SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease.

AIMS: Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. METHODS: Quantitative real-time polymerase chain reactions were used to assess levels of SIRT1-3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno-associated viral vectors in mice. RESULTS: We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets and reduced mRNA levels of orexin (hypocretin), prodynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. CONCLUSIONS: We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus.

A novel in vivo approach to assess radial and axial distensibility of large and intermediate pulmonary artery branches.

Pulmonary arteries (PAs) distend to accommodate increases in cardiac output. PA distensibility protects the right ventricle (RV) from excessive increases in pressure. Loss of PA distensibility plays a critical role in the fatal progression of pulmonary arterial hypertension (PAH) toward RV failure. However, it is unclear how PA distensibility is distributed across the generations of PA branches, mainly because of the lack of appropriate in vivo methods to measure distensibility of vessels other than the large, conduit PAs. In this study, we propose a novel approach to assess the distensibility of individual PA branches. The metric of PA distensibility we used is the slope of the stretch ratio-pressure relationship. To measure distensibility, we combined invasive measurements of mean PA pressure with angiographic imaging of the PA network of six healthy female dogs. Stacks of 2D images of the PAs, obtained from either contrast enhanced magnetic resonance angiography (CE-MRA) or computed tomography digital subtraction angiography (CT-DSA), were used to reconstruct 3D surface models of the PA network, from the first bifurcation down to the sixth generation of branches. For each branch of the PA, we calculated radial and longitudinal stretch between baseline and a pressurized state obtained via acute embolization of the pulmonary vasculature. Our results indicated that large and intermediate PA branches have a radial distensibility consistently close to 2%/mmHg. Our axial distensibility data, albeit affected by larger variability, suggested that the PAs distal to the first generation may not significantly elongate in vivo, presumably due to spatial constraints. Results from both angiographic techniques were comparable to data from established phase-contrast (PC) magnetic resonance imaging (MRI) and ex vivo mechanical tests, which can only be used in the first branch generation. Our novel method can be used to characterize PA distensibility in PAH patients undergoing clinical right heart catheterization (RHC) in combination with MRI.

Female elk contacts are neither frequency nor density dependent.

Identifying drivers of contact rates among individuals is critical to understanding disease dynamics and implementing targeted control measures. We studied the interaction patterns of 149 female elk (Cervus canadensis) distributed across five different regions of western Wyoming over three years, defining a contact as an approach within one body length (-2 min). Using hierarchical models that account for correlations within individuals, pairs, and groups, we found that pairwise contact rates within a group declined by a factor of three as group sizes increased 33-fold. Per capita contact rates, however, increased with group size according to a power function, such that female elk contact rates fell in between the predictions of density- or frequency-dependent disease models. We found similar patterns for the duration of contacts. Our results suggest that larger elk groups are likely to play a disproportionate role in the disease dynamics of directly transmitted infections in elk. Supplemental feeding of elk had a limited impact on pairwise interaction rates and durations, but per capita rates were more than two times higher on feeding grounds. Our statistical approach decomposes the variation in contact rate into individual, dyadic, and environmental effects, and provides insight into factors that may be targeted by disease control programs. In particular, female elk contact patterns were driven more by environmental factors such as group size than by either individual or dyad effects.

An ecological perspective on Brucella abortus in the western United States.

After a hiatus during the 1990s, outbreaks of Brucella abortus in cattle are occurring more frequently in some of the western states of the United States, namely, Montana, Wyoming and Idaho. This increase is coincidentwith increasing brucellosis seroprevalence in elk (Cervus elaphus), which is correlated with elk density. Vaccines are a seductive solution, but their use in wildlife systems remains limited by logistical, financial, and scientific constraints. Cattle vaccination is ongoing in the region. Livestock regulations, however, tend to be based on serological tests that test for previous exposure and available vaccines do not protect against seroconversion. The authors review recent ecological studies of brucellosis, with particular emphasis on the Greater Yellowstone Area, and highlight the management options and implications of this work, including the potential utility of habitat modifications and targeted hunts, as well as scavengers and predators. Finally, the authors discuss future research directions that will help us to understand and manage brucellosis in wildlife.

The mitogen-activated protein kinases p38 and ERK1/2 are increased in lesional psoriatic skin.

BACKGROUND: Alterations in specific signal transduction pathways may explain the hyperproliferation and abnormal differentiation of the keratinocytes as well as the increased expression of inflammatory cytokines seen in psoriasis. Major signalling pathways used by eukaryotic cells to transduce extracellular signals into cellular responses impinge on the mitogen-activated protein kinases (MAPKs). OBJECTIVES: To investigate the expression of the MAPK p38, extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) in psoriatic skin. METHODS: Keratome biopsies were taken from patients with plaque-type psoriasis. Western blot analysis was used to determine p38, ERK and JNK activity and protein levels, whereas kinase assays were used to examine the kinase activity of p38. RESULTS: We demonstrated increased levels of the phosphorylated forms of p38 and ERK1/2 in lesional psoriatic skin compared with nonlesional psoriatic skin. No abnormality was found in the activation and expression of JNK1/2. Ex vivo kinase assays confirmed the increased activation of p38, and furthermore demonstrated increased kinase activity of the p38 isoforms p38alpha, p38beta and p38delta in lesional compared with nonlesional psoriatic skin. p38gamma was not detected in the psoriatic skin. Clearance of the psoriatic lesions, induced by climatotherapy at the Dead Sea for 4 weeks, led to a normalization in the activity of both p38 and ERK1/2. CONCLUSIONS: Taken together, our results demonstrate that the activity of the MAPKs p38alpha, p38beta and p38delta and ERK1/2 are increased in lesional psoriatic skin compared with nonlesional psoriatic skin, and that clearance of psoriasis normalizes the p38 and ERK1/2 activity. Thus, p38 and ERK1/2 might be potential targets in the treatment of psoriasis.

Modulation of keratinocyte gene expression and differentiation by PPAR-selective ligands and tetradecylthioacetic acid.

Peroxisome proliferator-activated receptors (PPARs) are pleiotropic regulators of growth and differentiation of many cell types. We have performed a comprehensive analysis of the expression of PPARs, transcriptional cofactors, and marker genes during differentiation of normal human keratinocytes using a combination of reverse transcriptase polymerase chain reaction, Northern and Western blotting, and immunohistochemistry. PPARdelta was the predominant PPAR subtype in human keratinocytes and highly expressed in basal cells and suprabasal cells. Induction of PPARalpha and PPARgamma expression was linked to differentiation, and accordingly, expression of PPARalpha and PPARgamma was in essence confined to suprabasal cells. Differentiation was not accompanied by significant changes in the expression of the coactivators CREB-binding protein, p300, steroid receptor coactivator 1, or the corepressors nuclear receptor corepressor and silence mediator for retinoid and thyroid hormone receptors. We critically evaluated the effects of selective PPAR ligands and a synthetic fatty acid analog, tetradecylthioacetic acid. Tetradecylthioacetic acid activated all human PPAR subtypes in the ranking order PPARdelta >> PPARalpha > PPARgamma. All selective PPAR ligands marginally induced transglutaminase-1 expression with the PPARdelta-selective ligand L165041 being the most potent. The PPARalpha- and PPARgamma-selective ligands Wy14643 and BRL49653 had negligible effect on involucrin expression, whereas a dose-dependent induction was observed with L165041. Simultaneous addition of L165041 and BRL49653 synergistically induced strong involucrin expression. Additionally, L165041 potently induced CD36 mRNA expression. Administration of tetradecylthioacetic acid resulted in a dramatic decrease in proliferation and a robust upregulation of the expression of involucrin and transglutaminase. Our results indicate that tetradecylthioacetic acid may affect keratinocyte gene expression and differentiation via PPAR-dependent and PPAR-independent pathways, and that the latter play an important role.

The (22(0)1-00(0)0) Band of CO(2) at 6348 cm(-1): Linestrengths, Broadening Parameters, and Pressure Shifts.

The (22(0)1-00(0)0) combination band of CO(2) around 6348 cm(-1) is studied with diode-laser spectroscopy, and linestrengths, collision-broadening parameters, and pressure shifts are determined. Linestrengths are modeled with a third-order Herman-Wallis expansion, and discrepancies with values reported in the literature are explained. Copyright 2000 Academic Press.

The 0 --> 3 Overtone Band of CO: Precise Linestrengths and Broadening Parameters.

Linestrengths and self-broadening parameters are determined with a standard uncertainty of 1% for 21 lines in the R branch of the 0 --> 3 overtone band of CO around 1.57 µm. The values are lower than those given in the Hitran database by 6-8% for the linestrengths and 1-5% for the collision broadening parameters, and they agree within 0-2% with more recent results obtained with FTIR. Also, results are given for foreign gas broadening by N2 and H2O. The line profiles show clear evidence for collisional narrowing with deviations corresponding to those expected for a Galatry profile. When analyzed in terms of a Voigt profile, this effect causes a reduction in effective Doppler width of about 5%. The linestrengths determined for gas mixtures are used for producing independent values for the CO concentrations. These results are derived without reference to any certified gas standard, and it is suggested that optical spectroscopy satisfies the criteria of a primary method set up by the Consultative Committee for Quantity of Matter (CCQM). Copyright 1999 Academic Press.

Sensitive measurement of adsorption dynamics with nonresonant gas phase photoacoustics.

A nonresonant photoacoustic cell, excited by 10-micros CO(2) laser pulses, is compared with conventional resonant cells excited with modulated cw radiation. By combining high sensitivity with small volume and small surface area, the nonresonant cell shows superior performance in measurements of time-dependent concentrations. The potential of the cell is illustrated by measurements of the time evolution of adsorption and desorption of ammonia molecules from surfaces of quartz and stainless steel.

Photoacoustic spectroscopy of C(2)H(4) with a tunable waveguide CO(2) laser.

A photoacoustic gas spectrometer using a wave-guide CO(2), laser, tunable over 500-MHz windows in 70 lines, is described. The spectrometer is used for mapping Doppler-limited spectral signatures of ethylene and for measuring pressure-broadening rates for collisions with N(2), Ar, and He. A total of 41 observed transitions are assigned to the nu(7), nu(10), and nu(4) bands of normal ethylene and to the nu(7) band of the (13)C(12)CH(4) isotopomer.

Blood pressure measurements in the conscious rat. An improved photoelectric, sphygmomanometric device.

A photoelectric device for repeated, noninvasive registration of blood pressure in the tail of the rat was built, mainly using available materials and components. A description of the measuring system is given. Comparison between blood pressure measurements performed simultaneously in the tail of the rat and intravascularly in the aorta are in good agreement.