Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Raised arterial blood pressure in neurokinin-1 receptor-deficient mice (NK1R−/−): evidence for a neural rather than a vascular mechanism

NEW FINDINGS: What is the central question of this study? Does genetic ablation of neurokinin-1 receptors alter arterial blood pressure? What is the main finding and its importance? NK1R(-/-) mice have increased mean arterial blood pressure, but without a concomitant change in vascular reactivity. This finding suggests that neurokinin-1 receptors play a role in the neural regulation of blood pressure. Mice with functional ablation of the neurokinin-1 receptor gene, Tacr1, (NK1R(-/-) ) express behavioural abnormalities equivalent to those seen in attention deficit hyperactivity disorder (ADHD). An established model of ADHD is the spontaneously hypertensive rat, which exhibits high blood pressure owing to increased central sympathetic drive. In light of the evidence that the neurokinin-1 receptor (NK1R) also influences cardiovascular haemodynamics, we have investigated whether NK1R(-/-) mice exhibit raised blood pressure. Cardiovascular parameters were recorded for 24 h in conscious mice using radiotelemetry. Vascular function was assessed in mesenteric resistance arteries by wire myography. The NK1R(-/-) mice exhibited a higher blood pressure than wild-type animals throughout the 24 h period. Heart rate and locomotor activity in NK1R(-/-) mice were higher than in wild-type mice during the night period (active phase), consistent with an ADHD-like phenotype, but not during the day. Mesenteric and renal arteries from NK1R(-/-) mice exhibited normal vascular function; the responses to vasoconstrictors (U46619 and phenylephrine) and the endothelium-dependent vasodilator, acetylcholine, were not altered in these animals, suggesting that the NK1R does not regulate vascular tone. Analysis of heart rate variability revealed a higher low-frequency to high-frequency ratio in NK1R(-/-) mice, indicative of increased cardiac sympathetic activity. We propose that the raised blood pressure in NK1R(-/-) mice could be due to a neural mechanism rather than a change in vascular reactivity. Further studies are required to understand this mechanism and to establish whether a subgroup of ADHD patients with polymorphism of the equivalent (TACR1) gene are affected in a similar way

Candida glabrata : a review of its features and resistance

Candida species belong to the normal microbiota of the oral cavity and gastrointestinal and vaginal tracts, and are responsible for several clinical manifestations, from mucocutaneous overgrowth to bloodstream infections. Once believed to be non-pathogenic, Candida glabrata was rapidly blamable for many human diseases. Year after year, these pathological circumstances are more recurrent and problematic to treat, especially when patients reveal any level of immunosuppression. These difficulties arise from the capacity of C. glabrata to form biofilms and also from its high resistance to traditional antifungal therapies. Thus, this review intends to present an excerpt of the biology, epidemiology, and pathology of C. glabrata, and detail an approach to its resistance mechanisms based on studies carried out up to the present.The authors are grateful to strategic project PTDC/SAU-MIC/119069/2010 for the financial support to the research center and for Celia F. Rodrigues' grant

Dispersion as an Important Step in the Candida albicans Biofilm Developmental Cycle

Biofilms are dynamic microbial communities in which transitions between planktonic and sessile modes of growth occur interchangeably in response to different environmental cues. In the last decade, early events associated with C. albicans biofilm formation have received considerable attention. However, very little is known about C. albicans biofilm dispersion or the mechanisms and signals that trigger it. This is important because it is precisely C. albicans cells dispersed from biofilms that are the main culprits associated with candidemia and establishment of disseminated invasive disease, two of the gravest forms of candidiasis. Using a simple flow biofilm model recently developed by our group, we have performed initial investigations into the phenomenon of C. albicans biofilm dispersion, as well as the phenotypic characteristics associated with dispersed cells. Our results indicate that C. albicans biofilm dispersion is dependent on growing conditions, including carbon source and pH of the media used for biofilm development. C. albicans dispersed cells are mostly in the yeast form and display distinct phenotypic properties compared to their planktonic counterparts, including enhanced adherence, filamentation, biofilm formation and, perhaps most importantly, increased pathogenicity in a murine model of hematogenously disseminated candidiasis, thus indicating that dispersed cells are armed with a complete arsenal of “virulence factors” important for seeding and establishing new foci of infection. In addition, utilizing genetically engineered strains of C. albicans (tetO-UME6 and tetO-PES1) we demonstrate that C. albicans biofilm dispersion can be regulated by manipulating levels of expression of these key genes, further supporting the evidence for a strong link between biofilms and morphogenetic conversions at different stages of the C. albicans biofilm developmental cycle. Overall, our results offer novel and important insight into the phenomenon of C. albicans biofilm dispersion, a key part of the biofilm developmental cycle, and provide the basis for its more detailed analysis

Variation in cytokine genes can contribute to severity of acetabular osteolysis and risk for revision in patients with ABG 1 total hip arthroplasty: a genetic association study

<p>Abstract</p> <p>Background</p> <p>The differences in total hip arthroplasty (THA) survivorship may be influenced by individual susceptibility to periprosthetic osteolysis. This may be driven by functional polymorphisms in the genes for cytokines and cytokine receptors involved in the development of osteolysis in THA, thereby having an effect on the individual's phenotype.</p> <p>Methods</p> <p>We performed a study on 22 single-nucleotide polymorphisms (SNPs) for 11 cytokines and two cytokine receptor candidate genes for association with severity of acetabular osteolysis and risk to failure in THA. Samples from 205 unrelated Caucasian patients with cementless type THA (ABG 1) were investigated. Distribution of investigated SNP variants between the groups of mild and severe acetabular osteolysis was determined by univariate and multivariate analysis. Time-dependent output variables were analyzed by the Cox hazards model.</p> <p>Results</p> <p>Univariate analysis showed: 1) <it>TNF</it>-238*A allele was associated with severe osteolysis (odds ratio, OR = 6.59, <it>p </it>= 0.005, population attributable risk, PAR 5.2%); 2) carriers of the <it>IL6</it>-174*G allele were 2.5 times more prone to develop severe osteolysis than non-carriers (OR = 2.51, <it>p </it>= 0.007, PAR = 31.5%); 3) the carriage of <it>IL2</it>-330*G allele was associated with protection from severe osteolysis (OR = 0.55, <it>p </it>= 0.043). Based on logistic regression, the alleles <it>TNF</it>-238*A and <it>IL6</it>-174*G were independent predictors for the development of severe acetabular osteolysis. Carriers of <it>TNF</it>-238*A had increased cumulative hazard of THA failure according to Cox model (<it>p </it>= 0.024). In contrast, <it>IL2</it>-330*G allele predicted lower cumulative hazard of THA failure (<it>p </it>= 0.019).</p> <p>Conclusion</p> <p>Genetic variants of proinflammatory cytokines TNF-alpha and IL-6 confer susceptibility to severe OL. In this way, presence of the minor <it>TNF </it>allele could increase the cumulative risk of THA failure. Conversely, SNP in the <it>IL2 </it>gene may protect carriers from the above THA complications.</p

In vitro activities of natural products against oral Candida isolates from denture wearers

Background: Candida-associated denture stomatitis is a frequent infectious disease. Treatment of this oral condition is difficult because failures and recurrences are common. The aim of this study was to test the in vitro antifungal activity of pure constituents of essentials oils. -- Methods: Eight terpenic derivatives (carvacrol, farnesol, geraniol, linalool, menthol, menthone, terpinen-4-ol, and aterpineol), a phenylpropanoid (eugenol), a phenethyl alcohol (tyrosol) and fluconazole were evaluated against 38 Candida isolated from denture-wearers and 10 collection Candida strains by the CLSI M27-A3 broth microdilution method. -- Results: Almost all the tested compounds showed antifungal activity with MIC ranges of 0.03-0.25% for eugenol and linalool, 0.03-0.12% for geraniol, 0.06-0.5% for menthol, a-terpineol and terpinen-4-ol, 0.03-0.5% for carvacrol, and 0.06-4% for menthone. These compounds, with the exception of farnesol, menthone and tyrosol, showed important in vitro activities against the fluconazole-resistant and susceptible-dose dependent Candida isolates. -- Conclusions: Carvacrol, eugenol, geraniol, linalool and terpinen-4-ol were very active in vitro against oral Candida isolates. Their fungistatic and fungicidal activities might convert them into promising alternatives for the topic treatment of oral candidiasis and denture stomatitis.Funding: this work has been funded in part by projects GIC07 123-IT-222-07 (Departamento de Educacion, Universidades e Investigacion, Gobierno Vasco), S-PR09UN01 and S-PR10UN03 (Saiotek 2009 and 2010, Departamento de Industria, Comercio y Turismo, Gobierno Vasco)

Nutrition in children with CRF and on dialysis

The objectives of this study are: (1) to understand the importance of nutrition in normal growth; (2) to review the methods of assessing nutritional status; (3) to review the dietary requirements of normal children throughout childhood, including protein, energy, vitamins and minerals; (4) to review recommendations for the nutritional requirements of children with chronic renal failure (CRF) and on dialysis; (5) to review reports of spontaneous nutritional intake in children with CRF and on dialysis; (6) to review the epidemiology of nutritional disturbances in renal disease, including height, weight and body composition; (7) to review the pathological mechanisms underlying poor appetite, abnormal metabolic rate and endocrine disturbances in renal disease; (8) to review the evidence for the benefit of dietetic input, dietary supplementation, nasogastric and gastrostomy feeds and intradialytic nutrition; (9) to review the effect of dialysis adequacy on nutrition; (10) to review the effect of nutrition on outcome

ε/ζ systems: their role in resistance, virulence, and their potential for antibiotic development

Cell death in bacteria can be triggered by activation of self-inflicted molecular mechanisms. Pathogenic bacteria often make use of suicide mechanisms in which the death of individual cells benefits survival of the population. Important elements for programmed cell death in bacteria are proteinaceous toxin–antitoxin systems. While the toxin generally resides dormant in the bacterial cytosol in complex with its antitoxin, conditions such as impaired de novo synthesis of the antitoxin or nutritional stress lead to antitoxin degradation and toxin activation. A widespread toxin–antitoxin family consists of the ε/ζ systems, which are distributed over plasmids and chromosomes of various pathogenic bacteria. In its inactive state, the bacteriotoxic ζ toxin protein is inhibited by its cognate antitoxin ε. Upon degradation of ε, the ζ toxin is released allowing this enzyme to poison bacterial cell wall synthesis, which eventually triggers autolysis. ε/ζ systems ensure stable plasmid inheritance by inducing death in plasmid-deprived offspring cells. In contrast, chromosomally encoded ε/ζ systems were reported to contribute to virulence of pathogenic bacteria, possibly by inducing autolysis in individual cells under stressful conditions. The capability of toxin–antitoxin systems to kill bacteria has made them potential targets for new therapeutic compounds. Toxin activation could be hijacked to induce suicide of bacteria. Likewise, the unique mechanism of ζ toxins could serve as template for new drugs. Contrarily, inhibition of virulence-associated ζ toxins might attenuate infections. Here we provide an overview of ε/ζ toxin–antitoxin family and its potential role in the development of new therapeutic approaches in microbial defense