37 specimens tested, five (14%) were positive for RV by culture and 20 (54%) were positive by RT-PCR. Only six patients with RV infections developed lower respiratory tract illnesses; these patients had received either autologous or allogeneic transplants and developed illnesses between 41 and 2666 days post transplant. Although RV infections were common in SCT outpatients during the RV season, most participants had upper respiratory tract infections, which resolved without the need for hospitalization.

Tissue Doppler echocardiography in patients with thalassaemia detects early myocardial dysfunction related to myocardial iron overload.

AIMS: To compare an echocardiographic method for detecting abnormal cardiac function before development of overt cardiomyopathy with a recently validated technique of quantifying myocardial iron load. METHODS AND RESULTS: We examined thalassaemia patients whose myocardial iron load had been evaluated with magnetic resonance imaging (MRI). By tissue Doppler echocardiography, myocardial velocities were sampled continuously from base to apex in the RV and LV free wall, and the septum in 52 patients aged 29.2 (14.2-43.1) years and 52 age-matched controls. Ninety-six percent of patients had normal LV ejection fraction by MRI. Thirty-eight (73%) had abnormal iron loading of the myocardium, and 33 of those had regional wall motion abnormalities detected in the septum (n=29), LV (n=2), RV (n=1), and septum plus LV (n=1). The incidence of wall motion abnormalities was significantly higher (P<0.04) in patients with myocardial iron overload (87%) than in the 14 without (35%). Furthermore, myocardial iron overload was suggested by a low T2(*)(15.1+/-15.8 ms) in patients with wall motion abnormalities vs those with normal wall motion (T2(*): 30+/-19 ms) (P<0.007). CONCLUSIONS: Wall motion abnormalities may represent an early sign of cardiac disease despite preserved global function. The regional abnormalities are related to iron overload and easily detectable with tissue Doppler echocardiography.