Influence of pregnancy and smoking on brachial artery flow-mediated dilation values and time until maximum response

To evaluate the effect of pregnancy and smoking on endothelial function using brachial artery flow-mediated dilation (FMD) and to determine the time necessary until the occurrence of maximum brachial artery dilation after stimulus. This study was an observational study evaluating 133 women, who were grouped as follows: non-smoking pregnant women (N = 47), smoking pregnant women (N = 33), non-smoking women (N = 34), and smoking pregnant women (N = 19). The diameter of the brachial artery was measured at baseline and at 30, 60, 90 and 120 s after stimulus. The relative change of brachial artery was determined for each of these four moments. FMD measured at 60 s after stimulus was compared between the groups. The maximum FMD was observed at 60 s after cuff release in all groups. FMD was greater among non-smoking pregnant women compared to smoking pregnant women (11.50 +/- A 5.77 vs. 8.74 +/- A 4.83; p = 0.03) and also between non-smoking non-pregnant women compared to smoking non-pregnant women (10.52 +/- A 4.76 vs. 7.21 +/- A 5.57; p = 0.03). Maximum FMD was observed approximately 60 s after stimulus in all groups regardless of smoking and pregnancy status. The smoking habit seems to lead to endothelial dysfunction both in pregnant and non-pregnant women, as demonstrated by the lower FMD in smokers.

Transcriptional profiling reveals genes in the human pathogen Trichophyton rubrum that are expressed in response to pH signaling

Trichophyton rubrum is a dermatophyte that infects human skin and nails. Its growth on keratin as its carbon source shifts the ambient pH from acidic to alkaline, which may be an efficient strategy for its successful infection and maintenance in the host. In this study, we used suppression subtractive hybridization to identify genes preferentially expressed in T rubrum incubated at either pH 5.0 or pH 8.0. The functional grouping of the 341 overexpressed unigenes indicated proteins putatively involved in diverse cellular processes, such as membrane remodeling, cellular transport, metabolism, cellular protection, fungal pathogenesis, gene regulation, interaction with the environment, and iron uptake. Although the basic metabolic machinery identified under both growth conditions seems to be functionally similar, distinct genes are upregulated at acidic or alkaline pHs. We also isolated a large number of genes of unknown function, probably unique to T rubrum or dermatophytes. Interestingly, the transcriptional profiling of several genes in a pacC mutant suggests that, in T rubrum, the transcription factor PacC has a diversity of metabolic functions, in response to either acidic or alkaline ambient pH. (C) 2009 Elsevier Ltd. All rights reserved.

Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response

Aicardi-Goutieres syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.

Involvement of hypothalamic paraventricular nucleus non-N-methyl-d-aspartate receptors in the pressor response to noradrenaline microinjected into the bed nucleus of the stria terminalis of unanesthetized rats

Microinjection of noradrenaline into the bed nucleus of the stria terminalis (BST) has been reported to cause a pressor response in unanesthetized rats, which was shown to be mediated by acute vasopressin release into the systemic circulation. In the present study we verified the involvement of magnocellular neurons of the hypothalamic paraventricular (PVN) or supraoptic (SON) nuclei and the local neurotransmitter involved in the pressor response to noradrenaline microinjection into the BST. The PVN pretreatment with the non-selective neurotransmission blocker CoCl(2) (1 nmol/100 nL) inhibited the noradrenaline-evoked pressor response. However, responses were not affected by SON treatment with CoCl(2). Further experiments were carried out to test if glutamatergic neurotransmission in the PVN mediates the pressor response evoked by noradrenaline microinjection into the BST. Pretreatment of the PVN with the selective N-methyl-d-aspartate (NMDA) receptor antagonist LY235959 (2 nmol/100 nL) did not affect the noradrenaline-evoked pressor response. However, PVN pretreatment with the selective non-NMDA receptor antagonist NBQX (2 nmol/100 nL) significantly reduced the pressor response to noradrenaline microinjection into the BST. In conclusion, our results suggest that pressor responses to noradrenaline microinjection into the BST are mediated by PVN magnocellular neurons without involvement of SON neurons. They also suggest that a glutamatergic neurotransmission through non-NMDA glutamate receptors in the PVN mediates the response.

Lower Extremities Magnetic Resonance Angiography With Blood Pressure Cuff Compression: Quantitative Dynamic Analysis

Purpose: To quantitatively evaluate changes induced by the application of a femoral blood-pressure cuff (BPC) on run-off magnetic resonance angiography (MRA). which is a method generally previously proposed to reduce venous contamination in the leg. Materials and Methods: This study was Health Insurance Portability and Accountability Act (HIPAA)- and Institutional Review Board (IRB)-compliant, We used time-resolved gradient-echo gadolinium (Gd)-enhanced MRA to measure BPC effects on arterial, venous, and soft-tissue enhancement. Seven healthy volunteers (six men) were studied with the BPC applied at the mid-femoral level unilaterally using a 1.5T MR system after intravenous injection of Gd-BOPTA. Different statistical tools were used such as the Wilcoxon signed rank test and a cubic smoothing spline fit. Results: We found that BPC application induces delayed venous filling (as previously described), but also induces significant decreases in arterial inflow, arterial enhancement, vascular-soft tissue contrast, and delayed peak enhancement (which have not been previously measured). Conclusion: The potential benefits from using a BPC for run-off MRA must be balanced against the potential pitfalls, elucidated by our findings.

The presence of CD56/CD16 in T-cell acute lymphoblastic leukaemia correlates with the expression of cytotoxic molecules and is associated with worse response to treatment

Some cases of T-cell acute lymphoblastic leukaemia (ALL) express markers found in natural-killer (NK) cells, such as CD56 and CD16. Out of 84 T-cell ALL cases diagnosed at our Institution, CD56 and/or CD16 was detected in 24 (28.5%), which we designated T/NK-ALL group. Clinical features, laboratory characteristics, survival and expression of cytotoxic molecules were compared in T/NK-ALL and T-ALL patients. Significant differences were observed regarding age (24.9 vs. 16.4 years in T/NK-ALL and T-ALL, respectively, P = 0.006) and platelet counts (177 x 10(9)/l vs. 75 x 10(9)/l in T/NK-ALL and T-ALL, respectively, P = 0.03). Immunophenotypic analysis demonstrated that CD34, CD45RA and CD33 were more expressed in T/NK-ALL patients, whereas CD8 and terminal deoxynucleotidyl transferase were more expressed in T-ALL patients (P < 0.05). The mean overall survival (863 vs. 1869 d, P = 0.02) and disease-free survival (855 vs. 2095 d, P = 0.002) were shorter in patients expressing CD56/CD16. However, multivariate analysis identified CD56/CD16 as an independent prognostic factor only for DFS. Cytotoxic molecules were highly expressed in T/NK-ALL compared to T-ALL. Perforin, granzyme B and TIA-1 were detected in 12/17, 4/17 and 7/24 T/NK-ALL patients and in 1/20, 0/20 and 1/20 T-ALL respectively (P < 0.001, P = 0.036 and P = 0.054). Therefore, the presence of CD56/CD16 was associated with distinct clinical features and expression of cytotoxic molecules in the blasts.

Focal CO2 dialysis in raphe obscurus does not stimulate ventilation but enhances the response to focal CO2 dialysis in the retrotrapezoid nucleus

Simultaneous inhibition of the retrotrapezoid nucleus (RTN) and raphe obscurus (ROb) decreased the systemic CO2 response by 51%, an effect greater than inhibition of RTN (- 24%) or ROb (0%) alone, suggesting that ROb modulates chemoreception by interaction with the RTN (19). We investigated this interaction further by simultaneous dialysis of artificial cerebrospinal fluid equilibrated with 25% CO2 in two probes located in or adjacent to the RTN and ROb in conscious adult male rats. Ventilation was measured in a whole body plethysmograph at 30 C. There were four groups (n = 5): 1) probes correctly placed in both RTN and ROb (RTN-ROb); 2) one probe correctly placed in RTN and one incorrectly placed in areas adjacent to ROb (RTN-peri-ROb); 3) one probe correctly placed in ROb and one probe incorrectly placed in areas adjacent to RTN (peri-RTN-ROb); and 4) neither probe correctly placed (peri-RTN-peri-ROb). Focal simultaneous acidification of RTN-ROb significantly increased ventilation ((V) over dot E) up to 22% compared with baseline, with significant increases in both breathing frequency and tidal volume. Focal acidification of RTN-peri-ROb increased (V) over dot E significantly by up to 15% compared with baseline. Focal acidification of ROb and peri-RTN had no significant effect. The simultaneous acidification of regions just outside the RTN and ROb actually decreased (V) over dot E by up to 11%. These results support a modulatory role for the ROb with respect to central chemoreception at the RTN.

Oleic acid modulation of the immune response in wound healing: A new approach for skin repair

Injury triggers inflammatory responses and tissue repair. Several treatments are currently in use to accelerate healing: however, more efficient formulations are still needed for specific injuries. Since unsaturated fatty acids modulate immune responses, we aimed to evaluate their therapeutic effects on wound healing. Skin wounds were induced in BALB/c mice and treated for 5 days with n-3, n-9 fatty acids or vehicle (control). n-9 treated mice presented smaller wounds than control and n-3 at 120 h post-surgery (p.s.). Collagen III mRNA,TIMP1 and MMP9 were significantly elevated in n-9 group compared to n-3 or vehicle at 120 h p.s. Among the inflammatory mediators studied we found that IL-10, TNF-alpha and IL-17 were also higher in n-9 treated group compared to n-3 or vehicle at 120 h p.s. Interestingly, COX2 had decreased expression on wound tissue treated with n-9. Inflammatory infiltrate analysis revealed diminished frequency of CD4(+), CD8(+) and CD11b(+) cells in n-9 wounds at 24 and 120 h p.s., which was not related to cell death, since in vitro apoptosis experiments did not show any cell damage after fatty acids administration. These results suggested that unsaturated fatty acids, specifically n-9, modulate the inflammation in the wound and enhance reparative response in vivo. n-9 may be a useful tool in the treatment of cutaneous wounds. (C) 2010 Elsevier GmbH. All rights reserved.

A DNA vaccine candidate encoding the structural prM/E proteins elicits a strong immune response and protects mice against dengue-4 virus infection

A DNA vaccine expressing dengue-4 virus premembrane (prM) and envelope (E) genes was produced by inserting these genes into a mammalian expression plasmid (pCI). Following a thorough screening, including confirmation of protein expression in vitro, a recombinant clone expressing these genes was selected and used to immunize BALB/c mice. After 3 immunizations all the animals produced detectable levels of neutralizing antibodies against dengue-4 virus. The cytokines levels and T cell proliferation, detected ex vivo from the spleen of the immunized mice, showed that our construction induced substantial immune stimulation after three doses. Even though the antibody levels, induced by our DNA vaccine, were lower than those obtained in mice immunized with dengue-4 virus the levels of protection were high with this vaccine. This observation is further supported by the fact that 80% of the vaccine immunized group was protected against lethal challenge. In conclusion, we developed a DNA vaccine employing the genes of the prM and E proteins from dengue-4 virus that protects mice against this virus. (C) 2010 Elsevier Ltd. All rights reserved.

The Stability of the Blood Oxygenation Level-Dependent Functional MRI Response to Motor Tasks Is Altered in Patients With Chronic Ischemic Stroke

Background and Purpose-Functional MRI is a powerful tool to investigate recovery of brain function in patients with stroke. An inherent assumption in functional MRI data analysis is that the blood oxygenation level-dependent (BOLD) signal is stable over the course of the examination. In this study, we evaluated the validity of such assumption in patients with chronic stroke. Methods-Fifteen patients performed a simple motor task with repeated epochs using the paretic and the unaffected hand in separate runs. The corresponding BOLD signal time courses were extracted from the primary and supplementary motor areas of both hemispheres. Statistical maps were obtained by the conventional General Linear Model and by a parametric General Linear Model. Results-Stable BOLD amplitude was observed when the task was executed with the unaffected hand. Conversely, the BOLD signal amplitude in both primary and supplementary motor areas was progressively attenuated in every patient when the task was executed with the paretic hand. The conventional General Linear Model analysis failed to detect brain activation during movement of the paretic hand. However, the proposed parametric General Linear Model corrected the misdetection problem and showed robust activation in both primary and supplementary motor areas. Conclusions-The use of data analysis tools that are built on the premise of a stable BOLD signal may lead to misdetection of functional regions and underestimation of brain activity in patients with stroke. The present data urge the use of caution when relying on the BOLD response as a marker of brain reorganization in patients with stroke. (Stroke. 2010; 41:1921-1926.)

Low mRNA Expression of the Apoptosis-Related Genes CASP3, CASP8, and FAS Is Associated With Low Induction Treatment Response in Childhood Acute Lymphoblastic Leukemia (ALL)

Background. Defects in apoptosis signaling have been considered to be responsible for treatment failure in many types of cancer, although with controversial results. The objective of the present study was to assess the expression profile of key apoptosis-related genes in terms of clinical and biological variables and of the survival of children with acute lymphoblastic leukemia (ALL). Procedure. The levels of mRNA expression of the apoptosis-related genes CASP3, CASP8, CASP9, FAS, and BCL2 were analyzed by quantitative real-time PCR in consecutive samples from 139 consecutive children with ALL at diagnosis treated by the Brazilian protocol (GBTLI-ALL 99). Gene expression levels and clinical and biological features were compared by the Mann-Whitney test. Event-free survival (EFS) was calculated by Kaplan-Meier plots and log-rank test. Results. A significant correlation was detected between CASP3, CASP8, CASP9, and FAS expression levels (P<0.01) in ALL samples. Higher levels of BCL2 were significantly associated with white blood cell (WBC) count <50,000/mm(3) at diagnosis (P=0.01) and low risk group classification (P=0.008). Lower expression levels of CASP3, CASP8 and FAS gene were associated with a poor response at day 7 according the GBTLI-ALL 99 protocol (P=0.03, P=0.02 and P=0.008, respectively). There was a relationship between FAS gene expression lower than the 75th percentile and lower 5-year EFS (P=0.02). Conclusion. These findings suggest an association between lower expression levels of the pro-apoptotic genes and a poor response to induction therapy at day 7 and prognosis in childhood ALL. Pediatr Blood Cancer 2010;55:100-107. (C) 2010 Wiley-Liss, Inc.

Aspects of adaptive management of coastal wetlands: Case studies of processes, conservation, restoration, impacts and assessment

Coastal wetlands are dynamic and include the freshwater-intertidal interface. In many parts of the world such wetlands are under pressure from increasing human populations and from predicted sea-level rise. Their complexity and the limited knowledge of processes operating in these systems combine to make them a management challenge.Adaptive management is advocated for complex ecosystem management (Hackney 2000; Meretsky et al. 2000; Thom 2000;National Research Council 2003).Adaptive management identifies management aims,makes an inventory/environmental assessment,plans management actions, implements these, assesses outcomes, and provides feedback to iterate the process (Holling 1978;Walters and Holling 1990). This allows for a dynamic management system that is responsive to change. In the area of wetland management recent adaptive approaches are exemplified by Natuhara et al. (2004) for wild bird management, Bunch and Dudycha (2004) for a river system, Thom (2000) for restoration, and Quinn and Hanna (2003) for seasonal wetlands in California. There are many wetland habitats for which we currently have only rudimentary knowledge (Hackney 2000), emphasizing the need for good information as a prerequisite for effective management. The management framework must also provide a way to incorporate the best available science into management decisions and to use management outcomes as opportunities to improve scientific understanding and provide feedback to the decision system. Figure 9.1 shows a model developed by Anorov (2004) based on the process-response model of Maltby et al. (1994) that forms a framework for the science that underlies an adaptive management system in the wetland context.

Arthrodesis of the equine proximal interphalangeal joint: a biomechanical comparison of 3-Hole 4.5 mm locking compression plate and 3-hole 4.5 mm narrow dynamic compression plate, with two transarticular 5.5 mm cortex screws

Objectives To compare the biomechanical characteristics of 2 arthrodesis techniques for the equine proximal interphalangeal joint (PIP) using either a 3-hole 4.5 mm locking compression plate (LCP) or 3-hole 4.5 mm narrow dynamic compression plate (DCP), both with 2 transarticular 5.5 mm cortex screws. Study Design Experimental. Sample Population Cadaveric adult equine forelimbs (*n=6 pairs). Methods For each forelimb pair, 1 limb was randomly assigned to 1 of 2 treatment groups and the contralateral limb by default to the other treatment group. Construct stiffness, gap formation across the PIP joint, and rotation about the PIP joint were determined for each construct before cyclic axial loading and after each of four, 5000 cycle loading regimens. After the 20,000 cycle axial loading regimen, each construct was loaded to failure. Results There were no significant differences in construct stiffness, gap formation, or sagittal plane rotation between the LCP and DCP treatment groups at any of the measured time points. Conclusion Biomechanically, fixation of the equine PIP joint with a 3-hole 4.5 mm LCP is equivalent to fixation with a 3-hole 4.5 mm narrow DCP under the test conditions used.

Effects of six carbohydrate sources on dog diet digestibility and post-prandial glucose and insulin response

The effects of six extruded diets with different starch sources (cassava flour, brewer`s rice, corn, sorghum, peas or lentils) on dog total tract apparent digestibility and glycemic and insulinemic response were investigated. The experiment was carried out on thirty-six dogs with six dogs per diet in a completely randomized design. The diets containing brewer`s rice and cassava flour presented the greatest digestibility of dry matter, organic matter and gross energy (p < 0.05), followed by corn and sorghum; pea and lentil diets had the lowest. Starch digestibility was greater than 98% in all diets and was greater for brewer`s rice and cassava flour than for lentils and peas diets (p < 0.05). Dogs` immediate post-prandial glucose and insulin responses (AUC <= 30 min) were greater for brewer`s rice, corn, and cassava flour diets (p < 0.05), and later meal responses (AUC >= 30 min) were greater for sorghum, lentil and pea diets (p < 0.05). Variations in diet digestibility and post-prandial response can be explained by differences in chemical composition of each starch source including fibre content and starch granule structure. The nutritional particularities of each starch ingredient can be explored through diet formulations designed to modulate glycemic response. However, more studies are required to support these.