Estimating the changing disease burden attributable to smoking in South Africa for 2000, 2006 and 2012.

BACKGROUND: Ongoing quantification of the disease burden attributable to smoking is important to monitor and strengthen tobacco control policies. OBJECTIVES: To estimate the attributable burden due to smoking in South Africa for 2000, 2006 and 2012. METHODS: We estimated attributable burden due to smoking for selected causes of death in South African (SA) adults aged ≥35 years for 2000, 2006 and 2012. We combined smoking prevalence results from 15 national surveys (1998 - 2017) and smoking impact ratios using national mortality rates. Relative risks between smoking and select causes of death were derived from local and international data. RESULTS: Smoking prevalence declined from 25.0% in 1998 (40.5% in males, 10.9% in females) to 19.4% in 2012 (31.9% in males, 7.9% in females), but plateaued after 2010. In 2012 tobacco smoking caused an estimated 31 078 deaths (23 444 in males and 7 634 in females), accounting for 6.9% of total deaths of all ages (17.3% of deaths in adults aged ≥35 years), a 10.5% decline overall since 2000 (7% in males; 18% in females). Age-standardised mortality rates (and disability-adjusted life years (DALYs)) similarly declined in all population groups but remained high in the coloured population. Chronic obstructive pulmonary disease accounted for most tobacco-attributed deaths (6 373), followed by lung cancer (4 923), ischaemic heart disease (4 216), tuberculosis (2 326) and lower respiratory infections (1 950). The distribution of major causes of smoking-attributable deaths shows a middle- to high-income pattern in whites and Asians, and a middle- to low-income pattern in coloureds and black Africans. The role of infectious lung disease (TB and LRIs) has been underappreciated. These diseases comprised 21.0% of deaths among black Africans compared with only 4.3% among whites. It is concerning that smoking rates have plateaued since 2010. CONCLUSION: The gains achieved in reducing smoking prevalence in SA have been eroded since 2010. An increase in excise taxes is the most effective measure for reducing smoking prevalence. The advent of serious respiratory pandemics such as COVID-19 has increased the urgency of considering the role that smoking cessation/abstinence can play in the prevention of, and post-hospital recovery from, any condition.

COVID deaths in South Africa: 99 days since South Africa's first death.

BACKGROUND: Understanding the pattern of deaths from COVID-19 in South Africa (SA) is critical to identifying individuals at high risk of dying from the disease. The Minister of Health set up a daily reporting mechanism to obtain timeous details of COVID-19 deaths from the provinces to track mortality patterns. OBJECTIVES: To provide an epidemiological analysis of the first COVID-19 deaths in SA. METHODS: Provincial deaths data from 28 March to 3 July 2020 were cleaned, information on comorbidities was standardised, and data were aggregated into a single data set. Analysis was performed by age, sex, province, date of death and comorbidities. RESULTS: SA reported 3 088 deaths from COVID-19, i.e. an age-standardised death rate of 64.5 (95% confidence interval (CI) 62.3 - 66.8) deaths per million population. Most deaths occurred in Western Cape (65.5%) followed by Eastern Cape (16.8%) and Gauteng (11.3%). The median age of death was 61 years (interquartile range 52 - 71). Males had a 1.5 times higher death rate compared with females. Individuals with two or more comorbidities accounted for 58.6% (95% CI 56.6 - 60.5) of deaths. Hypertension and diabetes were the most common comorbidities reported, and HIV and tuberculosis were more common in individuals aged <50 years. CONCLUSIONS: Data collection for COVID-19 deaths in provinces must be standardised. Even though the data had limitations, these findings can be used by the SA government to manage the pandemic and identify individuals who are at high risk of dying from COVID-19.

COVID deaths in South Africa: 99 days since South Africa's first death

Background. Understanding the pattern of deaths from COVID-19 in South Africa (SA) is critical to identifying individuals at high risk of dying from the disease. The Minister of Health set up a daily reporting mechanism to obtain timeous details of COVID-19 deaths from the provinces to track mortality patterns.Objectives. To provide an epidemiological analysis of the first COVID-19 deaths in SA.Methods. Provincial deaths data from 28 March to 3 July 2020 were cleaned, information on comorbidities was standardised, and data were aggregated into a single data set. Analysis was performed by age, sex, province, date of death and comorbidities.Results. SA reported 3 088 deaths from COVID-19, i.e. an age-standardised death rate of 64.5 (95% confidence interval (CI) 62.3 - 66.8) deaths per million population. Most deaths occurred in Western Cape (65.5%) followed by Eastern Cape (16.8%) and Gauteng (11.3%). The median age of death was 61 years (interquartile range 52 - 71). Males had a 1.5 times higher death rate compared with females. Individuals with two or more comorbidities accounted for 58.6% (95% CI 56.6 - 60.5) of deaths. Hypertension and diabetes were the most common comorbidities reported, and HIV and tuberculosis were more common in individuals aged <50 years.Conclusions. Data collection for COVID-19 deaths in provinces must be standardised. Even though the data had limitations, these findings can be used by the SA government to manage the pandemic and identify individuals who are at high risk of dying from COVID-19

Data-Driven Discovery of Extravasation Pathway in Circulating Tumor Cells.

Circulating tumor cells (CTCs) play a crucial role in cancer dissemination and provide a promising source of blood-based markers. Understanding the spectrum of transcriptional profiles of CTCs and their corresponding regulatory mechanisms will allow for a more robust analysis of CTC phenotypes. The current challenge in CTC research is the acquisition of useful clinical information from the multitude of high-throughput studies. To gain a deeper understanding of CTC heterogeneity and identify genes, pathways and processes that are consistently affected across tumors, we mined the literature for gene expression profiles in CTCs. Through in silico analysis and the integration of CTC-specific genes, we found highly significant biological mechanisms and regulatory processes acting in CTCs across various cancers, with a particular enrichment of the leukocyte extravasation pathway. This pathway appears to play a pivotal role in the migration of CTCs to distant metastatic sites. We find that CTCs from multiple cancers express both epithelial and mesenchymal markers in varying amounts, which is suggestive of dynamic and hybrid states along the epithelial-mesenchymal transition (EMT) spectrum. Targeting the specific molecular nodes to monitor disease and therapeutic control of CTCs in real time will likely improve the clinical management of cancer progression and metastases.

Region-specific role for Pten in maintenance of epithelial phenotype and integrity.

Previous studies have demonstrated resistance to naphthalene-induced injury in proximal airways of mice with lung epithelial-specific deletion of the tumor-suppressor gene Pten, attributed to increased proliferation of airway progenitors. We tested effects of Pten loss following bleomycin injury, a model typically used to study distal lung epithelial injury, in conditional PtenSFTPC-cre knockout mice. Pten-deficient airway epithelium exhibited marked hyperplasia, particularly in small bronchioles and at bronchoalveolar duct junctions, with reduced E-cadherin and ß-catenin expression between cells toward the luminal aspect of the hyperplastic epithelium. Bronchiolar epithelial and alveolar epithelial type II (AT2) cells in PtenSFTPC-cre mice showed decreased expression of epithelial markers and increased expression of mesenchymal markers, suggesting at least partial epithelial-mesenchymal transition at baseline. Surprisingly, and in contrast to previous studies, mutant mice were exquisitely sensitive to bleomycin, manifesting rapid weight loss, respiratory distress, increased early mortality (by day 5), and reduced dynamic lung compliance. This was accompanied by sloughing of the hyperplastic airway epithelium with occlusion of small bronchioles by cellular debris, without evidence of increased parenchymal lung injury. Increased airway epithelial cell apoptosis due to loss of antioxidant defenses, reflected by decreased expression of superoxide dismutase 3, in combination with deficient intercellular adhesion, likely predisposed to airway sloughing in knockout mice. These findings demonstrate an important role for Pten in maintenance of airway epithelial phenotype integrity and indicate that responses to Pten deletion in respiratory epithelium following acute lung injury are highly context-dependent and region-specific.

Antitumour potential of BPT: a dual inhibitor of cdk4 and tubulin polymerization.

The marine natural product fascaplysin (1) is a potent Cdk4 (cyclin-dependent kinase 4)-specific inhibitor, but is toxic to all cell types possibly because of its DNA-intercalating properties. Through the design and synthesis of numerous fascaplysin analogues, we intended to identify inhibitors of cancer cell growth with good therapeutic window with respect to normal cells. Among various non-planar tryptoline analogues prepared, N-(biphenyl-2-yl) tryptoline (BPT, 6) was identified as a potent inhibitor of cancer cell growth and free from DNA-binding properties owing to its non-planar structure. This compound was tested in over 60 protein kinase assays. It displayed inhibition of Cdk4-cyclin D1 enzyme in vitro far more potently than many other kinases including Cdk family members. Although it blocks growth of cancer cells deficient in the mitotic-spindle checkpoint at the G0/G1 phase of the cell cycle, the block occurs primarily at the G2/M phase. BPT inhibits tubulin polymerization in vitro and acts as an enhancer of tubulin depolymerization of paclitaxel-stabilized tubulin in live cells. Western blot analyses indicated that, in p53-positive cells, BPT upregulates the expression of p53, p21 and p27 proteins, whereas it downregulates the expression of cyclin B1 and Cdk1. BPT selectively kills SV40-transformed mouse embryonic hepatic cells and human fibroblasts rather than untransformed cells. BPT inhibited the growth of several human cancer cells with an IC50<1 µM. The pharmacokinetic study in BALB/c mice indicated good plasma exposure after intravenous administration. It was found to be efficacious at 1/10th the maximum-tolerated dose (1000 mg/kg) against human tumours derived from HCT-116 (colon) and NCI-H460 (lung) cells in SCID (severe-combined immunodeficient) mice models. BPT is a relatively better anticancer agent than fascaplysin with an unusual ability to block two overlapping yet crucial phases of the cell cycle, mitosis and G0/G1. Its ability to effectively halt tumour growth in human tumour-bearing mice would suggest that BPT has the potential to be a candidate for further clinical development.

Statistical profiling of hospital performance using acute coronary syndrome mortality.

BACKGROUND: In order to improve the quality of care delivered to patients and to enable patient choice, public reports comparing hospital performances are routinely published. Robust systems of hospital 'report cards' on performance monitoring and evaluation are therefore crucial in medical decision-making processes. In particular, such systems should effectively account for and minimise systematic differences with regard to definitions and data quality, care and treatment quality, and 'case mix'. METHODS: Four methods for assessing hospital performance on mortality outcome measures were considered. The methods included combinations of Bayesian fixed- and random-effects models, and risk-adjusted mortality rate, and rank-based profiling techniques. The methods were empirically compared using 30-day mortality in patients admitted with acute coronary syndrome. Agreement was firstly assessed using median estimates between risk-adjusted mortality rates for a hospital and between ranks associated with a hospital's risk-adjusted mortality rates. Secondly, assessment of agreement was based on a classification of hospitals into low, normal or high performing using risk-adjusted mortality rates and ranks. RESULTS: There was poor agreement between the point estimates of risk-adjusted mortality rates, but better agreement between ranks. However, for categorised performance, the observed agreement between the methods' classification of the hospital performance ranged from 90 to 98%. In only two of the six possible pair-wise comparisons was agreement reasonable, as reflected by a Kappa statistic; it was 0.71 between the methods of identifying outliers with the fixed-effect model and 0.77 with the hierarchical model. In the remaining four pair-wise comparisons, the agreement was, at best, moderate. CONCLUSIONS: Even though the inconsistencies among the studied methods raise questions about which hospitals performed better or worse than others, it seems that the choice of the definition of outlying performance is less critical than that of the statistical approach. Therefore there is a need to find robust systems of 'regulation' or 'performance monitoring' that are meaningful to health service practitioners and providers.

Chemistry and biology of fascaplysin, a potent marine-derived CDK-4 inhibitor.

Marine natural products offer an abundant source of pharmacologically active agents with great diversity and complexity, and the potential to produce valuable therapeutic entities. Indole alkaloids is one of the important class of marine-derived secondary metabolites, with wide occurrence amongst variety of marine sources such as sponges, tunicates, algae, worms and microorganisms and have been extensively studied for their biological activities. Among this chemical family, a sponge-derived bis-indole alkaloid fascaplysin (1) exhibited broad range of bioactivities including antibacterial, antifungal, antiviral, anti-HIV-1-RTase, p56 tyrosine kinase inhibition, antimalarial, anti-angiogenic, antiproliferative activity against numerous cancer cell lines, specific inhibition of cyclin-dependent kinase-4 (IC(50) 350 nM) and action as a DNA intercalator. In the present review, the chemical diversity of natural as well as synthetic analogues of fascaplysin has been reviewed with a detailed account on synthetic reports and pharmacological studies. Our analysis of the structure-activity relationships of this family of compounds highlights the existence of various potential leads for the development of novel anticancer agents.

Interactions between ß-catenin and transforming growth factor-ß signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP).

Interactions between transforming growth factor-ß (TGF-ß) and Wnt are crucial to many biological processes, although specific targets, rationale for divergent outcomes (differentiation versus block of epithelial proliferation versus epithelial-mesenchymal transition (EMT)) and precise mechanisms in many cases remain unknown. We investigated ß-catenin-dependent and transforming growth factor-ß1 (TGF-ß1) interactions in pulmonary alveolar epithelial cells (AEC) in the context of EMT and pulmonary fibrosis. We previously demonstrated that ICG-001, a small molecule specific inhibitor of the ß-catenin/CBP (but not ß-catenin/p300) interaction, ameliorates and reverses pulmonary fibrosis and inhibits TGF-ß1-mediated α-smooth muscle actin (α-SMA) and collagen induction in AEC. We now demonstrate that TGF-ß1 induces LEF/TCF TOPFLASH reporter activation and nuclear ß-catenin accumulation, while LiCl augments TGF-ß-induced α-SMA expression, further confirming co-operation between ß-catenin- and TGF-ß-dependent signaling pathways. Inhibition and knockdown of Smad3, knockdown of ß-catenin and overexpression of ICAT abrogated effects of TGF-ß1 on α-SMA transcription/expression, indicating a requirement for ß-catenin in these Smad3-dependent effects. Following TGF-ß treatment, co-immunoprecipitation demonstrated direct interaction between endogenous Smad3 and ß-catenin, while chromatin immunoprecipitation (ChIP)-re-ChIP identified spatial and temporal regulation of α-SMA via complex formation among Smad3, ß-catenin, and CBP. ICG-001 inhibited α-SMA expression/transcription in response to TGF-ß as well as α-SMA promoter occupancy by ß-catenin and CBP, demonstrating a previously unknown requisite TGF-ß1/ß-catenin/CBP-mediated pro-EMT signaling pathway. Clinical relevance was shown by ß-catenin/Smad3 co-localization and CBP expression in AEC of IPF patients. These findings suggest a new therapeutic approach to pulmonary fibrosis by specifically uncoupling CBP/catenin-dependent signaling downstream of TGF-ß.

Ligand-independent transforming growth factor-ß type I receptor signalling mediates type I collagen-induced epithelial-mesenchymal transition.

Evidence suggests epithelial-mesenchymal transition (EMT) as one potential source of fibroblasts in idiopathic pulmonary fibrosis. To assess the contribution of alveolar epithelial cell (AEC) EMT to fibroblast accumulation in vivo following lung injury and the influence of extracellular matrix on AEC phenotype in vitro, Nkx2.1-Cre;mT/mG mice were generated in which AECs permanently express green fluorescent protein (GFP). On days 17-21 following intratracheal bleomycin administration, ~4% of GFP-positive epithelial-derived cells expressed vimentin or α-smooth muscle actin (α-SMA). Primary AECs from Nkx2.1-Cre;mT/mG mice cultured on laminin-5 or fibronectin maintained an epithelial phenotype. In contrast, on type I collagen, cells of epithelial origin displayed nuclear localization of Smad3, acquired spindle-shaped morphology, expressed α-SMA and phospho-Smad3, consistent with activation of the transforming growth factor-ß (TGFß) signalling pathway and EMT. α-SMA induction and Smad3 nuclear localization were blocked by the TGFß type I receptor (TßRI, otherwise known as Alk5) inhibitor SB431542, while AEC derived from Nkx2.1-Cre;Alk5(flox/KO) mice did not undergo EMT on collagen, consistent with a requirement for signalling via Alk5 in collagen-induced EMT. Inability of a pan-specific TGFß neutralizing antibody to inhibit effects of collagen together with absence of active TGFß in culture supernatants is consistent with TGFß ligand-independent activation of Smad signalling. These results support the notion that AECs can acquire a mesenchymal phenotype following injury in vivo and implicate type I collagen as a key regulator of EMT in AECs through signalling via Alk5, likely in a TGFß ligand-independent manner.

Role of endoplasmic reticulum stress in epithelial-mesenchymal transition of alveolar epithelial cells: effects of misfolded surfactant protein.

Endoplasmic reticulum (ER) stress has been implicated in alveolar epithelial type II (AT2) cell apoptosis in idiopathic pulmonary fibrosis. We hypothesized that ER stress (either chemically induced or due to accumulation of misfolded proteins) is also associated with epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AECs). ER stress inducers, thapsigargin (TG) or tunicamycin (TN), increased expression of ER chaperone, Grp78, and spliced X-box binding protein 1, decreased epithelial markers, E-cadherin and zonula occludens-1 (ZO-1), increased the myofibroblast marker, α-smooth muscle actin (α-SMA), and induced fibroblast-like morphology in both primary AECs and the AT2 cell line, RLE-6TN, consistent with EMT. Overexpression of the surfactant protein (SP)-C BRICHOS mutant SP-C(ΔExon4) in A549 cells increased Grp78 and α-SMA and disrupted ZO-1 distribution, and, in primary AECs, SP-C(ΔExon4) induced fibroblastic-like morphology, decreased ZO-1 and E-cadherin and increased α-SMA, mechanistically linking ER stress associated with mutant SP to fibrosis through EMT. Whereas EMT was evident at lower concentrations of TG or TN, higher concentrations caused apoptosis. The Src inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4]pyramidine) (PP2), abrogated EMT associated with TN or TG in primary AECs, whereas overexpression of SP-C(ΔExon4) increased Src phosphorylation, suggesting a common mechanism. Furthermore, increased Grp78 immunoreactivity was observed in AT2 cells of mice after bleomycin injury, supporting a role for ER stress in epithelial abnormalities in fibrosis in vivo. These results demonstrate that ER stress induces EMT in AECs, at least in part through Src-dependent pathways, suggesting a novel role for ER stress in fibroblast accumulation in pulmonary fibrosis.

Evaluation of risk scores for risk stratification of acute coronary syndromes in the Myocardial Infarction National Audit Project (MINAP) database.

OBJECTIVE: To compare the discriminative performance of the PURSUIT, GUSTO-1, GRACE, SRI and EMMACE risk models, assess their performance among risk supergroups and evaluate the EMMACE risk model over the wider spectrum of acute coronary syndrome (ACS). DESIGN: Observational study of a national registry. SETTING: All acute hospitals in England and Wales. PATIENTS: 100 686 cases of ACS between 2003 and 2005. MAIN OUTCOME MEASURES: Model performance (C-index) in predicting the likelihood of death over the time period for which they were designed. The C-index, or area under the receiver-operating curve, range 0-1, is a measure of the discriminative performance of a model. RESULTS: The C-indexes were: PURSUIT C-index 0.79 (95% confidence interval 0.78 to 0.80); GUSTO-1 0.80 (0.79 to 0.81); GRACE in-hospital 0.80 (0.80 to 0.81); GRACE 6-month 0.80 (0.79 to 0.80); SRI 0.79 (0.78 to 0.80); and EMMACE 0.78 (0.77 to 0.78). EMMACE maintained its ability to discriminate 30-day mortality throughout different ACS diagnoses. Recalibration of the model offered no notable improvement in performance over the original risk equation. For all models the discriminative performance was reduced in patients with diabetes, chronic renal failure or angina. CONCLUSION: The five ACS risk models maintained their discriminative performance in a large unselected English and Welsh ACS population, but performed less well in higher-risk supergroups. Simpler risk models had comparable performance to more complex risk models. The EMMACE risk score performed well across the wider spectrum of ACS diagnoses.

Spatial variation in prostate cancer survival in the Northern and Yorkshire region of England using Bayesian relative survival smoothing.

Primary Care Trust (PCT) estimates of survival lack robustness as there are small numbers of deaths per year in each area, even when incidence is high. We assess PCT-level spatial variation in prostate cancer survival using Bayesian spatial models of excess mortality. We extracted data on men diagnosed with prostate cancer between 1990 and 1999 from the Northern and Yorkshire Cancer Registry and Information Service database. Models were adjusted for age at diagnosis, period of diagnosis and deprivation. All covariates had a significant association with excess mortality; men from more deprived areas, older age at diagnosis and diagnosed in 1990-1994 had higher excess mortality. The unadjusted relative excess risks (RER) of death by PCT ranged from 0.75 to 1.66. After adjustment, areas of high and low excess mortality were smoothed towards the mean, and the RERs ranged from 0.74 to 1.49. Using Bayesian smoothing techniques to model cancer survival by geographic area offers many advantages over traditional methods; estimates in areas with small populations or low incidence rates are stabilised and shrunk towards local and global risk estimates improving reliability and precision, complex models are easily handled and adjustment for covariates can be made.

A practical guide to the staggered herringbone mixer.

An analytical model of mixing in the staggered herringbone mixer (SHM) was derived to estimate mixing parameters and provide practical expressions to guide mixer design and operation for a wide range of possible solutes and flow conditions. Mixing in microfluidic systems has historically been characterized by the mixing of a specific solute system or by the redistribution of flow streams; this approach does not give any insight into the ideal operational parameters of the mixer with an arbitrary real system. For Stokes-flow mixers, mixing can be computed from a relationship between solute diffusivity, flow rate, and mixer length. Confocal microscopy and computational fluid dynamics (CFD) modeling were used to directly determine the extent of mixing for several solutes in the staggered herringbone mixer over a range of Reynolds numbers (Re) and Péclet numbers (Pe); the results were used to develop and evaluate an analytical model of its behavior. Mixing was found to be a function of only Pe and downstream position in the mixer. Required mixer length was proportional to log(Pe); this analytical model matched well with the confocal data and CFD model for Pe<5 x 10(4), at which point the experiments reached the limit of resolution. For particular solutes, required length and mixing time depend upon Re and diffusivity. This analytical model is applicable to other solute systems, and possibly to other embodiments of the mixer, to enable optimal design, operation, and estimation of performance.

Predictors of in-hospital mortality for patients admitted with ST-elevation myocardial infarction: a real-world study using the Myocardial Infarction National Audit Project (MINAP) database.

OBJECTIVE: Although early thrombolysis reduces the risk of death in STEMI patients, mortality remains high. We evaluated factors predicting inpatient mortality for patients with STEMI in a "real-world" population. DESIGN: Analysis of the Myocardial Infarction National Audit Project (MINAP) database using multivariate logistic regression and area under the receiver operating curve analysis. SETTING: All acute hospitals in England and Wales. PATIENTS: 34 722 patients with STEMI from 1 January 2003 to 31 March 2005. RESULTS: Inpatient mortality was 10.6%. The highest odds ratios for inpatient survival were aspirin therapy given acutely and out-of-hospital thrombolysis, independently associated with a mortality risk reduction of over half. A 10-year increase in age doubled inpatient mortality risk, whereas cerebrovascular disease increased it by 1.7. The risk model comprised 14 predictors of mortality, C index = 0.82 (95% CI 0.82 to 0.83, p<0.001). A simple model comprising age, systolic blood pressure (SBP) and heart rate (HR) offered a C index of 0.80 (0.79 to 0.80, p<0.001). CONCLUSION: The strongest predictors of in-hospital survival for STEMI were aspirin therapy given acutely and out-of-hospital thrombolysis, Previous STEMI models have focused on age, SBP and HR We have confirmed the importance of these predictors in the discrimination of death after STEMI, but also demonstrated that other potentially modifiable variables impact upon the prediction of short-term mortality.

Constitutive homo- and hetero-oligomerization of TbetaRII-B, an alternatively spliced variant of the mouse TGF-beta type II receptor.

Transforming growth factor (TGF)-beta ligands signal through transmembrane type I and type II serine/threonine kinase receptors, which form heteromeric signalling complexes upon ligand binding. Type II TGF-beta receptors (TbetaRII) are reported to exist as homodimers at the cell surface, but the oligomerization pattern and dynamics of TbetaRII splice variants in live cells has not been demonstrated thus far. Using co-immunoprecipitation and bioluminescence resonance energy transfer (BRET), we demonstrate that the mouse TbetaRII receptor splice variant TbetaRII-B is capable of forming ligand-independent homodimers and heterodimers with TbetaRII. The homomeric interaction of mouse (m)TbetaRII-B isoforms, however, is less robust than the heteromeric interactions of mTbetaRII-B with wild-type TbetaRII, which indicates that these receptors may be more likely to heterodimerize when both receptors are expressed. Moreover, we demonstrate that mTbetaRII-B is a signalling receptor with ubiquitous tissue expression. Our study thus demonstrates previously unappreciated complex formation of TGF-beta type II receptors, and suggests that mTbetaRII-B can direct TGF-beta-induced signalling in vitro and in vivo.

Corrected TIMI frame counts correlate with stenosis severity and infarct zone wall motion after thrombolytic therapy.

BACKGROUND: The majority of patients with patent infarct-related arteries after thrombolytic therapy have slower than normal flow, which relates to myocardial perfusion. METHODS: To evaluate the relationships between blood levels of creatine kinase (CK) and the corrected Thrombolysis in Myocardial Infarction (TIMI) frame count (CTFC), infarct artery stenosis, and left ventricular function, we studied 397 patients with a first myocardial infarction who underwent angiography at 3 weeks. TIMI flow grades, the CTFC, infarct artery stenosis, and infarct zone wall motion (by contrast ventriculography using the centerline method) were assessed, and CK levels (in units per liter) were measured hourly for the first 4 hours after streptokinase (1.5 x 10(6) U over 30-60 minutes) and then every 4 hours over the next 20 hours, all blinded to treatment and outcome. RESULTS: Infarct artery stenosis and the CTFC, assessed as continuous variables, correlated in patients with patent infarct arteries (r = 0.33, P <.001). Also, there was a significant correlation between the CTFC and the sum of hypokinetic chords in the infarct zone (r = 0.15, P =.01). Patients with total occlusion or markedly slowed infarct artery flow (CTFC >100) had a higher fraction of chords with wall motion >2 SDs below normal (0.65 [0.41, 0.80] vs 0.37 [0.0, 0.67]) compared with patients with normal flow (CTFC < or =27) (P <.001). The rates of increase of median CK levels with respect to TIMI flow grades were 342 U/L/h for TIMI 3 versus 212 U/L/h for TIMI 2 versus 140 U/L/h for TIMI 0-1 (P <.0001). CONCLUSIONS: Prolonged corrected TIMI frame counts correlate with stenosis severity in the infarct artery after infarction, infarct zone regional wall motion, and CK levels.

Relationship between corrected TIMI frame counts at three weeks and late survival after myocardial infarction.

OBJECTIVES: To evaluate the corrected Thrombolysis in Myocardial Infarction (TIMI) frame count (CTFC) as a predictor of late survival after myocardial infarction. BACKGROUND: Thrombolysis in Myocardial Infarction flow grades predict late survival after myocardial infarction. The CTFC provides a more reproducible measurement of infarct-related artery blood flow than the TIMI flow grade, and has been linked to 30-day outcomes, but it has not yet been established how the CTFC correlates with late survival. METHODS: Of 1,001 patients with acute myocardial infarction presenting within 4 h of symptom onset, 882 underwent angiography at approximately three weeks. Infarct artery flow was assessed, blinded to clinical outcomes, according to the CTFC and TIMI flow grade. Late cardiac mortality and survival were determined in 97.5% of patients. RESULTS: The mean CTFC was 40 +/- 29 in 644 patent infarct arteries (median, 34 [interquartile range, 24 to 47]). The CTFC, assessed as a continuous univariate variable, was found to be a predictor of five-year survival, as was the TIMI flow grade (both p < 0.001). On multivariate analysis, factors associated with five-year survival included the ejection fraction or end-systolic volume index (both p < 0.001); exercise duration (p = 0.005), age (p = 0.008), diabetes (p = 0.02) and CTFC (p = 0.02) or TIMI flow (p = 0.02). The same factors, except for the CTFC and TIMI flow grade, were predictors of 10-year survival. CONCLUSIONS: The CTFC three weeks after myocardial infarction was an independent predictor of five-year survival, but not 10-year survival. Although the CTFC provided additional prognostic information within TIMI flow grades, its superiority was not demonstrated.

New Q waves on the presenting electrocardiogram independently predict increased cardiac mortality following a first ST-elevation myocardial infarction.

AIMS: The prognostic significance of pathological Q waves appearing in the acute phase of myocardial infarction has not been determined. We investigated whether new Q waves on the presenting electrocardiogram of patients with acute ST-segment elevation were independently associated with a worse outcome after a first myocardial infarction. METHODS AND RESULTS: The presence or absence of new Q waves on the presenting electrocardiogram was assessed in 481 patients who presented within 4 h of symptom onset and were randomized to receive either captopril or placebo within 2 h of streptokinase therapy for myocardial infarction. Ventriculography was performed at 22+/-6 days and mortality status was obtained at a median follow-up of 5.6 years. New Q waves were associated with a lower ejection fraction (51+/-13% vs 61+/-12%, P<0.0001), a larger end-systolic volume index (37 ml vs 28 ml, P<0.001), and increased cardiac mortality at 30 days (7% vs 2%, P=0.01) and at follow-up (17% vs 7%, P=0.002). On multivariate analysis, age (P<0.01), new Q waves at presentation (P<0.01) and a history of angina (P=0.046) were independent predictors of cardiac mortality, whereas randomization to captopril and the time from symptom onset to streptokinase administration were not. CONCLUSION: New Q waves at presentation are independently associated with a worse outcome after a first myocardial infarction. The presence of new Q waves on the presenting electrocardiogram allows very early identification of patients at risk of increased cardiac mortality.