p53 limits the proliferation of primary diploid fibroblasts by inducing a state of growth arrest named replicative senescence - a process which protects against oncogenic transformation and requires integrity of the p53 tumour suppressor pathway. However, little is known about the downstream target genes of p53 in this growth-limiting response. Here, we report that suppression of the p53 target gene encoding plasminogen activator inhibitor-1 (PAI-1) by RNA interference (RNAi) leads to escape from replicative senescence both in primary mouse embryo fibroblasts and primary human BJ fibroblasts. PAI-1 knockdown results in sustained activation of the PI(3)K-PKB-GSK3beta pathway and nuclear retention of cyclin D1, consistent with a role for PAI-1 in regulating growth factor signalling. In agreement with this, we find that the PI(3)K-PKB-GSK3beta-cyclin D1 pathway is also causally involved in cellular senescence. Conversely, ectopic expression of PAI-1 in proliferating p53-deficient murine or human fibroblasts induces a phenotype displaying all the hallmarks of replicative senescence. Our data indicate that PAI-1 is not merely a marker of senescence, but is both necessary and sufficient for the induction of replicative senescence downstream of p53.

Solid cancer cells commonly enter the blood and disseminate systemically, but are highly inefficient at forming distant metastases for poorly understood reasons. Here we studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NOD-SCID-Il2rg(-/-) (NSG) mice. We show that melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficiently metastasizing melanomas. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence on NADPH-generating enzymes in the folate pathway. Antioxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumours in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo.

HIV-1 reservoirs preclude virus eradication in patients receiving highly active antiretroviral therapy (HAART). The best characterized reservoir is a small, difficult-to-quantify pool of resting memory CD4(+) T cells carrying latent but replication-competent viral genomes. Because strategies targeting this latent reservoir are now being tested in clinical trials, well-validated high-throughput assays that quantify this reservoir are urgently needed. Here we compare eleven different approaches for quantitating persistent HIV-1 in 30 patients on HAART, using the original viral outgrowth assay for resting CD4(+) T cells carrying inducible, replication-competent viral genomes as a standard for comparison. PCR-based assays for cells containing HIV-1 DNA gave infected cell frequencies at least 2 logs higher than the viral outgrowth assay, even in subjects who started HAART during acute/early infection. This difference may reflect defective viral genomes. The ratio of infected cell frequencies determined by viral outgrowth and PCR-based assays varied dramatically between patients. Although strong correlations with the viral outgrowth assay could not be formally excluded for most assays, correlations achieved statistical significance only for integrated HIV-1 DNA in peripheral blood mononuclear cells and HIV-1 RNA/DNA ratio in rectal CD4(+) T cells. Residual viremia was below the limit of detection in many subjects and did not correlate with the viral outgrowth assays. The dramatic differences in infected cell frequencies and the lack of a precise correlation between culture and PCR-based assays raise the possibility that the successful clearance of latently infected cells may be masked by a larger and variable pool of cells with defective proviruses. These defective proviruses are detected by PCR but may not be affected by reactivation strategies and may not require eradication to accomplish an effective cure. A molecular understanding of the discrepancy between infected cell frequencies measured by viral outgrowth versus PCR assays is an urgent priority in HIV-1 cure research.

Obtaining reliable data and drawing meaningful and robust inferences from diffusion MRI can be challenging and is subject to many pitfalls. The process of quantifying diffusion indices and eventually comparing them between groups of subjects and/or correlating them with other parameters starts at the acquisition of the raw data, followed by a long pipeline of image processing steps. Each one of these steps is susceptible to sources of bias, which may not only limit the accuracy and precision, but can lead to substantial errors. This article provides a detailed review of the steps along the analysis pipeline and their associated pitfalls. These are grouped into 1 pre-processing of data; 2 estimation of the tensor; 3 derivation of voxelwise quantitative parameters; 4 strategies for extracting quantitative parameters; and finally 5 intra-subject and inter-subject comparison, including region of interest, histogram, tract-specific and voxel-based analyses. The article covers important aspects of diffusion MRI analysis, such as motion correction, susceptibility and eddy current distortion correction, model fitting, region of interest placement, histogram and voxel-based analysis. We have assembled 25 pitfalls (several previously unreported) into a single article, which should serve as a useful reference for those embarking on new diffusion MRI-based studies, and as a check for those who may already be running studies but may have overlooked some important confounds. While some of these problems are well known to diffusion experts, they might not be to other researchers wishing to undertake a clinical study based on diffusion MRI.

BACKGROUND

Transthoracic Doppler echocardiography is recommended for screening for the presence of pulmonary hypertension (PH). However, some recent studies have suggested that Doppler echocardiographic pulmonary artery pressure estimates may frequently be inaccurate.

OBJECTIVE

Evaluate the accuracy of Doppler echocardiography for estimating pulmonary artery pressure and cardiac output.

METHODS

We conducted a prospective study on patients with various forms of PH who underwent comprehensive Doppler echocardiography within 1 hour of a clinically indicated right-heart catheterization to compare noninvasive hemodynamic estimates with invasively measured values.

RESULTS

A total of 65 patients completed the study protocol. Using Bland-Altman analytic methods, the bias for the echocardiographic estimates of the pulmonary artery systolic pressure was -0.6 mm Hg with 95% limits of agreement ranging from +38.8 to -40.0 mm Hg. Doppler echocardiography was inaccurate (defined as being greater than +/-10 mm Hg of the invasive measurement) in 48% of cases. Overestimation and underestimation of pulmonary artery systolic pressure by Doppler echocardiography occurred with a similar frequency (16 vs. 15 instances, respectively). The magnitude of pressure underestimation was greater than overestimation (-30 +/- 16 vs. +19 +/- 11 mm Hg; P = 0.03); underestimates by Doppler also led more often to misclassification of the severity of the PH. For cardiac output measurement, the bias was -0.1 L/min with 95% limits of agreement ranging from +2.2 to -2.4 L/min.

CONCLUSIONS

Doppler echocardiography may frequently be inaccurate in estimating pulmonary artery pressure and cardiac output in patients being evaluated for PH.

BACKGROUND

The associations of low (<0.90) and high (>1.40) ankle brachial index (ABI) with risk of all-cause and cardiovascular disease (CVD) mortality have not been examined in a population-based setting.

RESULTS

We examined all-cause and CVD mortality in relation to low and high ABI in 4393 American Indians in the Strong Heart Study. Participants had bilateral ABI measurements at baseline and were followed up for 8.3+/-2.2 years (36 589 person-years). Cox regression was used to quantify mortality rates among participants with high and low ABI relative to those with normal ABI (0.90 < or =ABI < or =1.40). Death from all causes occurred in 1022 participants (23.3%; 27.9 deaths per 1000 person-years), and of these, 272 (26.6%; 7.4 deaths per 1000 person-years) were attributable to CVD. Low ABI was present in 216 participants (4.9%), and high ABI occurred in 404 (9.2%). Diabetes, albuminuria, and hypertension occurred with greater frequency among persons with low (60.2%, 44.4%, and 50.1%) and high (67.8%, 49.9%, and 45.1%) ABI compared with those with normal ABI (44.4%, 26.9%, and 36.5%), respectively (P<0.0001). Adjusted risk estimates for all-cause mortality were 1.69 (1.34 to 2.14) for low and 1.77 (1.48 to 2.13) for high ABI, and estimates for CVD mortality were 2.52 (1.74 to 3.64) for low and 2.09 (1.49 to 2.94) for high ABI.

CONCLUSIONS

The association between high ABI and mortality was similar to that of low ABI and mortality, highlighting a U-shaped association between this noninvasive measure of peripheral arterial disease and mortality risk. Our data suggest that the upper limit of normal ABI should not exceed 1.40.

A key challenge when imaging living cells is how to noninvasively extract the most spatiotemporal information possible. Unlike popular wide-field and confocal methods, plane-illumination microscopy limits excitation to the information-rich vicinity of the focal plane, providing effective optical sectioning and high speed while minimizing out-of-focus background and premature photobleaching. Here we used scanned Bessel beams in conjunction with structured illumination and/or two-photon excitation to create thinner light sheets (<0.5 μm) better suited to three-dimensional (3D) subcellular imaging. As demonstrated by imaging the dynamics of mitochondria, filopodia, membrane ruffles, intracellular vesicles and mitotic chromosomes in live cells, the microscope currently offers 3D isotropic resolution down to ∼0.3 μm, speeds up to nearly 200 image planes per second and the ability to noninvasively acquire hundreds of 3D data volumes from single living cells encompassing tens of thousands of image frames.

Antiretroviral therapy can reduce human immunodeficiency virus type 1 (HIV-1) viremia to below the detection limit of ultrasensitive clinical assays (50 copies of HIV-1 RNA/ml). However, latent HIV-1 persists in resting CD4+ T cells, and low residual levels of free virus are found in the plasma. Limited characterization of this residual viremia has been done because of the low number of virions per sample. Using intensive sampling, we analyzed residual viremia and compared these viruses to latent proviruses in resting CD4+ T cells in peripheral blood. For each patient, we found some viruses in the plasma that were identical to viruses in resting CD4+ T cells by pol gene sequencing. However, in a majority of patients, the most common viruses in the plasma were rarely found in resting CD4+ T cells even when the resting cell compartment was analyzed with assays that detect replication-competent viruses. Despite the large diversity of pol sequences in resting CD4+ T cells, the residual viremia was dominated by a homogeneous population of viruses with identical pol sequences. In the most extensively studied case, a predominant plasma sequence was also found in analysis of the env gene, and linkage by long-distance reverse transcriptase PCR established that these predominant plasma sequences represented a single predominant plasma virus clone. The predominant plasma clones were released for months to years without evident sequence change. Thus, in some patients on antiretroviral therapy, the major mechanism for residual viremia involves prolonged production of a small number of viral clones without evident evolution, possibly by cells other than circulating CD4+ T cells. The sequences have been deposited in GenBank. The accession numbers are DQ 391282 to DQ 391351 (for env) and DQ 391352 to DQ 392955 (for RT).

Despite general agreement about the boundaries of Alzheimer disease (AD), establishing a maximum <em>limit</em> for Alzheimer-type pathology in cognitively intact individuals might aid in defining more precisely the point at which Alzheimer pathology becomes clinically relevant. In this study, we examined the neuropathological changes in the brains of 39 longitudinally followed. cognitively normal elderly individuals (24 women, 15 men; age range 74-95, median 85 years). Neuropathological changes of the Alzheimer type were quantified by determining neurofibrillary tangle (NFT) staging by the method of Braak and Braak and by quantification of the abundance of diffuse, cored, and neuritic plaque burden using the scheme developed by the Consortium to Establish a Registry for Alzheimer Disease (CERAD). Vascular, Lewy body, and argyrophilic grain pathology were also assessed. We found 34 subjects (87%) with a Braak stage <IV; 32 subjects (82%) with less than moderate numbers of cored plaques and 37 subjects (95%) with less than moderate numbers of tau-positive neuritic plaques. Many subjects had moderate or frequent diffuse plaques (n = 19, 49%). By the National Institute on Aging-Reagan Institute (NIA-RI) criteria, none of our cases met criteria for high "likelihood" of AD. Four met NIA-RI criteria for intermediate "likelihood." Seven cases met CERAD criteria for possible AD. Nineteen met Khachaturian criteria for AD. Only 1 subject had neocortical Lewy bodies. Small, old infarcts were common, but no subjects had more than 2 of these and none had a single large infarction. Thus, the majority of individuals who are cognitively normal near the time of their death have minimal amounts of tau-positive neuritic pathology (Braak stage <IV and neuritic plaques <6 per x100 field in the most affected neocortical region). The few subjects with more severe AD pathology can be expected based on incidence rates of AD in the very elderly.

Nonsense-mediated decay (NMD) eliminates mRNAs containing premature termination codons and thus helps limit the synthesis of abnormal proteins. New results uncover a broader role of NMD as a pathway that also affects the expression of wild-type genes and alternative-splice products. Because the mechanisms by which NMD operates have received much attention, we discuss here the emerging awareness of the impact of NMD on the manifestation of human genetic diseases. We explore how an understanding of NMD accounts for phenotypic differences in diseases caused by premature termination codons. Specifically, we consider how the protective function of NMD sometimes benefits heterozygous carriers and, in contrast, sometimes contributes to a clinical picture of protein deficiency by inhibiting expression of partially functional proteins. Potential 'NMD therapeutics' will therefore need to strike a balance between the general physiological benefits of NMD and its detrimental effects in cases of specific genetic mutations.

In the mammalian brain, astrocytes modulate neuronal function, in part, by synchronizing neuronal firing and coordinating synaptic networks. Little, however, is known about how this is accomplished from a structural standpoint. To investigate the structural basis of astrocyte-mediated neuronal synchrony and synaptic coordination, the three-dimensional relationships between cortical astrocytes and neurons was investigated. Using a transgenic and viral approach to label astrocytes with enhanced green fluorescent protein, we performed a three-dimensional reconstruction of astrocytes from tissue sections or live animals in vivo. We found that cortical astrocytes occupy nonoverlapping territories similar to those described in the hippocampus. Using immunofluorescence labeling of neuronal somata, a single astrocyte enwraps on average four neuronal somata with an upper limit of eight. Single-neuron dye-fills allowed us to estimate that one astrocyte contacts 300-600 neuronal dendrites. Together with the recent findings showing that glial Ca2+ signaling is restricted to individual astrocytes in vivo, and that Ca2+ signaling leads to gliotransmission, we propose the concept of functional islands of synapses in which groups of synapses confined within the boundaries of an individual astrocyte are modulated by the gliotransmitter environment controlled by that astrocyte. Our description offers a new structurally based conceptual framework to evaluate functional data involving interactions between neurons and astrocytes in the mammalian brain.

BACKGROUND

Despite growth in implementation research, limited scientific attention has focused on understanding and improving sustainability of health interventions. Models of sustainability have been evolving to reflect challenges in the fit between intervention and context.

CONCLUSIONS

We examine the development of concepts of sustainability, and respond to two frequent assumptions -'voltage drop,' whereby interventions are expected to yield lower benefits as they move from efficacy to effectiveness to implementation and sustainability, and 'program drift,' whereby deviation from manualized protocols is assumed to decrease benefit. We posit that these assumptions limit opportunities to improve care, and instead argue for understanding the changing context of healthcare to continuously refine and improve interventions as they are sustained. Sustainability has evolved from being considered as the endgame of a translational research process to a suggested 'adaptation phase' that integrates and institutionalizes interventions within local organizational and cultural contexts. These recent approaches locate sustainability in the implementation phase of knowledge transfer, but still do not address intervention improvement as a central theme. We propose a Dynamic Sustainability Framework that involves: continued learning and problem solving, ongoing adaptation of interventions with a primary focus on fit between interventions and multi-level contexts, and expectations for ongoing improvement as opposed to diminishing outcomes over time.

CONCLUSIONS

A Dynamic Sustainability Framework provides a foundation for research, policy and practice that supports development and testing of falsifiable hypotheses and continued learning to advance the implementation, transportability and impact of health services research.

OBJECTIVE

We updated a long-term cancer control outcome in a large anatomical radical retropubic prostatectomy (RRP) series. We also evaluated the perioperative parameters that predict cancer specific outcomes following surgery.

METHODS

From May 1983 to February 2003, 1 surgeon (WJC) performed RRP in 3,478 consecutive men. Patients were followed with semiannual serum prostate specific antigen (PSA) tests and annual digital rectal examinations. We used Kaplan-Meier product limit estimates to calculate actuarial 10-year probabilities of biochemical progression-free survival, cancer specific survival and overall survival. Multivariate Cox proportional hazards models were used to determine independent perioperative predictors of cancer progression.

RESULTS

At a mean followup of 65 months (range 0 to 233) actuarial 10-year biochemical progression-free, cancer specific and overall survival probabilities were 68%, 97% and 83%, respectively. On multivariate analysis biochemical progression-free survival probability was significantly associated with preoperative PSA, clinical tumor stage, Gleason sum, pathological stage and treatment era. Cancer specific survival and overall survival rates were also significantly associated with clinicopathological parameters.

CONCLUSIONS

RRP can be performed with excellent survival outcomes. Favorable clinicopathological parameters and treatment in the PSA era are associated with improved cancer control.

Abdominal aortic aneurysms represent a life-threatening condition characterized by chronic inflammation, destructive remodeling of the extracellular matrix, and increased local expression of matrix metalloproteinases (MMPs). Both 92-kD gelatinase (MMP-9) and macrophage elastase (MMP-12) have been implicated in this disease, but it is not known if either is necessary in aneurysmal degeneration. We show here that transient elastase perfusion of the mouse aorta results in delayed aneurysm development that is temporally associated with transmural mononuclear inflammation, increased local production of several elastolytic MMPs, and progressive destruction of the elastic lamellae. Elastase-induced aneurysmal degeneration was suppressed by treatment with a nonselective MMP inhibitor (doxycycline) and by targeted gene disruption of MMP-9, but not by isolated deficiency of MMP-12. Bone marrow transplantation from wild-type mice prevented the aneurysm-resistant phenotype in MMP-9-deficient animals, and wild-type mice acquired aneurysm resistance after transplantation from MMP-9-deficient donors. These results demonstrate that inflammatory cell expression of MMP-9 plays a critical role in an experimental model of aortic aneurysm disease, suggesting that therapeutic strategies targeting MMP-9 may limit the growth of small abdominal aortic aneurysms.

Plants transport fixed carbon predominantly as sucrose, which is produced in mesophyll cells and imported into phloem cells for translocation throughout the plant. It is not known how sucrose migrates from sites of synthesis in the mesophyll to the phloem, or which cells mediate efflux into the apoplasm as a prerequisite for phloem loading by the SUT sucrose-H(+) (proton) cotransporters. Using optical sucrose sensors, we identified a subfamily of SWEET sucrose efflux transporters. AtSWEET11 and 12 localize to the plasma membrane of the phloem. Mutant plants carrying insertions in AtSWEET11 and 12 are defective in phloem loading, thus revealing a two-step mechanism of SWEET-mediated export from parenchyma cells feeding H(+)-coupled import into the sieve element-companion cell complex. We discuss how restriction of intercellular transport to the interface of adjacent phloem cells may be an effective mechanism to limit the availability of photosynthetic carbon in the leaf apoplasm in order to prevent pathogen infections.

Globally, soil organic matter (SOM) contains more than three times as much carbon as either the atmosphere or terrestrial vegetation. Yet it remains largely unknown why some SOM persists for millennia whereas other SOM decomposes readily--and this limits our ability to predict how soils will respond to climate change. Recent analytical and experimental advances have demonstrated that molecular structure alone does not control SOM stability: in fact, environmental and biological controls predominate. Here we propose ways to include this understanding in a new generation of experiments and soil carbon models, thereby improving predictions of the SOM response to global warming.

The publication of crystal structures of the 50S and 30S ribosomal subunits and the intact 70S ribosome is revolutionizing our understanding of protein synthesis. This review is an attempt to correlate the structures with biochemical and genetic data to identify the gaps and limits in our current knowledge of the mechanisms involved in translation.

Diverse and rapidly evolving pathogens cause plant diseases and epidemics that threaten crop yield and food security around the world. Research over the last 25 years has led to an increasingly clear conceptual understanding of the molecular components of the plant immune system. Combined with ever-cheaper DNA-sequencing technology and the rich diversity of germ plasm manipulated for over a century by plant breeders, we now have the means to begin development of durable (long-lasting) disease resistance beyond the limits imposed by conventional breeding and in a manner that will replace costly and unsustainable chemical controls.

Chronic pancreatitis is a well-known risk factor for pancreatic ductal adenocarcinoma (PDA) development in humans, and inflammation promotes PDA initiation and progression in mouse models of the disease. However, the mechanistic link between inflammatory damage and PDA initiation is unclear. Using a Kras-driven mouse model of PDA, we establish that the inflammatory mediator Stat3 is a critical component of spontaneous and pancreatitis-accelerated PDA precursor formation and supports cell proliferation, metaplasia-associated inflammation, and MMP7 expression during neoplastic development. Furthermore, we show that Stat3 signaling enforces MMP7 expression in PDA cells and that MMP7 deletion limits tumor size and metastasis in mice. Finally, we demonstrate that serum MMP7 level in human patients with PDA correlated with metastatic disease and survival.

Radiation damage is the main problem which prevents the determination of the structure of a single biological macromolecule at atomic resolution using any kind of microscopy. This is true whether neutrons, electrons or X-rays are used as the illumination. For neutrons, the cross-section for nuclear capture and the associated energy deposition and radiation damage could be reduced by using samples that are fully deuterated and 15N-labelled and by using fast neutrons, but single molecule biological microscopy is still not feasible. For naturally occurring biological material, electrons at present provide the most information for a given amount of radiation damage. Using phase contrast electron microscopy on biological molecules and macromolecular assemblies of approximately 10(5) molecular weight and above, there is in theory enough information present in the image to allow determination of the position and orientation of individual particles: the application of averaging methods can then be used to provide an atomic resolution structure. The images of approximately 10,000 particles are required. Below 10(5) molecular weight, some kind of crystal or other geometrically ordered aggregate is necessary to provide a sufficiently high combined molecular weight to allow for the alignment. In practice, the present quality of the best images still falls short of that attainable in theory and this means that a greater number of particles must be averaged and that the molecular weight limitation is somewhat larger than the predicted limit. For X-rays, the amount of damage per useful elastic scattering event is several hundred times greater than for electrons at all wavelengths and energies and therefore the requirements on specimen size and number of particles are correspondingly larger. Because of the lack of sufficiently bright neutron sources in the foreseeable future, electron microscopy in practice provides the greatest potential for immediate progress.

The frontopolar cortex (FPC), the most anterior part of the frontal lobes, forms the apex of the executive system underlying decision-making. Here, we review empirical evidence showing that the FPC function enables contingent interposition of two concurrent behavioral plans or mental tasks according to respective reward expectations, overcoming the serial constraint that bears upon the control of task execution in the prefrontal cortex. This function is mechanistically explained by interactions between FPC and neighboring prefrontal regions. However, its capacity appears highly limited, which suggests that the FPC is efficient for protecting the execution of long-term mental plans from immediate environmental demands and for generating new, possibly more rewarding, behavioral or cognitive sequences, rather than for complex decision-making and reasoning.

In the presence of multivalent cations, high molecular weight DNA undergoes a dramatic condensation to a compact, usually highly ordered toroidal structure. This review begins with an overview of DNA condensation: condensing agents, morphology, kinetics, and reversibility, and the minimum size required to form orderly condensates. It then summarizes the statistical mechanics of the collapse of stiff polymers, which shows why DNA condensation is abrupt and why toroids are favored structures. Various ways to estimate or measure intermolecular forces in DNA condensation are discussed, all of them agreeing that the free energy change per base pair is very small, on the order of 1% of thermal energy. Experimental evidence is surveyed showing that DNA condensation occurs when about 90% of its charge is neutralized by counterions. The various intermolecular forces whose interplay gives rise to DNA condensation are then reviewed. The entropy loss upon collapse of the expanded wormlike coil costs free energy, and stiffness sets limits on tight curvature. However, the dominant contributions seem to come from ions and water. Electrostatic repulsions must be overcome by high salt concentrations or by the correlated fluctuations of territorially bound multivalent cations. Hydration must be adjusted to allow a cooperative accommodation of the water structure surrounding surface groups on the DNA helices as they approach. Undulations of the DNA in its confined surroundings extend the range of the electrostatic forces. The condensing ions may also subtly modify the local structure of the double helix.

BACKGROUND

The metabolic syndrome is a high-risk state for diabetes and cardiovascular disease. Little is known about its prevalence and prevention in those with impaired glucose tolerance.

OBJECTIVE

To determine the prevalence of the metabolic syndrome at baseline in the Diabetes Prevention Program and the effect of intensive lifestyle intervention and metformin therapy on the syndrome's incidence and resolution.

METHODS

Randomized, controlled clinical trial.

METHODS

Research and community-based centers.

METHODS

Participants had impaired glucose tolerance (World Health Organization criteria plus fasting plasma glucose level>>or=5.3 mmol/L >>or=95 mg/dL]) and were followed for a mean of 3.2 years after random assignment to intensive lifestyle intervention, metformin therapy, or placebo.

METHODS

Metformin, 850 mg twice daily, or intensive lifestyle intervention designed to achieve and maintain a 7% weight loss and 150 minutes of exercise per week.

METHODS

The metabolic syndrome was defined as having 3 or more characteristics (waist circumference; blood pressure; and levels of high-density lipoprotein cholesterol, triglycerides, and fasting plasma glucose) that met criteria from the National Cholesterol Education Program Adult Treatment Panel III.

RESULTS

Fifty-three percent of participants (n = 1711) had the metabolic syndrome at baseline; incidence did not vary substantially by age. However, low levels of high-density lipoprotein cholesterol predominated in younger participants (age 25 to 44 years), and high blood pressure predominated in older participants (age 60 to 82 years). In life-table analyses (log-rank test), incidence of the metabolic syndrome was reduced by 41% in the lifestyle group (P < 0.001) and by 17% in the metformin group (P = 0.03) compared with placebo. Three-year cumulative incidences were 51%, 45%, and 34% in the placebo, metformin, and lifestyle groups, respectively. There was no significant heterogeneity by ethnic group.

CONCLUSIONS

The study involved a volunteer group with impaired glucose tolerance, which limits generalizability.

CONCLUSIONS

The metabolic syndrome affected approximately half of the participants in the Diabetes Prevention Program at baseline. Both lifestyle intervention and metformin therapy reduced the development of the syndrome in the remaining participants.

OBJECTIVE

The Cancer Imaging Program of the National Cancer Institute convened a workshop to assess the current status of hypoxia imaging, to assess what is known about the biology of hypoxia as it relates to cancer and cancer therapy, and to define clinical scenarios in which in vivo hypoxia imaging could prove valuable.

RESULTS

Hypoxia, or low oxygenation, has emerged as an important factor in tumor biology and response to cancer treatment. It has been correlated with angiogenesis, tumor aggressiveness, local recurrence, and metastasis, and it appears to be a prognostic factor for several cancers, including those of the cervix, head and neck, prostate, pancreas, and brain. The relationship between tumor oxygenation and response to radiation therapy has been well established, but hypoxia also affects and is affected by some chemotherapeutic agents. Although hypoxia is an important aspect of tumor physiology and response to treatment, the lack of simple and efficient methods to measure and image oxygenation hampers further understanding and limits their prognostic usefulness. There is no gold standard for measuring hypoxia; Eppendorf measurement of pO(2) has been used, but this method is invasive. Recent studies have focused on molecular markers of hypoxia, such as hypoxia inducible factor 1 (HIF-1) and carbonic anhydrase isozyme IX (CA-IX), and on developing noninvasive imaging techniques.

CONCLUSIONS

This workshop yielded recommendations on using hypoxia measurement to identify patients who would respond best to radiation therapy, which would improve treatment planning. This represents a narrow focus, as hypoxia measurement might also prove useful in drug development and in increasing our understanding of tumor biology.