Extensive and complex defects of the scalp, middle third of the face, and palate: the role of microsurgical reconstruction

Twenty-one patients with gigantic defects of the scalp and middle third of the face and palate following excision of neglected or recurrent tumors, burns, and infections have undergone microsurgical reconstruction. Wide resection of the middle third of the face, orbit, and palate requires "complex" three-dimensional volume reconstruction, whereas extensive defects of the scalp and skull (exceeding 80 cm2) require coverage of the larger surface area soft-tissue defect and the exposed brain and dura. The latissimus dorsi free-muscle flap and split-thickness skin graft have become our methods of choice for extensive scalp and skull defects. The latissimus dorsi musculocutaneous free flap is preferable for reconstruction of complex palatal and external skin and orbital defects of the middle third of the face. Microsurgical free-tissue transfer reliably frees the oncologic surgeon from the constraints imposed by conventional reconstructive techniques and may therefore allow improved curative or at least palliative resection of these extensive tumors.     

Targeting Apoptosis Signalling Kinase-1 (ASK-1) Does Not Prevent the Development of Neuropathy in Streptozotocin-Induced Diabetic Mice

Apoptosis signal-regulating kinase-1 (ASK1) is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K) which lies upstream of the stress-activated MAPKs, JNK and p38. ASK1 may be activated by a variety of extracellular and intracellular stimuli. MAP kinase activation in the sensory nervous system as a result of diabetes has been shown in numerous preclinical and clinical studies. As a common upstream activator of both p38 and JNK, we hypothesised that activation of ASK1 contributes to nerve dysfunction in diabetic neuropathy. We therefore wanted to characterize the expression of ASK1 in sensory neurons, and determine whether the absence of functional ASK1 would protect against the development of neuropathy in a mouse model of experimental diabetes. ASK1 mRNA and protein is constitutively expressed by multiple populations of sensory neurons of the adult mouse lumbar DRG. Diabetes was induced in male C57BL/6 and transgenic ASK1 kinase-inactive (ASK1n) mice using streptozotocin. Levels of ASK1 do not change in the DRG, spinal cord, or sciatic nerve following induction of diabetes. However, levels of ASK2 mRNA increase in the spinal cord at 4 weeks of diabetes, which could represent a future target for this field. Neither motor nerve conduction velocity deficits, nor thermal or mechanical hypoalgesia were prevented or ameliorated in diabetic ASK1n mice. These results suggest that activation of ASK1 is not responsible for the nerve deficits observed in this mouse model of diabetic neuropathy.     

Influence of muscle-tendon unit structure on rate of force development during the squat, countermovement, and drop jumps

Previous research has highlighted the importance of muscle and tendon structure to stretch shortening cycle performance. However, the relationships between muscle and tendon structure to performance are highly dependent on the speed and intensity of the movement. The purpose of this study was to determine if muscle and tendon structure is associated with the rate of force development (RFD) throughout static squat jump (SJ), countermovement jump (CMJ), and drop jump (DJ; 30-cm height). Twenty-five strength- and power-trained men participated in the study. Using ultrasonography, vastus lateralis (VL) and gastrocnemius (GAS) pennation (PEN) and fascicle length (FL), and Achilles tendon (AT) thickness and length were measured. Subjects then performed SJ, CMJ, and DJ, during which RFD was calculated over time 5 distinct time intervals. During CMJs, early RFD could be predicted between 0 and 10 milliseconds by both GAS-FL (r2 = 0.213, β = 0.461) and AT-length (r2 = 0.191, β = 20.438). Between 10 and 30 milliseconds GAS-FL was a significant predictor of CMJ-RFD (r2 = 0.218, β = 0.476). During DJ, initial RFD (0-10 milliseconds) could be significantly predicted by GAS-FL (r2 = 0.185, β = 20.434), VL-PEN (r2 = 0.189, β = 0.435), and GAS-PEN (r2 = 0.188, β = 0.434). These findings suggest that longer ATs may have increased elasticity, which can decrease initial RFD during CMJ; thus, their use in talent identification is not recommended. The GAS fascicle length had an intensity-dependent relationship with RFD, serving to positively predict RFD during early CMJs and an inverse predictor during early DJs. During DDJs, subjects with greater PEN were better able to redirected initial impact forces. Although both strength and plyometric training have been shown to increase FL, only heavy strength training has been shown to increase PEN. Thus, when a high eccentric load or multiple jumps are required, heavy strength training might be used to elicit muscular adaptations that are suited to fast force production during jumping.     

Likely health outcomes for untreated acute febrile illness in the tropics in decision and economic models; a Delphi survey

Background

Modelling is widely used to inform decisions about management of malaria and acute febrile illnesses. Most models depend on estimates of the probability that untreated patients with malaria or bacterial illnesses will progress to severe disease or death. However, data on these key parameters are lacking and assumptions are frequently made based on expert opinion. Widely diverse opinions can lead to conflicting outcomes in models they inform.

Methods and Findings

A Delphi survey was conducted with malaria experts aiming to reach consensus on key parameters for public health and economic models, relating to the outcome of untreated febrile illnesses. Survey questions were stratified by malaria transmission intensity, patient age, and HIV prevalence. The impact of the variability in opinion on decision models is illustrated with a model previously used to assess the cost-effectiveness of malaria rapid diagnostic tests. Some consensus was reached around the probability that patients from higher transmission settings with untreated malaria would progress to severe disease (median 3%, inter-quartile range (IQR) 1–5%), and the probability that a non-malaria illness required antibiotics in areas of low HIV prevalence (median 20%). Children living in low transmission areas were considered to be at higher risk of progressing to severe malaria (median 30%, IQR 10–58%) than those from higher transmission areas (median 13%, IQR 7–30%). Estimates of the probability of dying from severe malaria were high in all settings (medians 60–73%). However, opinions varied widely for most parameters, and did not converge on resurveying.

Conclusions

This study highlights the uncertainty around potential consequences of untreated malaria and bacterial illnesses. The lack of consensus on most parameters, the wide range of estimates, and the impact of variability in estimates on model outputs, demonstrate the importance of sensitivity analysis for decision models employing expert opinion. Results of such models should be interpreted cautiously. The diversity of expert opinion should be recognised when policy options are debated.     

Mutations in protein-binding hot-spots on the hub protein Smad3 differentially affect its protein interactions and Smad3-regulated gene expression

Background

Hub proteins are connected through binding interactions to many other proteins. Smad3, a mediator of signal transduction induced by transforming growth factor beta (TGF-β), serves as a hub protein for over 50 protein-protein interactions. Different cellular responses mediated by Smad3 are the product of cell-type and context dependent Smad3-nucleated protein complexes acting in concert. Our hypothesis is that perturbation of this spectrum of protein complexes by mutation of single protein-binding hot-spots on Smad3 will have distinct consequences on Smad3-mediated responses.

Methodology/Principal Findings

We mutated 28 amino acids on the surface of the Smad3 MH2 domain and identified 22 Smad3 variants with reduced binding to subsets of 17 Smad3-binding proteins including Smad4, SARA, Ski, Smurf2 and SIP1. Mutations defective in binding to Smad4, e.g., D408H, or defective in nucleocytoplasmic shuttling, e.g., W406A, were compromised in modulating the expression levels of a Smad3-dependent reporter gene or six endogenous Smad3-responsive genes: Mmp9, IL11, Tnfaip6, Fermt1, Olfm2 and Wnt11. However, the Smad3 mutants Y226A, Y297A, W326A, K341A, and E267A had distinct differences on TGF-β signaling. For example, K341A and Y226A both reduced the Smad3-mediated activation of the reporter gene by ∼50% but K341A only reduced the TGF-β inducibilty of Olfm2 in contrast to Y226A which reduced the TGF-β inducibility of all six endogenous genes as severely as the W406A mutation. E267A had increased protein binding but reduced TGF-β inducibility because it caused higher basal levels of expression. Y297A had increased TGF-β inducibility because it caused lower Smad3-induced basal levels of gene expression.

Conclusions/Significance

Mutations in protein binding hot-spots on Smad3 reduced the binding to different subsets of interacting proteins and caused a range of quantitative changes in the expression of genes induced by Smad3. This approach should be useful for unraveling which Smad3 protein complexes are critical for specific biological responses.     

Wet adhesion and adhesive locomotion of snails on anti-adhesive non-wetting surfaces

Creating surfaces capable of resisting liquid-mediated adhesion is extremely difficult due to the strong capillary forces that exist between surfaces. Land snails use this to adhere to and traverse across almost any type of solid surface of any orientation (horizontal, vertical or inverted), texture (smooth, rough or granular) or wetting property (hydrophilic or hydrophobic) via a layer of mucus. However, the wetting properties that enable snails to generate strong temporary attachment and the effectiveness of this adhesive locomotion on modern super-slippy superhydrophobic surfaces are unclear. Here we report that snail adhesion overcomes a wide range of these microscale and nanoscale topographically structured non-stick surfaces. For the one surface which we found to be snail resistant, we show that the effect is correlated with the wetting response of the surface to a weak surfactant. Our results elucidate some critical wetting factors for the design of anti-adhesive and bio-adhesion resistant surfaces.     

Specific changes in total and mitochondrial proteomes are associated with higher levels of heterosis in maize hybrids

The phenomenon of hybrid vigor (heterosis) has long been harnessed by plant breeders to improve world food production. However, the changes that are essential for heterotic responses and the mechanisms responsible for heterosis remain undefined. Large increases in biomass and yield in high-heterosis hybrids suggest that alterations in bioenergetic processes may contribute to heterosis. Progeny from crosses between various inbred lines vary in the extent of vigor observed. Field-grown maize F(1) hybrids that consistently exhibited either low or high heterosis across a variety of environments were examined for changes in proteins that may be correlated with increased plant vigor and yield. Unpollinated ears at the time of flowering (ear shoots) were selected for the studies because they are metabolically active, rich in mitochondria, and the sizes of the ears are diagnostic of yield heterosis. Total protein and mitochondrial proteomes were compared among low- and higher-heterosis hybrids. Two-dimensional difference gel electrophoresis was used to identify allelic and/or isoform differences linked to heterosis. Identification of differentially regulated spots by mass spectrometry revealed proteins involved in stress responses as well as primary carbon and protein metabolism. Many of these proteins were identified in multiple spots, but analysis of their abundances by label-free mass spectrometry suggested that most of the expression differences were due to isoform variation rather than overall protein amount. Thus, our proteomics studies suggest that expression of specific alleles and/or post-translational modification of specific proteins correlate with higher levels of heterosis.