Adenosine versus regadenoson comparative evaluation in myocardial perfusion imaging: results of the ADVANCE phase 3 multicenter international trial.

BACKGROUND: Earlier phase 1 and 2 studies have shown that regadenoson has desirable features as a stress agent for myocardial perfusion imaging. METHODS AND RESULTS: This multicenter, double-blinded phase 3 trial involved 784 patients at 54 sites. Each patient underwent 2 sets of gated single photon emission computed tomography myocardial perfusion imaging studies: an initial qualifying study with adenosine and a subsequent randomized study with either regadenoson (2/3 of patients) or adenosine. Regadenoson was administered as a rapid bolus (<10 seconds) of 400 mug. The primary endpoint was to demonstrate noninferiority by showing that the difference in the strength of agreement in detecting reversible defects, based on blinded reading, between sequential adenosine-regadenoson images and adenosine-adenosine images, lay above a prespecified noninferiority margin. Other prospectively defined safety and tolerability comparisons and supporting analyses were also performed. The average agreement rate based on the median of 3 independent blinded readers was 0.63 +/- 0.03 for regadenoson-adenosine and 0.64 +/- 0.04 for adenosine-adenosine-a 1% absolute difference with the lower limit of the 95% confidence interval lying above the prespecified noninferiority margin. Side-by-side interpretation of regadenoson and adenosine images provided comparable results for detecting reversible defects. The peak increase in heart rate was greater with regadenoson than adenosine, but the blood pressure nadir was similar. A summed symptom score of flushing, chest pain, and dyspnea was less with regadenoson than adenosine (P = .013). CONCLUSIONS: This phase 3 trial shows that regadenoson provides diagnostic information comparable to a standard adenosine infusion. There were no serious drug-related side effects, and regadenoson was better tolerated than adenosine.     

Hamstrings Stiffness and Landing Biomechanics Linked to Anterior Cruciate Ligament Loading

Context:

Greater hamstrings stiffness is associated with less anterior tibial translation during controlled perturbations. However, it is unclear how hamstrings stiffness influences anterior cruciate ligament (ACL) loading mechanisms during dynamic tasks.

Objective:

To evaluate the influence of hamstrings stiffness on landing biomechanics related to ACL injury.

Design:

Cross-sectional study.

Setting:

Research laboratory.

Patients or Other Participants:

A total of 36 healthy, physically active volunteers (18 men, 18 women; age = 23 ± 3 years, height = 1.8 ± 0.1 m, mass = 73.1 ± 16.6 kg).

Intervention(s):

Hamstrings stiffness was quantified via the damped oscillatory technique. Three-dimensional lower extremity kinematics and kinetics were captured during a double-legged jump-landing task via a 3-dimensional motion-capture system interfaced with a force plate. Landing biomechanics were compared between groups displaying high and low hamstrings stiffness via independent-samples t tests.

Main Outcome Measure(s):

Hamstrings stiffness was normalized to body mass (N/m·kg⁻¹). Peak knee-flexion and -valgus angles, vertical and posterior ground reaction forces, anterior tibial shear force, internal knee-extension and -varus moments, and knee-flexion angles at the instants of each peak kinetic variable were identified during the landing task. Forces were normalized to body weight, whereas moments were normalized to the product of weight and height.

Results:

Internal knee-varus moment was 3.6 times smaller in the high-stiffness group (t₂₂ = 2.221, P = .02). A trend in the data also indicated that peak anterior tibial shear force was 1.1 times smaller in the high-stiffness group (t₂₂ = 1.537, P = .07). The high-stiffness group also demonstrated greater knee flexion at the instants of peak anterior tibial shear force and internal knee-extension and -varus moments (t₂₂ range = 1.729–2.224, P < .05).

Conclusions:

Greater hamstrings stiffness was associated with landing biomechanics consistent with less ACL loading and injury risk. Musculotendinous stiffness is a modifiable characteristic; thus exercises that enhance hamstrings stiffness may be important additions to ACL injury-prevention programs.Key Words: viscoelastic, musculotendinous, valgus, anterior tibial shear force

Key Points

• Individuals with greater hamstrings stiffness displayed more favorable landing biomechanics for anterior cruciate ligament (ACL) loading and injury risk than individuals with less hamstrings stiffness as evidenced by smaller frontal-plane knee moments and a more-flexed knee at the instants of critical biomechanical knee events.
• Greater hamstrings stiffness was associated with smaller anterior tibial shear forces.
• A high level of hamstrings stiffness may limit ACL injury risk by limiting frontal- and sagittal-plane ACL-loading mechanisms.

Anterior cruciate ligament (ACL) injury commonly occurs during landing,¹ and researchers have suggested that a landing biomechanics profile consisting of large ground reaction forces, anterior tibial shear force, knee-valgus angle, and external knee-flexion and -valgus moments increases ACL loading.^2–4 A more-extended knee during landing exacerbates this profile, whereas a more-flexed knee decreases these variables,^4–6 likely limiting ACL loading and injury risk. For example, Blackburn and Padua⁵ demonstrated that increasing knee-flexion angle during landing reduced ground reaction forces. Similarly, Pollard et al⁶ categorized participants into high- and low-flexion groups based on performance of a landing task and reported smaller knee-valgus angles and moments in the high-flexion group.Stiffness quantifies the resistance of the musculotendinous unit to lengthening, and hamstrings stiffness may have important implications for ACL loading and injury risk. Greater hamstrings stiffness is associated with greater function in ACL-deficient individuals.⁷ During controlled perturbations, healthy individuals with greater hamstrings stiffness also display less anterior tibial translation, which is an arthrokinematic motion that directly loads the ACL.⁸ Given that anterior tibial translation results from anterior tibial shear force, greater hamstrings stiffness seemingly would resist anterior tibial shear force during landing more effectively than less hamstrings stiffness. Greater hamstrings stiffness also is correlated with less hamstrings flexibility.⁹ This heightened resistance to knee extension may lead to a more flexed knee during landing, producing more favorable landing biomechanics for ACL loading and injury risk. This notion is supported by Boden et al,¹ who reported that participants with ACL injuries displayed greater hamstrings flexibility than an uninjured cohort, suggesting that “above-average” hamstrings flexibility and, therefore, less hamstrings stiffness may increase ACL injury risk.Musculotendinous stiffness is a modifiable neuromuscular property^10,11 that could be targeted in ACL injury-prevention programs. Whereas greater hamstrings stiffness appears to limit ACL loading during controlled perturbations,⁸ it is unclear how hamstrings stiffness influences biomechanical ACL-loading mechanisms during dynamic tasks in which ACL injury commonly occurs. Therefore, the purpose of our investigation was to evaluate the influence of hamstrings musculotendinous stiffness on lower extremity kinematics and kinetics during landing. We hypothesized that individuals with greater hamstrings stiffness would display greater knee flexion during landing, resulting in smaller peak ground reaction forces, anterior tibial shear forces, internal knee-extension and -varus moments (ie, the internal/muscular responses to external moments), and knee-valgus angles. We also hypothesized that individuals with greater hamstrings stiffness would display greater knee-flexion angles at the instants of peak kinetics.     

Early and late coronary deaths in the US Railroad study predicted by major coronary risk factors.

BACKGROUND: The purpose of this study was to explore the duration of the association of major coronary risk factors measured on a single occasion with coronary heart disease (CHD) deaths during 40 years in a population sample of middle-aged men. DESIGN: Measurement of age, systolic blood pressure, serum total cholesterol, and cigarette smoking was made on a single occasion in 2376 cardiovascular disease free men, aged 40-59, belonging to the US Railroad cohort of the Seven Countries Study enrolled in the late 1950s. During 40 years of follow up 627 men died from typical CHD (sudden death coronary death or definite myocardial infarction). METHODS: Eight partitioned proportional hazards models were solved, one for each independent 5-year block of follow up, to predict the risk of CHD death. Eight 5-year partitioned hazard scores, derived from the coefficients, were cumulated for each risk factor. RESULTS: The resulting curves showed a regularly increasing time trend in risk for coronary deaths as a function of serum cholesterol, systolic blood pressure and cigarette smoking, for the first 30-35 years of follow up followed by a loss of predictive power thereafter. The curves fit straight lines, with large squared correlation coefficients ranging from 0.96 to 0.99. There was a relatively constant strength in the association of risk factors levels with events, which are predicted irrespective of the distance from risk factor measurements. CONCLUSIONS: Measurement of major coronary risk factors taken on a single occasion in middle-aged men maintained a regular and almost monotonic relationship with the subsequent occurrence of CHD deaths for at least 30-35 years of follow up.     

Amplification of genes encoding human myeloid membrane antigens after DNA-mediated gene transfer

Spontaneous amplification of genes encoding two different human myeloid surface antigens was observed after DNA-mediated gene transfer of cellular DNA from the human myeloid cell line HL-60 into NIH-3T3 mouse fibroblasts. Transformed recipient cells with highly amplified expression of either of two donor membrane polypeptides, gp150 or p67, were isolated with a fluorescence-activated cell sorter (FACS), using monoclonal antibodies specific for human myeloid cells. Immunoprecipitation of enzymatically radioiodinated polypeptides from the surface of transformed NIH-3T3 cells confirmed that expression of these proteins was amplified tenfold to 20-fold in comparison to their expression on human myeloid cell lines. The cellular DNA of cloned secondary and tertiary transformants expressing high levels of gp150 and p67 contained amplified sets of DNA restriction fragments that hybridized with human repetitive DNA sequences. Cytogenetic analysis of subclones overexpressing gp150 revealed extrachromosomal double minutes (DMs), whose presence correlated with the unstable expression of the membrane polypeptide. Human sequences in gp150-positive clones did not localize to chromosomes, consistent with their association with extrachromosomal DMs. By contrast, p67-positive subclones stably expressed the antigen, and in situ hybridization to metaphase spreads demonstrated that amplified human DNA sequences were integrated into a specific marker chromosome. Cytogenetic analysis of the parental NIH- 3T3 subclone used in these studies disclosed DMs in a low percentage of metaphases, suggesting that the recipient cells have a propensity for amplifying donor DNA.     

Tufted puffin reproduction reveals ocean climate variability

Anomalously warm sea-surface temperatures (SSTs) are associated with interannual and decadal variability as well as with long-term climate changes indicative of global warming. Such oscillations could precipitate changes in a variety of oceanic processes to affect marine species worldwide. As global temperatures continue to rise, it will be critically important to be able to predict the effects of such changes on species' abundance, distribution, and ecological relationships so as to identify vulnerable populations. Off the coast of British Columbia, warm SSTs have persisted through the last two decades. Based on 16 years of reproductive data collected between 1975 and 2002, we show that the extreme variation in reproductive performance exhibited by tufted puffins (Fratercula cirrhata) was related to changes in SST both within and among seasons. Especially warm SSTs corresponded with drastically decreased growth rates and fledging success of puffin nestlings. Puffins may partially compensate for within-season changes associated with SST by adjusting their breeding phenology, yet our data also suggest that they are highly vulnerable to the effects of climate change at this site and may serve as a valuable indicator of biological change in the North Pacific. Further and prolonged increases in ocean temperature could make Triangle Island, which contains the largest tufted puffin colony in Canada, unsuitable as a breeding site for this species.     

Establishing and managing a periodontal biobank for research: the sharing of experience

Periodontal bio‐repositories, which allow banking of clinically validated human data and biological samples, provide an opportunity to derive biomarkers for periodontal diagnosis, prognosis and therapeutic activities which are expected to improve patient management. This article presents the establishing of the Malaysian Periodontal Database and Biobank System (MPDBS) which was initiated in 2011 with the aim to facilitate periodontal research. Partnerships were established with collaborating centres. Policies on specimen access, authorship and acknowledgement policies were agreed upon by all participating centres before the initiation of the periodontal biobank. Ethical approval for the collection of samples and data were obtained from institutional ethics review boards. A broad‐based approach for informed consent was used, which covered areas related to quality of life impacts, genetics and molecular aspects of periodontal disease. Sample collection and processing was performed using a standardized protocol. Biobanking resources such as equipment and freezers were shared with the Malaysian Oral Cancer Database and Tissue Bank System (MOCDTBS). In the development of the MPDBS, challenges that were previously faced by the MOCDTBS were considered. Future challenges in terms of ethical and legal issues will be faced when international collaborations necessitate the transportation of specimens across borders.     

Telomerase, telomere length, and coronary artery calcium in black and white men in the CARDIA study

ObjectiveTo evaluate whether telomerase activity, measured in circulating blood leukocytes, might be associated with prevalent atherosclerosis, or predict future coronary artery disease risk.Methods and resultsWe examined associations of telomerase activity levels measured at year 15 in the Coronary Artery Risk Development in Young Adults (CARDIA) Study with prevalent coronary artery calcium (CAC), progressive CAC at year 20, and incident CAC between years 15 and 20, in 440 black and white men aged 33–45 years. Telomere length was also measured in a subset of participants (N = 129).In multivariate-adjusted analysis, higher quartiles of telomerase were cross-sectionally associated with greater odds of prevalent CAC at year 15 (quartile 2: OR = 1.32, 95% CI: 0.54–3.23; quartile 3: OR = 1.40, 95% CI: 0.60–3.30; quartile 4: OR = 3.27, 95% CI: 1.39–7.71 compared with quartile 1, p-continuous = 0.012) and progressive CAC at year 20, but telomerase was not significantly associated with incidence of newly detectable CAC. Higher telomerase activity levels predicted greater CAC progression at year 20 among persons with short telomere length; low telomerase and short TL predicted less CAC progression.ConclusionTelomerase activity in leukocytes was associated with calcified atherosclerotic plaque, and was also a predictor of advancing plaque among persons with short telomeres.     

20th-Century “medical Marco Polos” in the origins of preventive cardiology and cardiovascular disease epidemiology

In mid-20th century, several streams of knowledge converged to create the new academic discipline of cardiovascular disease epidemiology and the new practice of preventive cardiology. One stream was modern cardiology, with the ability to diagnose myocardial infarction, to characterize and count its victims, and to report vital statistics on cardiovascular causes of death. Another stream came from burgeoning clinical and laboratory research and greater understanding of the underlying processes of atherosclerosis and hypertension. A third stream came from the observations of intellectually curious "medical Marco Polos," who brought back from travels their tales of unusual population frequencies of heart attacks, along with ideas about sociocultural causes. This led to more formal research about cardiovascular disease risk and causes among populations and about mechanisms in the clinic and laboratory. The broad river of investigation thus formed produced a risk paradigm of the multiple biologic, behavioral, and societal factors in causal pathways to the common cardiovascular diseases. An evidence base was built for sound clinical and public health approaches to prevention. Here, the author tells brief stories about 5 early and particularly observant world travelers and their influence on knowledge and thinking about prevention.