METHODS

Update of the 2004 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for lung cancer.

METHODS

The USPSTF reviewed the evidence on the efficacy of low-dose computed tomography, chest radiography, and sputum cytologic evaluation for lung cancer screening in asymptomatic persons who are at average or high risk for lung cancer (current or former smokers) and the benefits and harms of these screening tests and of surgical resection of early-stage non-small cell lung cancer. The USPSTF also commissioned modeling studies to provide information about the optimum age at which to begin and end screening, the optimum screening interval, and the relative benefits and harms of different screening strategies.

METHODS

This recommendation applies to asymptomatic adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.

CONCLUSIONS

The USPSTF recommends annual screening for lung cancer with low-dose computed tomography in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. (B recommendation).

Membrane subdomains have been implicated in T cell signaling, although their properties and mechanisms of formation remain controversial. Here, we have used single-molecule and scanning confocal imaging to characterize the behavior of GFP-tagged signaling proteins in Jurkat T cells. We show that the coreceptor CD2, the adaptor protein LAT, and tyrosine kinase Lck cocluster in discrete microdomains in the plasma membrane of signaling T cells. These microdomains require protein-protein interactions mediated through phosphorylation of LAT and are not maintained by interactions with actin or lipid rafts. Using a two color imaging approach that allows tracking of single molecules relative to the CD2/LAT/Lck clusters, we demonstrate that these microdomains exclude and limit the free diffusion of molecules in the membrane but also can trap and immobilize specific proteins. Our data suggest that diffusional trapping through protein-protein interactions creates microdomains that concentrate or exclude cell surface proteins to facilitate T cell signaling.

In Alzheimer's disease (AD), abnormal accumulations of beta-amyloid are present in the brain and degenerating neurons exhibit cytoskeletal aberrations (neurofibrillary tangles). Roles for beta-amyloid in the neuronal degeneration of AD have been suggested based on recent data obtained in rodent studies demonstrating neurotoxic actions of beta-amyloid. However, the cellular mechanism of action of beta-amyloid is unknown, and there is no direct information concerning the biological activity of beta-amyloid in human neurons. We now report on experiments in human cerebral cortical cell cultures that tested the hypothesis that beta-amyloid can destabilize neuronal calcium regulation and render neurons more vulnerable to environmental stimuli that elevate intracellular calcium levels. Synthetic beta-amyloid peptides (beta APs) corresponding to amino acids 1-38 or 25-35 of the beta-amyloid protein enhanced glutamate neurotoxicity in cortical cultures, while a peptide with a scrambled sequence was without effect. beta APs alone had no effect on neuronal survival during a 4 d exposure period. beta APs enhanced both kainate and NMDA neurotoxicity, indicating that the effect was not specific for a particular subtype of glutamate receptor. The effects of beta APs on excitatory amino acid (EAA)-induced neuronal degeneration were concentration dependent and required prolonged (days) exposures. The beta APs also rendered neurons more vulnerable to calcium ionophore neurotoxicity, indicating that beta APs compromised the ability of the neurons to reduce intracellular calcium levels to normal limits. Direct measurements of intracellular calcium levels demonstrated that beta APs elevated rest levels of calcium and enhanced calcium responses to EAAs and calcium ionophore. The neurotoxicity caused by EAAs and potentiated by beta APs was dependent upon calcium influx since it did not occur in calcium-deficient culture medium. Finally, the beta APs made neurons more vulnerable to neurofibrillary tangle-like antigenic changes induced by EAAs or calcium ionophore (i.e., increased staining with tau and ubiquitin antibodies). Taken together, these data suggest that beta-amyloid destabilizes neuronal calcium homeostasis and thereby renders neurons more vulnerable to environmental insults.

BACKGROUND

Age-related physiological changes in the gastrointestinal tract, as well as modifications in lifestyle, nutritional behaviour, and functionality of the host immune system, inevitably affect the gut microbiota, resulting in a greater susceptibility to infections.

RESULTS

By using the Human Intestinal Tract Chip (HITChip) and quantitative PCR of 16S rRNA genes of Bacteria and Archaea, we explored the age-related differences in the gut microbiota composition among young adults, elderly, and centenarians, i.e subjects who reached the extreme limits of the human lifespan, living for over 100 years. We observed that the microbial composition and diversity of the gut ecosystem of young adults and seventy-years old people is highly similar but differs significantly from that of the centenarians. After 100 years of symbiotic association with the human host, the microbiota is characterized by a rearrangement in the Firmicutes population and an enrichment in facultative anaerobes, notably pathobionts. The presence of such a compromised microbiota in the centenarians is associated with an increased inflammatory status, also known as inflammageing, as determined by a range of peripheral blood inflammatory markers. This may be explained by a remodelling of the centenarians' microbiota, with a marked decrease in Faecalibacterium prauznitzii and relatives, symbiotic species with reported anti-inflammatory properties. As signature bacteria of the long life we identified specifically Eubacterium limosum and relatives that were more than ten-fold increased in the centenarians.

CONCLUSIONS

We provide evidence for the fact that the ageing process deeply affects the structure of the human gut microbiota, as well as its homeostasis with the host's immune system. Because of its crucial role in the host physiology and health status, age-related differences in the gut microbiota composition may be related to the progression of diseases and frailty in the elderly population.

Oncogenic Ras transforms immortal rodent cells to a tumorigenic state, in part, by constitutively transmitting mitogenic signals through the mitogen-activated protein kinase (MAPK) cascade. In primary cells, Ras is initially mitogenic but eventually induces premature senescence involving the p53 and p16(INK4a) tumor suppressors. Constitutive activation of MEK (a component of the MAPK cascade) induces both p53 and p16, and is required for Ras-induced senescence of normal human fibroblasts. Furthermore, activated MEK permanently arrests primary murine fibroblasts but forces uncontrolled mitogenesis and transformation in cells lacking either p53 or INK4a. The precisely opposite response of normal and immortalized cells to constitutive activation of the MAPK cascade implies that premature senescence acts as a fail-safe mechanism to limit the transforming potential of excessive Ras mitogenic signaling. Consequently, constitutive MAPK signaling activates p53 and p16 as tumor suppressors.

Vertebrates constantly remodel bone. The resorption of preexisting bone by osteoclasts and the formation of new bone by osteoblasts is strictly coordinated to maintain bone mass within defined limits. A few molecular determinants of bone remodelling that affect osteoclast activity have been characterized, but the molecular determinants of osteoblast activity are unknown. To investigate the role of osteocalcin, the most abundant osteoblast-specific non-collagenous protein, we have generated osteocalcin-deficient mice. These mice develop a phenotype marked by higher bone mass and bones of improved functional quality. Histomorphometric studies done before and after ovariectomy showed that the absence of osteocalcin leads to an increase in bone formation without impairing bone resorption. To our knowledge, this study provides the first evidence that osteocalcin is a determinant of bone formation.

An ultrasensitive method for detecting protein analytes has been developed. The system relies on magnetic microparticle probes with antibodies that specifically bind a target of interest [prostate-specific antigen (PSA) in this case] and nanoparticle probes that are encoded with DNA that is unique to the protein target of interest and antibodies that can sandwich the target captured by the microparticle probes. Magnetic separation of the complexed probes and target followed by dehybridization of the oligonucleotides on the nanoparticle probe surface allows the determination of the presence of the target protein by identifying the oligonucleotide sequence released from the nanoparticle probe. Because the nanoparticle probe carries with it a large number of oligonucleotides per protein binding event, there is substantial amplification and PSA can be detected at 30 attomolar concentration. Alternatively, a polymerase chain reaction on the oligonucleotide bar codes can boost the sensitivity to 3 attomolar. Comparable clinically accepted conventional assays for detecting the same target have sensitivity limits of approximately 3 picomdar, six orders of magnitude less sensitive than what is observed with this method.

Breast cancer is known to have an inherited component, consistent in some families with autosomal dominant inheritance; in such families the disease often occurs in association with ovarian cancer. Previous genetic linkage studies have established that in some such families disease occurrence is linked to markers on chromosome 17q. This paper reports the results of a collaborative linkage study involving 214 breast cancer families, including 57 breast-ovarian cancer families; this represents almost all the known families with 17q linkage data. Six markers on 17q, spanning approximately 30 cM, were typed in the families. The aims of the study were to define more precisely the localization of the disease gene, the extent of genetic heterogeneity and the characteristics of linked families and to estimate the penetrance of the 17q gene. Under the assumption of no genetic heterogeneity, the strongest linkage evidence was obtained with D17S588 (maximum LOD score [Zmax] = 21.68 at female recombination fraction [theta f] = .13) and D17S579 (Zmax = 13.02 at theta f = .16). Multipoint linkage analysis allowing for genetic heterogeneity provided evidence that the predisposing gene lies between the markers D17S588 and D17S250, an interval whose genetic length is estimated to be 8.3 cM in males and 18.0 cM in females. This position was supported over other intervals by odds of 66:1. The location of the gene with respect to D17S579 could not be determined unequivocally. Under the genetic model used in the analysis, the best estimate of the proportion of linked breast-ovarian cancer families was 1.0 (lower LOD-1 limit 0.79). In contrast, there was significant evidence of genetic heterogeneity among the families without ovarian cancer, with an estimated 45% being linked. These results suggest that a gene(s) on chromosome 17q accounts for the majority of families in which both early-onset breast cancer and ovarian cancer occur but that other genes predisposing to breast cancer exist. By examining the fit of the linkage data to different penetrance functions, the cumulative risk associated with the 17q gene was estimated to be 59% by age 50 years and 82% by age 70 years. The corresponding estimates for the breast-ovary families were 67% and 76%, and those for the families without ovarian cancer were 49% and 90%; these penetrance functions did not differ significantly from one another.

Human body composition is important in numerous cancer research domains. Our objective was to evaluate clinically accessible methods to achieve practical and precise measures of body composition in cancer patients. Dual-energy X-ray absorptiometry (DXA)-based analysis of fat and fat-free mass was performed in 50 cancer patients and compared with bioelectrical impedance analysis (BIA) and with regional computed tomography (CT) images available in the patients' medical records. BIA overestimated or underestimated fat-free mass substantially compared with DXA as the method of reference (up to 9.3 kg difference). Significant changes in fat-free mass over time detected with DXA in a subset of 21 patients (+2.2 +/- 3.2%/100 days, p = 0.003), was beyond the limits of detection of BIA. Regional analysis of fat and fat-free tissue at the 3rd lumbar vertebra with either DXA or CT strongly predicted whole-body fat and fat-free mass (r = 0.86-0.94; p < 0.001). CT images provided detail on specific muscles, adipose tissues and organs, not provided by DXA or BIA. CT presents great practical significance due to the prevalence of these images in patient diagnosis and follow-up, thus marrying clinical accessibility with high precision to quantify specific tissues and to predict whole-body composition.

We reviewed studies that reported results of systematic cytomegalovirus (CMV) screening on fetuses and/or live-born infants. The overall birth prevalence of congenital CMV infection was 0.64%, but varied considerably among different study populations. About 11% of live-born infants with congenital CMV infection were symptomatic, but the inter-study differences in definitions of symptomatic cases limit the interpretation of these data. Non-white race, low socioeconomic status (SES), premature birth, and neonatal intensive care unit admittance were risk factors for congenital CMV infection. Birth prevalence increased with maternal CMV seroprevalence. Maternal seroprevalence accounted for 29% of the variance in birth prevalence between study populations. Maternal seroprevalence and birth prevalence were both higher in study populations that were ascertained at birth rather than in the prenatal period. Thus, timing of ascertainment should be considered when interpreting birth prevalence estimates. Birth prevalence was inversely correlated with mean maternal age, but this relationship was not significant when controlling for maternal seroprevalence. The rate of transmission to infants born to mothers who had a primary infection or a recurrent infection during pregnancy was 32% and 1.4%, respectively. Possible maternal primary infections (i.e. seropositive mother with CMV IgM) resulted in congenital infections about 20% of the time, but are likely to represent a mixture of primary and recurrent infections. In summary, CMV is a common congenital infection worldwide that can lead to permanent disabilities. There is an urgent need for interventions that can reduce the substantial burden of this often overlooked disease.

Devic's disease [neuromyelitis optica (NMO)] is an idiopathic inflammatory demyelinating disease of the CNS, characterized by attacks of optic neuritis and myelitis. The mechanisms that result in selective localization of inflammatory demyelinating lesions to the optic nerves and spinal cord are unknown. Serological and clinical evidence of B cell autoimmunity has been observed in a high proportion of patients with NMO. The purpose of this study was to investigate the importance of humoral mechanisms, including complement activation, in producing the necrotizing demyelination seen in the spinal cord and optic nerves. Eighty-two lesions were examined from nine autopsy cases of clinically confirmed Devic's disease. Demyelinating activity in the lesions was immunocytochemically classified as early active (21 lesions), late active (18 lesions), inactive (35 lesions) or remyelinating (eight lesions) by examining the antigenic profile of myelin degradation products within macrophages. The pathology of the lesions was analysed using a broad spectrum of immunological and neurobiological markers, and lesions were defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction and the immunopathological evidence of complement activation. The pathology was identical in all nine patients. Extensive demyelination was present across multiple spinal cord levels, associated with cavitation, necrosis and acute axonal pathology (spheroids), in both grey and white matter. There was a pronounced loss of oligodendrocytes within the lesions. The inflammatory infiltrates in active lesions were characterized by extensive macrophage infiltration associated with large numbers of perivascular granulocytes and eosinophils and rare CD3(+) and CD8(+) T cells. There was a pronounced perivascular deposition of immunoglobulins (mainly IgM) and complement C9neo antigen in active lesions associated with prominent vascular fibrosis and hyalinization in both active and inactive lesions. The extent of complement activation, eosinophilic infiltration and vascular fibrosis observed in the Devic NMO cases is more prominent compared with that in prototypic multiple sclerosis, and supports a role for humoral immunity in the pathogenesis of NMO. Based on this study, future therapeutic strategies designed to limit the deleterious effects of complement activation, eosinophil degranulation and neutrophil/macrophage/microglial activation are worthy of further investigation.

The slow afterhyperpolarization that follows an action potential is generated by the activation of small-conductance calcium-activated potassium channels (SK channels). The slow afterhyperpolarization limits the firing frequency of repetitive action potentials (spike-frequency adaptation) and is essential for normal neurotransmission. SK channels are voltage-independent and activated by submicromolar concentrations of intracellular calcium. They are high-affinity calcium sensors that transduce fluctuations in intracellular calcium concentrations into changes in membrane potential. Here we study the mechanism of calcium gating and find that SK channels are not gated by calcium binding directly to the channel alpha-subunits. Instead, the functional SK channels are heteromeric complexes with calmodulin, which is constitutively associated with the alpha-subunits in a calcium-independent manner. Our data support a model in which calcium gating of SK channels is mediated by binding of calcium to calmodulin and subsequent conformational alterations in the channel protein.

1. The electrical activity of Purkinje cells was studied in guinea-pig cerebellar slices in vitro. Intracellular recordings from Purkinje cell somata were obtained under direct vision, and antidromic, synaptic and direct electroresponsiveness was demonstrated. Synaptic potentials produced by the activation of the climbing fibre afferent could be reversed by direct membrane depolarization. 2. Input resistance of impaled neurones ranged from 10 to 19 M omega and demonstrated non-linearities in both hyperpolarizing and depolarizing directions. 3. Direct activation of a Purkinje cell indicated that repetitive firing of fast somatic spikes (s.s.) occurs, after a threshold, with a minimum spike frequency of about 30 spikes/sec, resembling the '2-class' response of crab nerve (Hodgkin, 1948). 4. As the amplitude of the stimulus was increased, a second form of electroresponsiveness characterized by depolarizing spike bursts (d.s.b.) was observed and was often accomppanied by momentary inactivation of the s.s. potentials. Upon application of tetrodotoxin (TTX) or removal of Na+ ions from the superfusion fluid, the s.s. potentials were abolished while the burst responses remained intact. However, Ca conductance blockers such as Co, Cd, Mn and D600, or the replacement of Ca by Mg, completely abolish d.s.b.s. 5. If Ca conductance was blocked, or Ca removed from the superfusion fluid without blockage of Na conductance, two types of Na-dependent electroresponsiveness were seen: (a) the s.s. potentials and (b) slow rising all-or-none responses which reached plateau at approximately -15 mV and could last for several seconds. These all-or-none Na-dependent plateau depolarizations outlasted the stimulus and were accompanied by a large increase in membrane conductance. Within certain limits the rate of rise and amplitude of the plateau were independent of stimulus strength. The latency, however, was shortened as stimulus amplitude was increased. These potentials were blocked by TTX or by Na-free solutions. 6. Substitution of extracellular Ca by Ba or intracellular injection of tetraethylammonium generated prolonged action potentials lasting for several seconds and showing a plateau more ositive than those obtained in norrmal circumstances by either non-inactivating Na or Ca currents. 7. Spontaneous firing of the Purkinje cell was characterized by burst-like activity consisting of both s.s. and d.s.b. responses. Addition of TTX to the bath left the basic spontaneous activity and its frequency unaltered, indicating tha Ca spiking and Ca-dependent K conductance changes are the main events underlying this oscillatory behaviour. 8...

Despite the frequent detection of circulating tumor antigen-specific T cells, either spontaneously or following active immunization or adoptive transfer, immune-mediated cancer regression occurs only in the minority of patients. One theoretical rate-limiting step is whether effector T cells successfully migrate into metastatic tumor sites. Affymetrix gene expression profiling done on a series of metastatic melanoma biopsies revealed a major segregation of samples based on the presence or absence of T-cell-associated transcripts. The presence of lymphocytes correlated with the expression of defined chemokine genes. A subset of six chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8(+) effector T cells, and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8(+) effector cells in vitro. Screening by chemokine protein array identified a subset of melanoma cell lines that produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8(+) effector T cells when implanted as xenografts in nonobese diabetic/severe combined immunodeficient mice in vivo. Chemokine blockade with specific antibodies inhibited migration of CD8(+) T cells. Our results suggest that lack of critical chemokines in a subset of melanoma metastases may limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity.

Dengue and chikungunya are increasing global public health concerns due to their rapid geographical spread and increasing disease burden. Knowledge of the contemporary distribution of their shared vectors, Aedes aegypti and Aedes albopictus remains incomplete and is complicated by an ongoing range expansion fuelled by increased global trade and travel. Mapping the global distribution of these vectors and the geographical determinants of their ranges is essential for public health planning. Here we compile the largest contemporary database for both species and pair it with relevant environmental variables predicting their global distribution. We show Aedes distributions to be the widest ever recorded; now extensive in all continents, including North America and Europe. These maps will help define the spatial limits of current autochthonous transmission of dengue and chikungunya viruses. It is only with this kind of rigorous entomological baseline that we can hope to project future health impacts of these viruses.

Thrombospondin-1 (TSP-1) is a naturally occurring inhibitor of angiogenesis that limits vessel density in normal tissues and curtails tumor growth. Here, we show that the inhibition of angiogenesis in vitro and in vivo and the induction of apoptosis by thrombospondin-1 all required the sequential activation of CD36, p59fyn, caspase-3 like proteases and p38 mitogen-activated protein kinases. We also detected increased endothelial cell apoptosis in situ at the margins of tumors in mice treated with thrombospondin-1. These results indicate that thrombospondin-1, and possibly other broad-spectrum natural inhibitors of angiogenesis, act in vivo by inducing receptor-mediated apoptosis in activated microvascular endothelial cells.

The cellular stress response is a universal mechanism of extraordinary physiological/pathophysiological significance. It represents a defense reaction of cells to damage that environmental forces inflict on macromolecules. Many aspects of the cellular stress response are not stressor specific because cells monitor stress based on macromolecular damage without regard to the type of stress that causes such damage. Cellular mechanisms activated by DNA damage and protein damage are interconnected and share common elements. Other cellular responses directed at re-establishing homeostasis are stressor specific and often activated in parallel to the cellular stress response. All organisms have stress proteins, and universally conserved stress proteins can be regarded as the minimal stress proteome. Functional analysis of the minimal stress proteome yields information about key aspects of the cellular stress response, including physiological mechanisms of sensing membrane lipid, protein, and DNA damage; redox sensing and regulation; cell cycle control; macromolecular stabilization/repair; and control of energy metabolism. In addition, cells can quantify stress and activate a death program (apoptosis) when tolerance limits are exceeded.

This review offers an introduction to the principles and generic applications of FT-ICR mass spectrometry, directed to readers with no prior experience with the technique. We are able to explain the fundamental FT-ICR phenomena from a simplified theoretical treatment of ion behavior in idealized magnetic and electric fields. The effects of trapping voltage, trap size and shape, and other nonidealities are manifested mainly as perturbations that preserve the idealized ion behavior modified by appropriate numerical correction factors. Topics include: effect of ion mass, charge, magnetic field, and trapping voltage on ion cyclotron frequency; excitation and detection of ICR signals; mass calibration; mass resolving power and mass accuracy; upper mass limit(s); dynamic range; detection limit, strategies for mass and energy selection for MSn; ion axialization, cooling, and remeasurement; and means for guiding externally formed ions into the ion trap. The relation of FT-ICR MS to other types of Fourier transform spectroscopy and to the Paul (quadrupole) ion trap is described. The article concludes with selected applications, an appendix listing accurate fundamental constants needed for ultrahigh-precision analysis, and an annotated list of selected reviews and primary source publications that describe in further detail various FT-ICR MS techniques and applications.

The National High Blood Pressure Education Program Coordinating Committee published its first statement on the primary prevention of hypertension in 1993. This article updates the 1993 report, using new and further evidence from the scientific literature. Current recommendations for primary prevention of hypertension involve a population-based approach and an intensive targeted strategy focused on individuals at high risk for hypertension. These 2 strategies are complementary and emphasize 6 approaches with proven efficacy for prevention of hypertension: engage in moderate physical activity; maintain normal body weight; limit alcohol consumption; reduce sodium intake; maintain adequate intake of potassium; and consume a diet rich in fruits, vegetables, and low-fat dairy products and reduced in saturated and total fat. Applying these approaches to the general population as a component of public health and clinical practice can help prevent blood pressure from increasing and can help decrease elevated blood pressure levels for those with high normal blood pressure or hypertension.

Metastatic disease remains the primary cause of death for patients with breast cancer. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and their microenvironment. Within this local microenvironment and in distant organs, immune cells and their mediators are known to facilitate metastasis formation. However, the precise contribution of tumour-induced systemic inflammation to metastasis and the mechanisms regulating systemic inflammation are poorly understood. Here we show that tumours maximize their chance of metastasizing by evoking a systemic inflammatory cascade in mouse models of spontaneous breast cancer metastasis. We mechanistically demonstrate that interleukin (IL)-1β elicits IL-17 expression from gamma delta (γδ) T cells, resulting in systemic, granulocyte colony-stimulating factor (G-CSF)-dependent expansion and polarization of neutrophils in mice bearing mammary tumours. Tumour-induced neutrophils acquire the ability to suppress cytotoxic T lymphocytes carrying the CD8 antigen, which limit the establishment of metastases. Neutralization of IL-17 or G-CSF and absence of γδ T cells prevents neutrophil accumulation and downregulates the T-cell-suppressive phenotype of neutrophils. Moreover, the absence of γδ T cells or neutrophils profoundly reduces pulmonary and lymph node metastases without influencing primary tumour progression. Our data indicate that targeting this novel cancer-cell-initiated domino effect within the immune system--the γδ T cell/IL-17/neutrophil axis--represents a new strategy to inhibit metastatic disease.

BACKGROUND

Intravenous bolus fluorouracil plus leucovorin is the standard adjuvant treatment for colon cancer. The oral fluoropyrimidine capecitabine is an established alternative to bolus fluorouracil plus leucovorin as first-line treatment for metastatic colorectal cancer. We evaluated capecitabine in the adjuvant setting.

METHODS

We randomly assigned a total of 1987 patients with resected stage III colon cancer to receive either oral capecitabine (1004 patients) or bolus fluorouracil plus leucovorin (Mayo Clinic regimen; 983 patients) over a period of 24 weeks. The primary efficacy end point was at least equivalence in disease-free survival; the primary safety end point was the incidence of grade 3 or 4 toxic effects due to fluoropyrimidines.

RESULTS

Disease-free survival in the capecitabine group was at least equivalent to that in the fluorouracil-plus-leucovorin group (in the intention-to-treat analysis, P<0.001 for the comparison of the upper limit of the hazard ratio with the noninferiority margin of 1.20). Capecitabine improved relapse-free survival (hazard ratio, 0.86; 95 percent confidence interval, 0.74 to 0.99; P=0.04) and was associated with significantly fewer adverse events than fluorouracil plus leucovorin (P<0.001).

CONCLUSIONS

Oral capecitabine is an effective alternative to intravenous fluorouracil plus leucovorin in the adjuvant treatment of colon cancer.

The consequences of cardiac excitation-contraction coupling by calcium-induced calcium release were studied theoretically, using a series of idealized models solved by analytic and numerical methods. "Common-pool" models, those in which the trigger calcium and released calcium pass through a common cytosolic pool, gave nearly all-or-none regenerative calcium releases (in disagreement with experiment), unless their loop gain was made sufficiently low that it provided little amplification of the calcium entering through the sarcolemma. In the linear (small trigger) limit, it was proven rigorously that no common-pool model can give graded high amplification unless it is operated on the verge of spontaneous oscillation. To circumvent this problem, we considered two types of "local-control" models. In the first type, the local calcium from a sarcolemmal L-type calcium channel directly stimulates a single, immediately opposed SR calcium release channel. This permits high amplification without regeneration, but requires high conductance of the SR channel. This problem is avoided in the second type of local control model, in which one L-type channel triggers a regenerative cluster of several SR channels. Statistical recruitment of clusters results in graded response with high amplification. In either type of local-control model, the voltage dependence of SR calcium release is not exactly the same as that of the macroscopic sarcolemmal calcium current, even though calcium is the only trigger for SR release. This results from the existence of correlations between the stochastic openings of individual sarcolemmal and SR channels. Propagation of regenerative calcium-release waves (under conditions of calcium overload) was analyzed using analytically soluble models in which SR calcium release was treated phenomenalogically. The range of wave velocities observed experimentally is easily explained; however, the observed degree of refractoriness to wave propagation requires either a strong dependence of SR calcium release on the rate of rise of cytosolic calcium or localization of SR release sites to one point in the sarcomere. We conclude that the macroscopic behavior of calcium-induced calcium release depends critically on the spatial relationships among sarcolemmal and SR calcium channels, as well as on their kinetics.

Networks and the epidemiology of directly transmitted infectious diseases are fundamentally linked. The foundations of epidemiology and early epidemiological models were based on population wide random-mixing, but in practice each individual has a finite set of contacts to whom they can pass infection; the ensemble of all such contacts forms a 'mixing network'. Knowledge of the structure of the network allows models to compute the epidemic dynamics at the population scale from the individual-level behaviour of infections. Therefore, characteristics of mixing networks-and how these deviate from the random-mixing norm-have become important applied concerns that may enhance the understanding and prediction of epidemic patterns and intervention measures. Here, we review the basis of epidemiological theory (based on random-mixing models) and network theory (based on work from the social sciences and graph theory). We then describe a variety of methods that allow the mixing network, or an approximation to the network, to be ascertained. It is often the case that time and resources limit our ability to accurately find all connections within a network, and hence a generic understanding of the relationship between network structure and disease dynamics is needed. Therefore, we review some of the variety of idealized network types and approximation techniques that have been utilized to elucidate this link. Finally, we look to the future to suggest how the two fields of network theory and epidemiological modelling can deliver an improved understanding of disease dynamics and better public health through effective disease control.

Multivariate analysis methods such as independent component analysis (ICA) have been applied to the analysis of functional magnetic resonance imaging (fMRI) data to study brain function. Because of the high dimensionality and high noise level of the fMRI data, order selection, i.e., estimation of the number of informative components, is critical to reduce over/underfitting in such methods. Dependence among fMRI data samples in the spatial and temporal domain limits the usefulness of the practical formulations of information-theoretic criteria (ITC) for order selection, since they are based on likelihood of independent and identically distributed (i.i.d.) data samples. To address this issue, we propose a subsampling scheme to obtain a set of effectively i.i.d. samples from the dependent data samples and apply the ITC formulas to the effectively i.i.d. sample set for order selection. We apply the proposed method on the simulated data and show that it significantly improves the accuracy of order selection from dependent data. We also perform order selection on fMRI data from a visuomotor task and show that the proposed method alleviates the over-estimation on the number of brain sources due to the intrinsic smoothness and the smooth preprocessing of fMRI data. We use the software package ICASSO (Himberg et al. [ 2004]: Neuroimage 22:1214-1222) to analyze the independent component (IC) estimates at different orders and show that, when ICA is performed at overestimated orders, the stability of the IC estimates decreases and the estimation of task related brain activations show degradation.