Unilateral abducens nerve palsy: A presenting sign of sphenoid sinus mucocoeles

Sphenoid sinus mucocoeles can stimulate a variety of pathological conditions and patients can present to a range of specialists. Because of the relative rarity of sphenoid sinus mucocoeles, diagnosis is often delayed and these lesions can progressively expand and cause direct mechanical compression on adjacent structures. We present three cases which presented with an abducens nerve palsy. Early surgical intervention is advocated and these patients' symptoms resolved following surgery. Although several conditions can present with an abducens nerve palsy, it is important to consider a sphenoid sinus mucocoele in the differential diagnosis

A mechanistic explanation of the transition to simple multicellularity in fungi.

Development of multicellularity was one of the major transitions in evolution and occurred independently multiple times in algae, plants, animals, and fungi. However recent comparative genome analyses suggest that fungi followed a different route to other eukaryotic lineages. To understand the driving forces behind the transition from unicellular fungi to hyphal forms of growth, we develop a comparative model of osmotrophic resource acquisition. This predicts that whenever the local resource is immobile, hard-to-digest, and nutrient poor, hyphal osmotrophs outcompete motile or autolytic unicellular osmotrophs. This hyphal advantage arises because transporting nutrients via a contiguous cytoplasm enables continued exploitation of remaining resources after local depletion of essential nutrients, and more efficient use of costly exoenzymes. The model provides a mechanistic explanation for the origins of multicellular hyphal organisms, and explains why fungi, rather than unicellular bacteria, evolved to dominate decay of recalcitrant, nutrient poor substrates such as leaf litter or wood

Mitochondrial network state scales mtDNA genetic dynamics

Mitochondrial DNA (mtDNA) mutations cause severe congenital diseases but may also be associated with healthy aging. MtDNA is stochastically replicated and degraded, and exists within organelles which undergo dynamic fusion and fission. The role of the resulting mitochondrial networks in the time evolution of the cellular proportion of mutated mtDNA molecules (heteroplasmy), and cell-to-cell variability in heteroplasmy (heteroplasmy variance), remains incompletely understood. Heteroplasmy variance is particularly important since it modulates the number of pathological cells in a tissue. Here, we provide the first wide-reaching theoretical framework which bridges mitochondrial network and genetic states. We show that, under a range of conditions, the (genetic) rate of increase in heteroplasmy variance and de novo mutation are proportionally modulated by the (physical) fraction of unfused mitochondria, independently of the absolute fission-fusion rate. In the context of selective fusion, we show that intermediate fusion/fission ratios are optimal for the clearance of mtDNA mutants. Our findings imply that modulating network state, mitophagy rate and copy number to slow down heteroplasmy dynamics when mean heteroplasmy is low could have therapeutic advantages for mitochondrial disease and healthy aging

Stochastic survival of the densest and mitochondrial DNA clonal expansion in aging.

The expansion of mitochondrial DNA molecules with deletions has been associated with aging, particularly in skeletal muscle fibers; its mechanism has remained unclear for three decades. Previous accounts have assigned a replicative advantage (RA) to mitochondrial DNA containing deletion mutations, but there is also evidence that cells can selectively remove defective mitochondrial DNA. Here we present a spatial model that, without an RA, but instead through a combination of enhanced density for mutants and noise, produces a wave of expanding mutations with speeds consistent with experimental data. A standard model based on RA yields waves that are too fast. We provide a formula that predicts that wave speed drops with copy number, consonant with experimental data. Crucially, our model yields traveling waves of mutants even if mutants are preferentially eliminated. Additionally, we predict that mutant loads observed in single-cell experiments can be produced by de novo mutation rates that are drastically lower than previously thought for neutral models. Given this exemplar of how spatial structure (multiple linked mtDNA populations), noise, and density affect muscle cell aging, we introduce the mechanism of stochastic survival of the densest (SSD), an alternative to RA, that may underpin other evolutionary phenomena

Evidence that conflict regarding size of haemodynamic response to interventricular delay optimization of cardiac resynchronization therapy may arise from differences in how atrioventricular delay is kept constant.

Aims: Whether adjusting interventricular (VV) delay changes haemodynamic efficacy of cardiac resynchronization therapy (CRT) is controversial, with conflicting results. This study addresses whether the convention for keeping atrioventricular (AV) delay constant during VV optimization might explain these conflicts. / Method and results: Twenty-two patients in sinus rhythm with existing CRT underwent VV optimization using non-invasive systolic blood pressure. Interventricular optimization was performed with four methods for keeping the AV delay constant: (i) atrium and left ventricle delay kept constant, (ii) atrium and right ventricle delay kept constant, (iii) time to the first-activated ventricle kept constant, and (iv) time to the second-activated ventricle kept constant. In 11 patients this was performed with AV delay of 120 ms, and in 11 at AV optimum. At AV 120 ms, time to the first ventricular lead (left or right) was the overwhelming determinant of haemodynamics (13.75 mmHg at ±80 ms, P < 0.001) with no significant effect of time to second lead (0.47 mmHg, P = 0.50), P < 0.001 for difference. At AV optimum, time to first ventricular lead again had a larger effect (5.03 mmHg, P < 0.001) than time to second (2.92 mmHg, P = 0.001), P = 0.02 for difference. / Conclusion: Time to first ventricular activation is the overwhelming determinant of circulatory function, regardless of whether this is the left or right ventricular lead. If this is kept constant, the effect of changing time to the second ventricle is small or nil, and is not beneficial. In practice, it may be advisable to leave VV delay at zero. Specifying how AV delay is kept fixed might make future VV delay research more enlightening

Intergenerational effects of ocean temperature variation: Early life benefits are short-lived in threespine stickleback

Current climate change models predict an increase in temperature variability and extreme events such as heatwaves, and organisms need to cope with consequent changes to environmental variation. Non-genetic inheritance mechanisms can enable parental generations to prime their offspring’s abilities to acclimate to environmental change–but they may also be deleterious. When parents are exposed to predictable environments, intergenerational plasticity can lead to better offspring trait performance in matching environments. Alternatively, parents exposed to variable or unpredictable environments may use plastic bet-hedging strategies to adjust the phenotypic variance among offspring. Here, we used a model species, the threespine stickleback (Gasterosteus aculeatus), to test whether putatively adaptive intergenerational effects can occur in response to shifts in environmental variation as well as to shifts in environmental mean, and whether parents employ plastic bet-hedging strategies in response to increasing environmental variation. We used a full-factorial, split-clutch experiment with parents and offspring exposed to three temperature regimes: constant, natural variation, and increased variation. We show that within-generation exposure to increased temperature variation reduces growth of offspring, but having parents that were exposed to natural temperature variation during gametogenesis may offset some early-life negative growth effects. However, these mitigating intergenerational effects do not appear to persist later in life. We found no indication that stickleback mothers plastically altered offspring phenotypic variance (egg size or clutch size) in response to temperature variation. However, lower inter-individual variance of juvenile fish morphology in offspring of increased variation parents may imply the presence of conservative bet-hedging strategies in natural populations. Overall, in our experiment, parental exposure to temperature variation had limited effects on offspring fitness-related traits. Natural levels of environmental variation promoted a potentially adaptive intergenerational response in early life development, but under more challenging conditions associated with increased environmental variation, the effect was lost.</jats:p

Evolution of cell-to-cell variability in stochastic, controlled, heteroplasmic mtDNA populations

Populations of physiologically vital mitochondrial DNA (mtDNA) molecules evolve in cells under control from the nucleus. The evolution of populations of mixed mtDNA types is complicated and poorly understood, and variability of these controlled admixtures plays a central role in the inheritance and onset of genetic disease. Here, we develop a mathematical theory describing the evolution of, and variability in, these stochastic populations for any type of cellular control, showing that cell-to-cell variability in mtDNA and mutant load inevitably increases with time, according to rates that we derive and which are notably independent of the mechanistic details of feedback signaling. We show with a set of experimental case studies that this theory explains disparate quantitative results from classical and modern experimental and computational research on heteroplasmy variance in different species. We demonstrate that our general model provides a host of specific insights, including a modification of the often-used but hard-to-interpret Wright formula to correspond directly to biological observables, the ability to quantify selective and mutational pressure in mtDNA populations, and characterization of the pronounced variability inevitably arising from the action of possible mtDNA quality-control mechanisms. Our general theoretical framework, supported by existing experimental results, thus helps us to understand and predict the evolution of stochastic mtDNA populations in cell biology

Does Gender Discrimination Impact Regular Mammography Screening? Findings from the Race Differences in Screening Mammography Study

Objective: To determine if gender discrimination, conceptualized as a negative life stressor, is a deterrent to adherence to mammography screening guidelines. Methods: African American and white women (1451) aged 40–79 years who obtained an index screening mammogram at one of five urban hospitals in Connecticut between October 1996 and January 1998 were enrolled in this study. This logistic regression analysis includes the 1229 women who completed telephone interviews at baseline and follow-up (average 29.4 months later) and for whom the study outcome, nonadherence to age-specific mammography screening guidelines, was determined. Gender discrimination was measured as lifetime experience in seven possible situations. Results: Gender discrimination, reported by nearly 38% of the study population, was significantly associated with non-adherence to mammography guidelines in women with annual family incomes of $50,000 or greater (or 1.99, 95% CI 1.33, 2.98) and did not differ across racial/ethnic groups. Conclusions: Our findings suggest that gender discrimination can adversely influence regular mammography screening in some women. With nearly half of women nonadherent to screening mammography guidelines in this study and with decreasing mammography rates nationwide, it is important to address the complexity of nonadherence across subgroups of women. Life stressors, such as experiences of gender discrimination, may have considerable consequences, potentially influencing health prevention prioritization in women