A systematic review of the literature examining the diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma

BACKGROUND: Fractionated plasma metanephrine measurements are commonly used in biochemical testing in search of pheochromocytoma. METHODS: We aimed to critically appraise the diagnostic efficacy of fractionated plasma free metanephrine measurements in detecting pheochromocytoma. Nine electronic databases, meeting abstracts, and the Science Citation Index were searched and supplemented with previously unpublished data. Methodologic and reporting quality was independently assessed by two endocrinologists using a checklist developed by the Standards for Reporting of Diagnostic Studies Accuracy Group and data were independently abstracted. RESULTS: Limitations in methodologic quality were noted in all studies. In all subjects (including those with genetic predisposition): the sensitivities for detection of pheochromocytoma were 96%-100% (95% CI ranged from 82% to 100%), whereas the specificities were 85%-100% (95% CI ranged from 78% to 100%). Statistical heterogeneity was noted upon pooling positive likelihood ratios when those with predisposition to disease were included (p < 0.001). However, upon pooling the positive or negative likelihood ratios for patients with sporadic pheochromocytoma (n = 191) or those at risk for sporadic pheochromocytoma (n = 718), no statistical heterogeneity was noted (p = 0.4). For sporadic subjects, the pooled positive likelihood ratio was 5.77 (95% CI = 4.90, 6.81) and the pooled negative likelihood ratio was 0.02 (95% CI = 0.01, 0.07). CONCLUSION: Negative plasma fractionated free metanephrine measurements are effective in ruling out pheochromocytoma. However, a positive test result only moderately increases suspicion of disease, particularly when screening for sporadic pheochromocytoma.     

Physical schemata underlying biological pattern formation-examples, issues and strategies

Biological systems excel at building spatial structures on scales ranging from nanometers to kilometers and exhibit temporal patterning from milliseconds to years. One approach that nature has taken to accomplish this relies on the harnessing of pattern-forming processes of non-equilibrium physics and chemistry. For these systems, the study of biological pattern formation starts with placing a biological phenomenon of interest within the context of the proper pattern-formation schema and then focusing on the ways in which control is exerted to adapt the pattern to the needs of the organism. This approach is illustrated by several examples, notably bacterial colonies (diffusive-growth schema) and intracellular calcium waves (excitable-media schema).     

Development by self-digestion: molecular mechanisms and biological functions of autophagy

Autophagy is the major cellular pathway for the degradation of long-lived proteins and cytoplasmic organelles. It involves the rearrangement of subcellular membranes to sequester cargo for delivery to the lysosome where the sequestered material is degraded and recycled. For many decades, it has been known that autophagy occurs in a wide range of eukaryotic organisms and in multiple different cell types during starvation, cellular and tissue remodeling, and cell death. However, until recently, the functions of autophagy in normal development were largely unknown. The identification of a set of evolutionarily conserved genes that are essential for autophagy has opened up new frontiers for deciphering the role of autophagy in diverse biological processes. In this review, we summarize our current knowledge about the molecular machinery of autophagy and the role of the autophagic machinery in eukaryotic development.     

Mechanisms underlying the impacts of exotic plant invasions

Although the impacts of exotic plant invasions on community structure and ecosystem processes are well appreciated, the pathways or mechanisms that underlie these impacts are poorly understood. Better exploration of these processes is essential to understanding why exotic plants impact only certain systems, and why only some invaders have large impacts. Here, we review over 150 studies to evaluate the mechanisms underlying the impacts of exotic plant invasions on plant and animal community structure, nutrient cycling, hydrology and fire regimes. We find that, while numerous studies have examined the impacts of invasions on plant diversity and composition, less than 5% test whether these effects arise through competition, allelopathy, alteration of ecosystem variables or other processes. Nonetheless, competition was often hypothesized, and nearly all studies competing native and alien plants against each other found strong competitive effects of exotic species. In contrast to studies of the impacts on plant community structure and higher trophic levels, research examining impacts on nitrogen cycling, hydrology and fire regimes is generally highly mechanistic, often motivated by specific invader traits. We encourage future studies that link impacts on community structure to ecosystem processes, and relate the controls over invasibility to the controls over impact.     

Prothrombin binds to the surface of apoptotic,but not viable,cells and serves as a target of lupus anticoagulant autoantibodies

Anti-phospholipid Ab (aPL) are a heterogeneous group of autoantibodies directed against various combinations of phospholipids (PL) and PL-binding proteins. Lupus anticoagulant (LA) Ab, a subset of aPL, exhibit anticoagulant properties in vitro, but are procoagulant in vivo. Most LA Ab are specific for either beta(2)-glycoprotein I (beta(2)GPI) or prothrombin (PT), two PL-binding proteins. We have previously shown that beta(2)GPI and beta(2)GPI-dependent aPL bind specifically to apoptotic, but not viable, thymocytes. In this study, we demonstrate that PT, like beta(2)GPI, binds selectively to the surface of apoptotic, but not viable, Jurkat cells. Furthermore, PT supports the binding of systemic lupus erythematosus-derived polyclonal and murine monoclonal LA Ab to apoptotic cells. Two LA mAb, which differed dramatically in their relative affinities for PT, were studied. Although one mAb (29J3-62) had a high affinity for PT alone, the other (29I4-24) showed minimal reactivity with PT alone and required PL for elevated binding. Monovalent fragments of 29I4-24 reacted with PL-bound PT with high affinity, suggesting that this mAb recognizes a PL-dependent epitope. Despite these differences, PT-dependent binding of both mAb to apoptotic cells was 30-fold greater than that to viable cells. Moreover, binding of PT to apoptotic cells was, itself, increased in the presence of bivalent, but not monovalent, forms of either mAb. In summary, our data demonstrate the following: 1) specific binding of PT to apoptotic cells, an effect enhanced by PT-dependent LA Ab; 2) heterogeneity of PT-dependent LA Ab; and 3) potential pathogenicity of Ab of either low or high affinity for PT.     

Topoisomerase III can serve as the cellular decatenase in Escherichia coli

topB, encoding topoisomerase III, was identified as a high copy suppressor of the temperature-sensitive parC1215 allele, encoding one of the subunits of topoisomerase IV. Overexpression of topoisomerase III at the nonpermissive temperature was shown subsequently to restore timely chromosome decatenation and suppress lethality in strains carrying either temperature-sensitive parE or parC alleles. By developing an assay in vitro for precatenane unlinking, we demonstrated directly that both topoisomerase III and topoisomerase IV were efficient at this task, whereas DNA gyrase was very inefficient at precatenane removal. These observations suggest that precatenane unlinking is sufficient to sustain decatenation of replicating daughter chromosomes in the cell.     

Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons

Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson's disease. To investigate the pathogenic mechanism by which loss of parkin function causes Parkinson's disease, we generated a mouse model bearing a germline disruption in parkin. Parkin-/- mice are viable and exhibit grossly normal brain morphology. Quantitative in vivo microdialysis revealed an increase in extracellular dopamine concentration in the striatum of parkin-/- mice. Intracellular recordings of medium-sized striatal spiny neurons showed that greater currents are required to induce synaptic responses, suggesting a reduction in synaptic excitability in the absence of parkin. Furthermore, parkin-/- mice exhibit deficits in behavioral paradigms sensitive to dysfunction of the nigrostriatal pathway. The number of dopaminergic neurons in the substantia nigra of parkin-/- mice, however, is normal up to the age of 24 months, in contrast to the substantial loss of nigral neurons characteristic of Parkinson's disease. Steady-state levels of CDCrel-1, synphilin-1, and alpha-synuclein, which were identified previously as substrates of the E3 ubiquitin ligase activity of parkin, are unaltered in parkin-/- brains. Together these findings provide the first evidence for a novel role of parkin in dopamine regulation and nigrostriatal function, and a non-essential role of parkin in the survival of nigral neurons in mice.     

Economics versus alleles: balancing integrated pest management and insect resistance management for rotation-resistant western corn rootworm (Coleoptera: Chrysomelidae)

Western corn rootworm, Diabrotica virgifera virgifera LeConte, has overcome crop rotation in several areas of the central United States. We expanded a simple model of adult behavior and population genetics to explain how rotation resistance may have developed and to study ways to manage the western corn rootworm in a landscape of corn, soybean, and winter wheat where evolution of resistance may occur. We modeled six alternative management strategies over a 15-yr time horizon, as well as a strategy involving a 2-yr rotation of corn and soybean in 85% of the landscape, to investigate their effectiveness from both a biological and economic perspective. Generally, resistance to crop rotation evolves in fewer than 15 yr, and the rate of evolution increases as the level of rotated landscape (selection pressure) increases. When resistance is recessive, all six alternative strategies were effective at preventing evolution of rotation resistance. The two most successful strategies were the use of transgenic rotated corn in a 2-yr rotation and a 3-yr rotation of corn, soybean, and wheat with unattractive wheat (for oviposition) preceding corn. Results were most sensitive to increases in the initial allele frequency and modifications of the density-dependent survival function. Economically, three alternative strategies were robust solutions to the problem, if technology fees were not too high. Repellant soybean, attractive rotated corn, and transgenic rotated corn, all in 2-yr rotations, were economically valuable approaches. However, even the currently common 2-yr rotation was economical when resistance was recessive and the actual costs of resistance would not be paid until far in the future.