Suppression of Anti-Inflammatory Mediators in Metabolic Disease May Be Driven by Overwhelming Pro-Inflammatory Drivers

Obesity is a multifactorial disease and is associated with an increased risk of developing metabolic syndrome and co-morbidities. Dysregulated expansion of the adipose tissue during obesity induces local tissue hypoxia, altered secretory profile of adipokines, cytokines and chemokines, altered profile of local tissue inflammatory cells leading to the development of low-grade chronic inflammation. Low grade chronic inflammation is considered to be the underlying mechanism that increases the risk of developing obesity associated comorbidities. The glucocorticoid induced protein annexin A1 and its N-terminal peptides are anti-inflammatory mediators involved in resolving inflammation. The aim of the current study was to investigate the role of annexin A1 in obesity and associated inflammation. To achieve this aim, the current study analysed data from two feasibility studies in clinical populations: (1) bariatric surgery patients (Pre- and 3 months post-surgery) and (2) Lipodystrophy patients. Plasma annexin A1 levels were increased at 3-months post-surgery compared to pre-surgery (1.2 ± 0.1 ng/mL, n = 19 vs. 1.6 ± 0.1 ng/mL, n = 9, p = 0.009) and positively correlated with adiponectin (p = 0.009, r = 0.468, n = 25). Plasma annexin A1 levels were decreased in patients with lipodystrophy compared to BMI matched controls (0.2 ± 0.1 ng/mL, n = 9 vs. 0.97 ± 0.1 ng/mL, n = 30, p = 0.008), whereas CRP levels were significantly elevated (3.3 ± 1.0 μg/mL, n = 9 vs. 1.4 ± 0.3 μg/mL, n = 31, p = 0.0074). The roles of annexin A1 were explored using an in vitro cell based model (SGBS cells) mimicking the inflammatory status that is observed in obesity. Acute treatment with the annexin A1 N-terminal peptide, AC2-26 differentially regulated gene expression (including PPARA (2.8 ± 0.7-fold, p = 0.0303, n = 3), ADIPOQ (2.0 ± 0.3-fold, p = 0.0073, n = 3), LEP (0.6 ± 0.2-fold, p = 0.0400, n = 3), NAMPT (0.4 ± 0.1-fold, p = 0.0039, n = 3) and RETN (0.1 ± 0.03-fold, p < 0.0001, n = 3) in mature obesogenic adipocytes indicating that annexin A1 may play a protective role in obesity and inflammation. However, this effect may be overshadowed by the continued increase in systemic inflammation associated with rapid tissue expansion in obesity

Brain Activation During Working Memory Is Altered in Patients With Type 1 Diabetes During Hypoglycemia

OBJECTIVE To investigate the effects of acute hypoglycemia on working memory and brain function in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Using blood oxygen level–dependent (BOLD) functional magnetic resonance imaging during euglycemic (5.0 mmol/L) and hypoglycemic (2.8 mmol/L) hyperinsulinemic clamps, we compared brain activation response to a working-memory task (WMT) in type 1 diabetic subjects (n = 16) with that in age-matched nondiabetic control subjects (n = 16). Behavioral performance was assessed by percent correct responses. RESULTS During euglycemia, the WMT activated the bilateral frontal and parietal cortices, insula, thalamus, and cerebellum in both groups. During hypoglycemia, activation decreased in both groups but remained 80% larger in type 1 diabetic versus control subjects (P < 0.05). In type 1 diabetic subjects, higher HbA1c was associated with lower activation in the right parahippocampal gyrus and amygdala (R2 = 0.45, P < 0.002). Deactivation of the default-mode network (DMN) also was seen in both groups during euglycemia. However, during hypoglycemia, type 1 diabetic patients deactivated the DMN 70% less than control subjects (P < 0.05). Behavioral performance did not differ between glycemic conditions or groups. CONCLUSIONS BOLD activation was increased and deactivation was decreased in type 1 diabetic versus control subjects during hypoglycemia. This higher level of brain activation required by type 1 diabetic subjects to attain the same level of cognitive performance as control subjects suggests reduced cerebral efficiency in type 1 diabetes

Integrin-associated ILK and PINCH1 protein content are reduced in skeletal muscle of maintenance haemodialysis patients

Key points: Patients with renal failure undergoing maintenance haemodialysis are associated with insulin resistance and protein metabolism dysfunction. Novel research suggests that disruption to the transmembrane protein linkage between the cytoskeleton and the extracellular matrix in skeletal muscle may contribute to reduced amino acid metabolism and insulin resistance in haemodialysis. ILK, PINCH1 and pFAKTyr397 were significantly decreased in haemodialysis compared to controls, whereas Rac1 and Akt2 showed no different between groups. Rac1 deletion in the Rac1 knockout model did not alter the expression of integrin-associated proteins. Phenylalanine kinetics were reduced in the haemodialysis group at 30 and 60 min post meal ingestion compared to controls; both groups showed similar levels of insulin sensitivity and β-cell function. Key proteins in the integrin–cytoskeleton linkage are reduced in haemodialysis patients, suggesting for the first time that integrin-associated proteins dysfunction may contribute to reduced phenylalanine flux without affecting insulin resistance in haemodialysis patients. Abstract: Muscle atrophy, insulin resistance and reduced muscle phosphoinositide 3-kinase-Akt signalling are common characteristics of patients undergoing maintenance haemodialysis (MHD). Disruption to the transmembrane protein linkage between the cytoskeleton and the extracellular matrix in skeletal muscle may contribute to reduced amino acid metabolism and insulin resistance in MHD patients. Eight MHD patients (age: 56 ± 5 years: body mass index: 32 ± 2 kg m–2) and non-diseased controls (age: 50 ± 2 years: body mass index: 31 ± 1 kg m–2) received primed continuous l-[ring-2H5]phenylalanine before consuming a mixed meal. Phenylalanine metabolism was determined using two-compartment modelling. Muscle biopsies were collected prior to the meal and at 300 min postprandially. In a separate experiment, skeletal muscle tissue from muscle-specific Rac1 knockout (Rac1 mKO) was harvested to investigate whether Rac1 depletion disrupted the cytoskeleton-integrin linkage, allowing for cross-model examination of proteins of interest. ILK, PINCH1 and pFAKTyr397 were significantly lower in MHD (P

A generalized linear model with smoothing effects for claims reserving

In this paper, we continue the development of the ideas introduced in England & Verrall (2001) by suggesting the use of a reparameterized version of the generalized linear model (GLM) which is frequently used in stochastic claims reserving. This model enables us to smooth the origin, development and calendar year parameters in a similar way as is often done in practice, but still keep the GLM structure. Specifically, we use this model structure in order to obtain reserve estimates and to systemize the model selection procedure that arises in the smoothing process. Moreover, we provide a bootstrap procedure to achieve a full predictive distribution

Excitatory neurotransmitters in brain regions in interictal migraine patients

<p>Abstract</p> <p>Objective</p> <p>To examine biochemical differences in the anterior cingulate cortex (ACC) and insula during the interictal phase of migraine patients. We hypothesized that there may be differences in levels of excitatory amino acid neurotransmitters and/or their derivatives in migraine group based on their increased sensitivity to pain.</p> <p>Methods</p> <p>2D <it>J</it>-resolved proton magnetic resonance spectroscopy (¹H-MRS) data were acquired at 4.0 Tesla (T) from the ACC and insula in 10 migraine patients (7 women, 3 men, age 43 ± 11 years) and 8 age gender matched controls (7 women, 3 men, age 41 ± 9 years).</p> <p>Results</p> <p>Standard statistical analyses including analysis of variance (ANOVA) showed no significant metabolite differences between the two subject cohorts in the ACC nor the insula. However, linear discriminant analysis (LDA) introduced a clear separation between subject cohorts based on N-acetyl aspartylglutamate (NAAG) and glutamine (Gln) in the ACC and insula.</p> <p>Conclusion</p> <p>These results are consistent with glutamatergic abnormalities in the ACC and insula in migraine patients during their interictal period compared to healthy controls. An alteration in excitatory amino acid neurotransmitters and their derivatives may be a contributing factor for migraineurs for a decrease in sensitivity for migraine or a consequence of the chronic migraine state. Such findings, if extrapolated to other regions of the brain would offer new opportunities to modulate central system as interictal or preemptive medications in these patients.</p

Data Assimilation Enhancements to Air Force Weathers Land Information System

The United States Air Force (USAF) has a proud and storied tradition of enabling significant advancements in the area of characterizing and modeling land state information. 557th Weather Wing (557 WW; DoDs Executive Agent for Land Information) provides routine geospatial intelligence information to warfighters, planners, and decision makers at all echelons and services of the U.S. military, government and intelligence community. 557 WW and its predecessors have been home to the DoDs only operational regional and global land data analysis systems since January 1958. As a trusted partner since 2005, Air Force Weather (AFW) has relied on the Hydrological Sciences Laboratory at NASA/GSFC to lead the interagency scientific collaboration known as the Land Information System (LIS). LIS is an advanced software framework for high performance land surface modeling and data assimilation of geospatial intelligence (GEOINT) information

Search for dinucleon decay into pions at Super-Kamiokande

A search for dinucleon decay into pions with the Super-Kamiokande detector has been performed with an exposure of 282.1 kiloton-years. Dinucleon decay is a process that violates baryon number by two units. We present the first search for dinucleon decay to pions in a large water Cherenkov detector. The modes $^{16}$O$(pp) \rightarrow$ $^{14}$C$\pi^{+}\pi^{+}$, $^{16}$O$(pn) \rightarrow$ $^{14}$N$\pi^{+}\pi^{0}$, and $^{16}$O$(nn) \rightarrow$ $^{14}$O$\pi^{0}\pi^{0}$ are investigated. No significant excess in the Super-Kamiokande data has been found, so a lower limit on the lifetime of the process per oxygen nucleus is determined. These limits are: $\tau_{pp\rightarrow\pi^{+}\pi^{+}} > 7.22 \times 10^{31}$ years, $\tau_{pn\rightarrow\pi^{+}\pi^{0}} > 1.70 \times 10^{32}$ years, and $\tau_{nn\rightarrow\pi^{0}\pi^{0}} > 4.04 \times 10^{32}$ years. The lower limits on each mode are about two orders of magnitude better than previous limits from searches for dinucleon decay in iron.Comment: 20 pages, 17 figures. Accepted for publication in Physical Review D on March 30, 201