The Whole Picture: From Isolated to Global MRI Measures of Neurovascular and Neurodegenerative Disease.

Structural magnetic resonance imaging (MRI) has been used to characterise the appearance of the brain in cerebral small vessel disease (SVD), ischaemic stroke, cognitive impairment, and dementia. SVD is a major cause of stroke and dementia; features of SVD include white matter hyperintensities (WMH) of presumed vascular origin, lacunes of presumed vascular origin, microbleeds, and perivascular spaces. Cognitive impairment and dementia have traditionally been stratified into subtypes of varying origin, e.g., vascular dementia versus dementia of the Alzheimer's type (Alzheimer's disease; AD). Vascular dementia is caused by reduced blood flow in the brain, often as a result of SVD, and AD is thought to have its genesis in the accumulation of tau and amyloid-beta leading to brain atrophy. But after early seminal studies in the 1990s found neurovascular disease features in around 30% of AD patients, it is becoming recognised that so-called "mixed pathologies" (of vascular and neurodegenerative origin) exist in many more patients diagnosed with stroke, only one type of dementia, or cognitive impairment. On the back of these discoveries, attempts have recently been made to quantify the full extent of degenerative and vascular disease in the brain in vivo on MRI. The hope being that these "global" methods may one day lead to better diagnoses of disease and provide more sensitive measurements to detect treatment effects in clinical trials. Indeed, the "Total MRI burden of cerebral small vessel disease", the "Brain Health Index" (BHI), and "MRI measure of degenerative and cerebrovascular pathology in Alzheimer disease" have all been shown to have stronger associations with clinical and cognitive phenotypes than individual brain MRI features. This chapter will review individual structural brain MRI features commonly seen in SVD, stroke, and dementia. The relationship between these features and differing clinical and cognitive phenotypes will be discussed along with developments in their measurement and quantification. The chapter will go on to review emerging methods for quantifying the collective burden of structural brain MRI findings and how these "whole picture" methods may lead to better diagnoses of neurovascular and neurodegenerative disorders.

The effect of organohalogen contaminants on western Steller sea lion survival and movement in the Russian Far East.

The western stock of Steller sea lions (Eumetopias jubatus) have experienced dramatic declines since the 1960s, particularly in the western Alaskan and Asian portions, which have continued to decline or stabilized at low levels. Multiple causes for this decline have been proposed and may include anthropogenic contamination from organohalogen contaminants (OCs). These include polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDT), which have not been ruled out as a potential cause for the lack of recovery. The objective of this study was to determine the effects of OCs on survival and movement probabilities estimated in program MARK using resighting data collected from 2003 to 2009. PCBs and DDTs were measured in whole blood from 136 (74 males and 62 females) individually marked, free-ranging pups from four Russian Far East rookeries. The mean concentration of ∑PCB and ∑DDT was 4.25±5.12 and 3.22±4.28 ng g(-1) ww (n=136), respectively, and the average ∑PCB and ∑DDT concentration for those above the aggregate mean (n=44) was 9.25±6.55 and 7.65±5.21 ng g(-1) ww, and those below the aggregate mean (n=92) the concentration was 1.86±0.89 and 1.11±0.65 ng g(-1) ww, respectively. The lowest estimated probabilities of survival occurred in the first year, ranging from 38% to 74%, but increased for ages 1-9, ranging from 82% to 94%. The greatest movement occurred from Medny Island west toward the Kamchatka Peninsula (33%) and to Bering Island (18%), and low movement estimates for other natal rookeries was largely due to minimal resighting effort. The estimated probabilities of resighting varied by location (48%-87%), but had greater precision than survival or movement parameters. Survival and movement were most affected by age and location rather than OCs.

A direct method for computing extreme value (Gumbel) parameters for gapped biological sequence alignments.

We develop a general method for computing extreme value distribution (Gumbel, 1958) parameters for gapped alignments. Our approach uses mixture distribution theory to obtain associated BLOSUM matrices for gapped alignments, which in turn are used for determining significance of gapped alignment scores for pairs of biological sequences. We compare our results with parameters already obtained in the literature.

Relationship of farm salmon, sea lice, and wild salmon populations.

Increased farm salmon production has heightened concerns about the association between disease on farm and wild fish. The controversy is particularly evident in the Broughton Archipelago of Western Canada, where a high prevalence of sea lice (ectoparasitic copepods) was first reported on juvenile wild pink salmon (Oncorhynchus gorbuscha) in 2001. Exposure to sea lice from farmed Atlantic salmon (Salmo salar) was thought to be the cause of the 97% population decline before these fish returned to spawn in 2002, although no diagnostic investigation was done to rule out other causes of mortality. To address the concern that sea lice from fish farms would cause population extinction of wild salmon, we analyzed 10-20 y of fish farm data and 60 y of pink salmon data. We show that the number of pink salmon returning to spawn in the fall predicts the number of female sea lice on farm fish the next spring, which, in turn, accounts for 98% of the annual variability in the prevalence of sea lice on outmigrating wild juvenile salmon. However, productivity of wild salmon is not negatively associated with either farm lice numbers or farm fish production, and all published field and laboratory data support the conclusion that something other than sea lice caused the population decline in 2002. We conclude that separating farm salmon from wild salmon--proposed through coordinated fallowing or closed containment--will not increase wild salmon productivity and that medical analysis can improve our understanding of complex issues related to aquaculture sustainability.

A practical approach for computing the active site of the ribonucleoside hydrolase of E. coli encoded by rihC.

We predict the potential active and catalytic sites, the transition state and how it is stabilized, and the mechanism of rihC ribonucleoside hydrolase of E. coli. Our approach is based on well-known primary sequence analysis techniques. A canonically associated extreme value distribution is used to assess the significance of the prediction. Parameters for the extreme value distribution are computed directly from data. Our practical approach is consistent with known results in the literature. We obtain BLOSUM matrices in a way that is intrinsically tied to the data base, and we employ user-friendly techniques that should be applicable to a range of medically significant scenarios.

Failure of population recovery in relation to disease in Pacific herring.

Following an estimated 60% decline in population abundance in early 1993, recovery of the Pacific herring Clupea pallasii population of Prince William Sound, Alaska, USA, has been impaired by disease. Comprehensive epidemiological study from 1994 through 2002 validated an age-structured assessment (ASA) model of disease and population abundance; from 2003 to 2006, the impact of disease was modeled by analyzing only 2 lesions: ulcers and white foci in the heart. The ASA model identified increased natural mortality since 1993 that can be explained by (1) epidemics associated with ulcers (prevalence about 3%) and the North American strain of viral hemorrhagic septicemia virus (VHSV Type IVa; prevalence up to 14%) in 1994 and 1998 and (2) relatively high prevalence of the mesomycetozoean Ichthyophonus hoferi from 1994 through 2006, including epidemics with the greatest sample prevalence in 2001 (38%, by histopathology) and 2005 (51%, estimated histopathology prevalence). Fourteen other parasites occurred at prevalence > 10%, but none were considered significant contributors to fish mortality. We predict that if natural mortality after 1994 had returned to background levels that best fit the model from 1980 to 1992 (0.25 yr(-1)), population biomass in 2006 would have been 3 times the best estimate, despite relatively poor recruitment since 1994. In conclusion, disease information can be used to explain and predict changes in populations that have confounded traditional fisheries assessment.

Dynamics of prostate cancer stem cells with diffusion and organism response.

We develop a systems based model for prostate cancer, as a sub-system of the organism. We accomplish this in two stages. We first start with a general ODE that includes organism response terms. Then, to account for normally observed spatial diffusion of cell populations, the ODE is extended to a PDE that includes spatial terms. Numerical solutions of the full PDE are provided, and are indicative of traveling wave fronts. This motivates the use of a well known transformation to derive a canonically related (non-linear) system of ODEs for traveling wave solutions. For biological feasibility, we show that the non-negative cone for the traveling wave system is time invariant. We also prove that the traveling waves have a unique global attractor. Biologically, the global attractor would be the limit for the avascular tumor growth. We conclude with comments on clinical implications of the model.

Sustainability in single-species population models.

In this paper, we review the concept of sustainability with regard to a single-species, age-structured fish population with density dependence at some stage of its life history. We trace the development of the view of sustainability through four periods. The classical view of sustainability, prevalent in the 1970s and earlier, developed from deterministic production models, in which equilibrium abundance or biomass is derived as a function of fishing mortality. When there is no fishing mortality, the population equilibrates about its carrying capacity. We show that carrying capacity is the result of reproductive and mortality processes and is not a fixed constant unless these processes are constant. There is usually a fishing mortality, F(MSY), which results in MSY, and a higher value, F(ext), for which the population is eventually driven to extinction. For each F between 0 and F(ext), there is a corresponding sustainable population. From this viewpoint, the primary tool for achieving sustainability is the control of fishing mortality. The neoclassical view of sustainability, developed in the 1980s, involved population models with depensation and stochasticity. This view point is in accord with the perception that a population at a low level is susceptible to collapse or to a lack of rebuilding regardless of fishing. Sustainability occurs in a more restricted range from that in the classical view and includes an abundance threshold. A variety of studies has suggested that fishing mortality should not let a population drop below a threshold at 10-20% of carrying capacity. The modern view of sustainability in the 1990s moves further in the direction of precaution. The fishing mortality limit is the former target of F(MSY) (or some proxy), and the target fishing mortality is set lower. This viewpoint further reduces the range of permissible fishing mortalities and resultant desired population sizes. The objective has shifted from optimizing long-term catch to preserving spawning biomass and egg production for the future. The use of discount rates in objective functions involving catch is not a suitable alternative to protecting reproductive value. As we move into the post-modern time period, new definitions of sustainability will attempt to incorporate he economic and social aspects of fisheries and/or ecosystem and habitat requirements. These definitions now involve "warm and fuzzy" notions (healthy ecosystems and fishing communities, the needs of future generations, diverse fish communities) and value judgements of desired outcomes. Additional work is needed to make these definitions operational and to specify quantitative objectives to be achieved. In addition, multiple objectives may be incompatible, so trade-offs in what constitutes sustainability must be made. The advances made under the single-species approach should not be abandoned in the post-modern era, but rather enhanced and combined with new approaches in the multi-species and economic realms.