Search

This paper reviews the potential role of arachidonic acid in the pathophysiology of schizophrenia. We discuss how abnormal levels of arachidonic acid may arise, and how dysregulation of signaling molecules derived from it have the potential to disrupt not only dopamine signaling, but numerous other physiological processes associated with the illness. Pharmacological doses of niacin stimulate the release of arachidonic acid; and arachidonic acid-derived molecules in turn dilate blood vessels in the skin. A blunted skin flush response to niacin is reliably observed among patients with schizophrenia. The niacin response abnormality may thus serve as a biomarker to identify a physiological subtype of schizophrenia associated with defective arachidonic acid-derived signaling.

Wegener’s Granulomatosis (WG) is an idiopathic granulomatosis autoimmune vasculitis that primarily affects small vessels and is associated with glomerulonephritis and pulmonary granulomatous vasculitis. Anti-neutrophil cytoplasmic auto-antibodies (cANCA) against proteinase-3 are used to identify WG, but ANCA titers are not present in some patients with the localized disease. The objective of this study was to develop an antibody array to help identify protein expression patterns in serum from patients with WG as compared to normals. The arrays were tested for limits of detection, background, and cross reactivity using standard proteins. The arrays were hybridized with either normal patient serum (n = 30) or with serum samples from a population of WG patients (n = 26) that were age and sex matched. Data analysis and curve fitting of the standard dilution series calculated r 2 values and determined a sensitivity of ,50 pg/ mL for the majority of proteins. A total of 24 proteins were assessed. Several statistically significant increases (p,0.05) were seen in the expression of: angiotensin converting enzyme-I, IFN-g, IL-8, s-ICAM-1 and s-VCAM in WG patients as compared to controls. Utilizing the antibody microarray technology has led to the identification of potential biomarkers of vascular injury in the serum of WG patients.

Niacin dilates cutaneous blood vessels, resulting in a pronounced skin flush in most people. The flush response to niacin is attenuated in schizophrenia, but the quantification and physiological mechanism of this abnormality have not been described in detail. It is not clear whether the mechanism involves changes in the pharmacological sensitivity to niacin, or whether there is a reduced ability of the vasculature to dilate adequately in subjects with schizophrenia. We address this question in the present study by characterizing the dose-response relationship between topically applied alpha-methylnicotinate (AMN) and cutaneous blood flow changes, which were quantified by laser Doppler flowmetry. The dose-response curve was shifted to the right in subjects with schizophrenia. The EC(50) value of AMN was significantly increased in the schizophrenia group (mean: 1.66 mM; 95% confidence interval: 1.04-2.65 mM) as compared to the control group (mean: 0.38 mM; 95% confidence interval: 0.263-0.547 mM). The blood flow responses to higher AMN doses were lower in the schizophrenics; however, there was no statistically significant difference in the extrapolated maximal blood flow response value (F(max)) between the two groups. The results suggest that the skin flush abnormality in schizophrenia primarily reflects reduced pharmacological sensitivity to niacin rather than an inadequate cutaneous vasodilatory response to the stimulus. Since vasodilatation in response to niacin requires the release of prostaglandins, the data from this study suggest that schizophrenia is associated with abnormalities in enzymes, receptors, or signal transduction mechanisms that affect the synthesis, release, or response to vasodilatory prostaglandins.

The decline of employment-based health plans is commonly attributed to rising premium costs. Using restricted data and a matched sample from the Medical Expenditure Panel Survey–Insurance Component, the authors extend previous studies by testing the relationships among premium costs, employment relationships, and the provision of health benefits between 1999 and 2012. The authors report that both establishment- and state-level union densities are associated with a higher likelihood of employers’ providing health plans, whereas right-to-work legislation is associated with lower provision. These factors combined rival rising premium cost in predicting offering. This finding indicates that the declining provision of health benefits could be in part driven by the transformation of the employment relationship in the United States and that labor unions may remain a critical force in sustaining employment-based coverage in the twenty-first century.

The neurochemical pathology of Alzheimer's disease (AD) has been consistently shown to involve cholinergic degeneration in the cerebral cortex. This together with evidence from experimental animal studies showing that cholinergic neurones play a role in learning and memory processes has formed the basis of the cholinergic hypothesis of Alzheimer's dementia and the major rationale for neurotransmitter replacement therapy of the disorder.

The canine cytokine IL-31 induces pruritus in dogs and can be detected in dogs with atopic dermatitis; however very little is understood around its interactions with specific canine cells. We hypothesize that IL-31 is involved in the progression of allergic skin disease by coordinating the interaction between the immune system with skin and neuronal systems. The goal of the following work was to identify cells that produce IL-31 as well as cells that may respond to this cytokine. Peripheral blood mononuclear cells (PBMCs) were collected from naïve and house dust mite (HDM) allergen-sensitized beagle dogs and used for ex vivo characterization of cytokine production assessed using ELISpot and quantitative immunoassay. Sensitization to HDM allergen induced a T-helper type 2 (Th2) cell phenotype characterized by an increase in the production of IL-4 protein. Interestingly, repeated allergen challenge over time also resulted in an increase in IFN-γ. Further evaluation showed that co-stimulation of Th2 polarized cells with antigen and the bacterial component Staphylococcus enterotoxin B (SEB) produced higher levels of IL-31 compared to either stimulant alone. Production of IL-31 when PBMCs were stimulated by T cell mitogens suggests T cells as a source of IL-31. Quantitative real-time PCR was utilized to determine expression of the IL-31 receptor alpha chain in canine cell lines and tissue. Canine monocytic cells, keratinocytes, and dorsal root ganglia were shown to express the IL-31 receptor alpha chain mRNA. In a multifaceted disease such as canine atopic dermatitis, the combination of Th2 polarization and microbial presence may lead to IL-31 mediated effects driving inflammation and pruritus by immune cells, keratinocytes, and direct neuronal stimulation.

Atypical antipsychotic medications are associated with increased risks of obesity, glucose intolerance, and diabetes, and dyslipidemia compared to the typical antipsychotic medications. Most antipsychotic medications, typical and atypical, block the D2 (dopamine) receptor; this can lead to increased prolactin levels since dopamine prevents excess prolactin secretion from the pituitary gland. The increasingly widespread use of atypical antipsychotic medications, coupled with improved awareness of medical problems in psychiatric patients, will increase the role of the clinical laboratory in managing patients with severe and persistent mental illness.

We have characterized the molecular species and subcellular distribution of Alzheimer beta/A4 amyloid precursor protein (APP) in neutrophilic granulocytes purified from human peripheral blood. APP was readily detectable in these cells. Immunochemical analysis with a panel of antibodies revealed that this APP species lacked the transmembrane and cytoplasmic domains previously demonstrated in cell-associated APP. However, it contained a protease inhibitor domain of the Kunitz type, indicating that neutrophil APP is a potent inhibitor of certain serine proteases. Upon subcellular fractionation, APP was primarily localized to azurophilic granules, which are neutrophil-specific phagocytic organelles assigned to enzymatic digestion of invading microbes and dead or injured tissue. Apparently, in the neutrophil, a nonsecretory organelle stores truncated, soluble APP, a species previously found only in blood plasma and cerebrospinal fluid or in conditioned medium of cultured cells. Soluble APP in neutrophils may therefore have intracellular functions in addition to its previously described extracellular functions. These findings also indicate that there are previously uncharacterized cell-specific differences in processing, trafficking, and storage of the APP molecule. Finally, the precise subcellular localization of APP to neutrophil-specific phagocytic organelles is suggestive of a role for APP in the nonimmunological host defense.

The effects of beta-amyloid protein 1-40 (beta AP 1-40), substance P (SP), and the amidated and carboxylic acid C-terminated forms of the SP homologous beta AP fragment 25-35 (beta AP 25-35-NH2 and beta AP 25-35-COOH) were studied on [3H]MK-801 binding to the rat brain NMDA receptor cation channel. All peptides gave dose-dependent enhancements of [3H]MK-801 binding stimulated by low glycine. beta AP 25-35-COOH, but not beta AP 25-35-NH2 produced an inhibition of [3H]MK-801 binding stimulated by high glycine in the presence of either low or high glutamate. Low glutamate-stimulated [3H]MK-801 binding was also inhibited by SP but not by beta AP 1-40. It is concluded that beta AP related peptides exert differential effects on the NMDA receptor complex at the glycine and possibly also the glutamate recognition sites.

The effects of inhibition of cholinesterase on levels of extracellular acetylcholine in the striatum of freely moving rats, were investigated with a microdialysis technique. Acetylcholine could not be detected under basal conditions. However, local administration of the cholinesterase inhibitors neostigmine, physostigmine or heptyl-physostigmine through the dialysis probe elevated acetylcholine above the detection limit. Complex interactions between the effects of local and systemic cholinesterase inhibitors were observed. Whereas systemic administration of physostigmine or heptylphysostigmine alone increased the extracellular concentration of acetylcholine, they also caused acetylcholine to fall below baseline levels, which had been established by perfusing physostigmine through the microdialysis probe. These studies demonstrate the ability of local inhibition of cholinesterase to affect the observation of effects of systemically-administered drugs.

Background: Treatment studies about childhood obesity in primary care are lacking. We hypothesized that providing a paid family membership to the YMCA would be effective in reducing weight. Methods: Patients 5 to17 years old in at least the 85th body mass index (BMI) percentile were eligible. All participants were scheduled to attend 4 nutrition classes and to return for evaluation at 2, 4, 6, 9, and 12 months. Participants were randomized to nutrition classes only (n = 39) or nutrition classes and family YMCA membership (n = 44). The primary outcome measure was year change in BMI-for-age percentile. Results: Median BMI percentile at baseline was 99. Only 27 of 36 evaluable participants in the treatment group visited the YMCA. Four participants in the control group and one in the treatment group achieved the target reduction of 2 BMI percentile points (Fisher9s exact, P = .17). Within the treatment group, YMCA attendees had a mean increase of 0.30 BMI points compared with an increase of 0.60 BMI points in nonattendees (P = .28). Conclusion: In very obese children, eliminating financial barriers to YMCA membership is insufficient to induce more weight loss during 1 year compared with nutrition classes alone. Improvements in nutrition intake were reported by both groups.

Schizophrenia is associated with a blunted flush response to niacin. Since niacin-induced skin flushing is mediated by vasodilators derived from arachidonic acid (AA), we tested whether the blunted flush response to niacin is a marker of AA deficiency.Eight concentrations of methylnicotinate were applied to the forearms of 20 adults with schizophrenia and 20 controls. Laser Doppler measurement of blood flow responses was used to derive values for niacin sensitivity (defined as the concentration eliciting half-maximal response, i.e., EC(50) value) and efficacy (defined as the maximal evoked blood flow response). RBC membrane fatty acids were analyzed by gas chromatography.Niacin sensitivity and efficacy were reduced in schizophrenia. In the control group, there was significant correlation between AA levels and niacin sensitivity as well as a trend toward correlation between AA levels and niacin efficacy. In contrast, neither sensitivity nor efficacy of niacin correlated with AA levels in schizophrenia. An expected correlation between the levels of AA and its elongation product (adrenic acid) was absent in schizophrenia. Adrenic acid levels correlated with niacin efficacy in schizophrenia.The schizophrenia-associated niacin response abnormality involves both diminished sensitivity and reduced efficacy. The lack of expected correlation between levels of AA and adrenic acid suggests homeostatic imbalance within the n-6 polyunsaturated fatty acid (PUFA) pathway in schizophrenia. Though AA levels were unrelated to measures of niacin response in schizophrenia, the correlation between adrenic acid and niacin efficacy in schizophrenia suggests relevance of the n-6 PUFA pathway to the blunted niacin response.

Use of unmanned systems is rapidly growing within the military and civilian sectors in a variety of roles including reconnaissance, surveillance, explosive ordinance disposal (EOD), and force-protection and perimeter security. As utilization of these systems grows at an ever increasing rate, the need for unmanned systems teaming and inter-system collaboration becomes apparent. Collaboration provides a means of enhancing individual system capabilities through relevant data exchange that contributes to cooperative behaviors between systems and enables new capabilities not possible if the systems operate independently. A collaborative networked approach to development holds the promise of adding mission capability while simultaneously reducing the workload of system operators. The Joint Collaborative Technology Experiment (JCTE) joins individual technology development efforts within the Air Force, Navy, and Army to demonstrate the potential benefits of interoperable multiple system collaboration in a force-protection application. JCTE participants are the Air Force Research Laboratory, Materials and Manufacturing Directorate, Airbase Technologies Division, Force Protection Branch (AFRL/RXQF); the Army Aviation and Missile Research, Development, and Engineering Center Software Engineering Directorate (AMRDEC SED); and the Space and Naval Warfare Systems Center - Pacific (SSC Pacific) Unmanned Systems Branch operating with funding provided by the Joint Ground Robotics Enterprise (JGRE). This paper will describe the efforts to date in system development by the three partner organizations, development of collaborative behaviors and experimentation in the force-protection application, results and lessons learned at a technical demonstration, simulation results, and a path forward for future work.

The advent of the epigenetic era has sparked a new frontier in molecular research and the understanding of how development can be regulated beyond direct alterations of the genome. Thus far, the focal point of epigenetic regulation during development has been chromatin modifications that control differential gene expression by DNA methylation and histone alterations. But what of events that alter gene expression without direct influence on the DNA itself? The present review focuses on epigenetic pathways regulating development from oogenesis to organogenesis and back that do not involve methylation of cytosine in DNA. We discuss target components of epigenetic modification such as organelle development, compartmentalisation of maternal factors and molecular mediators in the oocyte and how these factors acting during oogenesis impact on later development. Epigenetic regulation of development, be it via cytosine methylation or not, has wide-ranging effects on the subsequent success of a pregnancy and the intrinsic health of offspring. Perturbations in epigenetic regulation have been clearly associated with disease states in adult offspring, including Type II diabetes, hypertension, cancers and infertility. A clear understanding of all epigenetic mechanisms is paramount when considering the increased use of assisted reproductive techniques and the risks associated with their use.

Antibodies against the N-terminal (NT) but not the basic domain (BD), DNA binding regions of the largest subunit (S1) of RNA polymerase I (RNAPI) were detected in the sera of MRL-lpr/lpr lupus mice. Antibodies against both RNAPI(S1)-NT and -BD, as well as other systemic lupus erythematosus (SLE) autoantigens (La, ribosomal P proteins and Sm/RNP) were produced by rabbits immunized with anti-DNA antibodies that had been affinity purified from SLE patients. Immunization of nonautoimmune mice (Balb/c) with RNAPI(S1)-NT, RNAPI(S1)-BD, or La in the form of GST fusion proteins, induced production of anti-double-stranded (ds) DNA and anti-Sm/RNP. GST-P1 did not induce an anti-dsDNA response in these mice. These results demonstrate that RNAPI(S1)-NT, RNAPI(S1)-BD and La can participate in an anti-autoantigen/anti-DNA antibody loop during an SLE-like autoimmune response.

Antibody microarrays are a high-throughput proteomic technology used to examine the expression of multiple proteins in complex solutions. Antibody microarrays can be manufactured on a variety of commercially available activated glass or coated slides. The goal of this study was to compare Hydrogel™, nitrocellulose, aldehyde-silane and epoxy-silane slides to determine the amount of antibody bound. The optimal substrate was defined as one that bound the greatest amount of antibody with minimal background. Our studies found that epoxy-silane enhanced surface (ES) slides gave the greatest degree of binding along with a minimal background. However, larger antibody microarrays showed variability in spot size, high intra-spot coefficient of variation and drying artifacts. Increasing the amount of glycerol in the spotting buffer caused a dose-dependent improvement in overall spot morphology. Glycerol was tested on 128 different antibodies and showed decreased: mean spot diameter, intra-spot coefficient of variation and drying artifacts. These studies revealed that the optimal slide substrate was epoxy-silane ES microarray slides. Furthermore, glycerol could normalize spot size, decrease intra-spot coefficient of variability, decrease drying artifacts and increase antibody-spotting density.

The Governor General and the Prime Ministers: The Making and Unmaking of Governments, Edward McWhinney, Vancouver: Ronsdale Press; 2005, pp. 193.The political drama surrounding Paul Martin's minority government awakened media observers to the significance of the governor general, an office long dismissed as a ceremonial vestige of colonialism. There are remarkably few works that might enlighten them about the role. In general, one must seek for such understanding piecemeal through historical studies. This lays a heavy burden of responsibility on any new work purporting to, as Edward McWhinney puts it, define “contemporary ground rules for the exercise of the reserve, discretionary powers of the office” (19). In this not-so-crowded field, a work by a political scientist of McWhinney's considerable reputation could well emerge as the authoritative work on the subject. McWhinney offers it in this spirit, even appending some “Rules of Constitutional Prudence for a Contemporary Governor General.” But a note of caution is in order.