Genotypic and Allelic Variability in CYP19A1 among Populations of African and European Ancestry

CYP19A1 facilitates the bioconversion of estrogens from androgens. CYP19A1 intron single nucleotide polymorphisms (SNPs) may alter mRNA splicing, resulting in altered CYP19A1 activity, and potentially influencing disease susceptibility. Genetic studies of CYP19A1 SNPs have been well documented in populations of European ancestry; however, studies in populations of African ancestry are limited. In the present study, ten ‘candidate’ intronic SNPs in CYP19A1 from 125 African Americans (AA) and 277 European Americans (EA) were genotyped and their frequencies compared. Allele frequencies were also compared with HapMap and ASW 1000 Genomes populations. We observed significant differences in the minor allele frequencies between AA and EA in six of the ten SNPs including rs10459592 (p<0.0001), rs12908960 (p<0.0001), rs1902584 (p = 0.016), rs2470144 (p<0.0001), rs1961177 (p<0.0001), and rs6493497 (p = 0.003). While there were no significant differences in allele frequencies between EA and CEU in the HapMap population, a 1.2- to 19-fold difference in allele frequency for rs10459592 (p = 0.004), rs12908960 (p = 0.0006), rs1902584 (p<0.0001), rs2470144 (p = 0.0006), rs1961177 (p<0.0001), and rs6493497 (p = 0.0092) was observed between AA and the Yoruba (YRI) population. Linkage disequilibrium (LD) blocks and haplotype clusters that is unique to the EA population but not AA was also observed. In summary, we demonstrate that differences in the allele frequencies of CYP19A1 intron SNPs are not consistent between populations of African and European ancestry. Thus, investigations into whether CYP19A1 intron SNPs contribute to variations in cancer incidence, outcomes and pharmacological response seen in populations of different ancestry may prove beneficial.     

Helicobacter pylori Infection Induces Anemia,Depletes Serum Iron Storage,and Alters Local Iron-Related and Adult Brain Gene Expression in Male INS-GAS Mice

Iron deficiency anemia (IDA) affects > 500 million people worldwide, and is linked to impaired cognitive development and function in children. Helicobacter pylori, a class 1 carcinogen, infects about half of the world’s population, thus creating a high likelihood of overlapping risk. This study determined the effect of H. pylori infection on iron homeostasis in INS-GAS mice. Two replicates of INS-GAS/FVB male mice (n = 9-12/group) were dosed with H. pylori (Hp) strain SS1 or sham dosed at 6–9 weeks of age, and were necropsied at 27–29 weeks of age. Hematologic and serum iron parameters were evaluated, as was gene expression in gastric and brain tissues. Serum ferritin was lower in Hp SS1-infected mice than uninfected mice (p < 0.0001). Infected mice had a lower red blood cell count (p<0.0001), hematocrit (p < 0.001), and hemoglobin concentration (p <0.0001) than uninfected mice. Relative expression of gastric hepcidin antimicrobial peptide (Hamp) was downregulated in mice infected with Hp SS1 compared to sham-dosed controls (p<0.001). Expression of bone morphogenic protein 4 (Bmp4), a growth factor upstream of hepcidin, was downregulated in gastric tissue of Hp SS1-infected mice (p<0.001). Hp SS1-infected mice had downregulated brain expression of tyrosine hydroxylase (Th) (p = 0.02). Expression of iron-responsive genes involved in myelination (myelin basic protein (Mbp) and proteolipid protein 2 (Plp2)) was downregulated in infected mice (p = 0.001 and p = 0.02). Expression of synaptic plasticity markers (brain derived neurotrophic factor 3 (Bdnf3), Psd95 (a membrane associated guanylate kinase), and insulin-like growth factor 1 (Igf1)) was also downregulated in Hp SS1-infected mice (p = 0.09, p = 0.04, p = 0.02 respectively). Infection of male INS-GAS mice with Hp SS1, without concurrent dietary iron deficiency, depleted serum ferritin, deregulated gastric and hepatic expression of iron regulatory genes, and altered iron-dependent neural processes. The use of Hp SS1-infected INS-GAS mice will be an appropriate animal model for further study of the effects of concurrent H. pylori infection and anemia on iron homeostasis and adult iron-dependent brain gene expression.     

Dysregulated Hepatic Methionine Metabolism Drives Homocysteine Elevation in Diet-Induced Nonalcoholic Fatty Liver Disease

Methionine metabolism plays a central role in methylation reactions, production of glutathione and methylarginines, and modulating homocysteine levels. The mechanisms by which these are affected in NAFLD are not fully understood. The aim is to perform a metabolomic, molecular and epigenetic analyses of hepatic methionine metabolism in diet-induced NAFLD. Female 129S1/SvlmJ;C57Bl/6J mice were fed a chow (n = 6) or high-fat high-cholesterol (HFHC) diet (n = 8) for 52 weeks. Metabolomic study, enzymatic expression and DNA methylation analyses were performed. HFHC diet led to weight gain, marked steatosis and extensive fibrosis. In the methionine cycle, hepatic methionine was depleted (30%, p< 0.01) while s-adenosylmethionine (SAM)/methionine ratio (p< 0.05), s-adenosylhomocysteine (SAH) (35%, p< 0.01) and homocysteine (25%, p< 0.01) were increased significantly. SAH hydrolase protein levels decreased significantly (p <0.01). Serine, a substrate for both homocysteine remethylation and transsulfuration, was depleted (45%, p< 0.01). In the transsulfuration pathway, cystathionine and cysteine trended upward while glutathione decreased significantly (p< 0.05). In the transmethylation pathway, levels of glycine N-methyltransferase (GNMT), the most abundant methyltransferase in the liver, decreased. The phosphatidylcholine (PC)/ phosphatidylethanolamine (PE) ratio increased significantly (p< 0.01), indicative of increased phosphatidylethanolamine methyltransferase (PEMT) activity. The protein levels of protein arginine methytransferase 1 (PRMT1) increased significantly, but its products, monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), decreased significantly. Circulating ADMA increased and approached significance (p< 0.06). Protein expression of methionine adenosyltransferase 1A, cystathionine β-synthase, γ-glutamylcysteine synthetase, betaine-homocysteine methyltransferase, and methionine synthase remained unchanged. Although gene expression of the DNA methyltransferase Dnmt3a decreased, the global DNA methylation was unaltered. Among individual genes, only HMG-CoA reductase (Hmgcr) was hypermethylated, and no methylation changes were observed in fatty acid synthase (Fasn), nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (Nfκb1), c-Jun, B-cell lymphoma 2 (Bcl-2) and Caspase 3. NAFLD was associated with hepatic methionine deficiency and homocysteine elevation, resulting mainly from impaired homocysteine remethylation, and aberrancy in methyltransferase reactions. Despite increased PRMT1 expression, hepatic ADMA was depleted while circulating ADMA was increased, suggesting increased export to circulation.     

Serum Amyloid A Truncations in Type 2 Diabetes Mellitus

Serum Amyloid A (SAA) is an acute phase protein complex consisting of several abundant isoforms. The N- terminus of SAA is critical to its function in amyloid formation. SAA is frequently truncated, either missing an arginine or an arginine-serine dipeptide, resulting in isoforms that may influence the capacity to form amyloid. However, the relative abundance of truncated SAA in diabetes and chronic kidney disease is not known.

Methods

Using mass spectrometric immunoassay, the abundance of SAA truncations relative to the native variants was examined in plasma of 91 participants with type 2 diabetes and chronic kidney disease and 69 participants without diabetes.

Results

The ratio of SAA 1.1 (missing N-terminal arginine) to native SAA 1.1 was lower in diabetics compared to non-diabetics (p = 0.004), and in males compared to females (p<0.001). This ratio was negatively correlated with glycated hemoglobin (r = −0.32, p<0.001) and triglyceride concentrations (r = −0.37, p<0.001), and positively correlated with HDL cholesterol concentrations (r = 0.32, p<0.001).

Conclusion

The relative abundance of the N-terminal arginine truncation of SAA1.1 is significantly decreased in diabetes and negatively correlates with measures of glycemic and lipid control.     

Why Do Women Deliver at Home? Multilevel Modeling of Ethiopian National Demographic and Health Survey Data

Background

Despite of the existing intensive efforts to improve maternal health in Ethiopia, the proportion of birth delivered at home remains high and is still the top priority among the national health threats.

Objective

The study aimed to examine effects of individual women and community-level factors of women’s decision on place of delivery in Ethiopia.

Methods

Data were obtained from the nationally representative 2011 Ethiopian Demographic and Health Survey (EDHS) which used a two-stage cluster sampling design with rural-urban and regions as strata. The EDHS collected data from a big sample size but our study focused on a sample of 7,908 women whose most recent birth was within five years preceding 2011 and 576 communities in which the women were living in. The data were analyzed using a two-level mixed-effects logistic regression to determine fixed-effects of individual- and community-level factors and random-intercept of between-cluster characteristics.

Results

In the current study, 6980 out of 7908 deliveries (88.3%) took place at home. Lower educational levels (OR=2.74, 95%CI:1.84,4.70; p<0.0001), making no or only a limited number of ANC visits (OR=3.72,95%CI:2.85, 4.83; p<0.0001), non-exposure to media (OR=1.51, 95%CI 1.13, 2.01; p=0.004), higher parity (OR=2.68, 95%CI:1.96,3.68; p<0.0001), and perceived distance problem to reach health facilities (OR=1.29, 95%CI:1.03,1.62; p=0.022) were positively associated with home delivery. About 75% of the total variance in the odds of giving birth at home was accounted for the between-community differences of characteristics (ICC=0.75, p<0.0001). With regard to community-level characteristics, rural communities (OR=4.67, 95%CI:3.06,7.11; p<0.0001), pastoralist communities (OR=4.53, 95%CI:2.81,7.28; p<0.0001), communities with higher poverty levels (OR=1.49 95%CI:1.08,2.22; p=0.048), with lower levels of ANC utilization (OR=2.01, 95%CI:1.42,2.85; p<0.0001) and problem of distance to a health facility (OR=1.29, 95%CI:1.03,1.62; p=0.004) had a positive influence on women to give birth at home.

Conclusions

Not only individual characteristics of women, but also community-level factors determine women’s decision to deliver at home.     

Autophagic Signaling and Proteolytic Enzyme Activity in Cardiac and Skeletal Muscle of Spontaneously Hypertensive Rats following Chronic Aerobic Exercise

Hypertension is a cardiovascular disease associated with deleterious effects in skeletal and cardiac muscle. Autophagy is a degradative process essential to muscle health. Acute exercise can alter autophagic signaling. Therefore, we aimed to characterize the effects of chronic endurance exercise on autophagy in skeletal and cardiac muscle of normotensive and hypertensive rats. Male Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) were assigned to a sedentary condition or 6 weeks of treadmill running. White gastrocnemius (WG) of hypertensive rats had higher (p<0.05) caspase-3 and proteasome activity, as well as elevated calpain activity. In addition, skeletal muscle of hypertensive animals had elevated (p<0.05) ATG7 and LC3I protein, LAMP2 mRNA, and cathepsin activity, indicative of enhanced autophagic signaling. Interestingly, chronic exercise training increased (p<0.05) Beclin-1, LC3, and p62 mRNA as well as proteasome activity, but reduced (p<0.05) Beclin-1 and ATG7 protein, as well as decreased (p<0.05) caspase-3, calpain, and cathepsin activity. Left ventricle (LV) of hypertensive rats had reduced (p<0.05) AMPKα and LC3II protein, as well as elevated (p<0.05) p-AKT, p-p70S6K, LC3I and p62 protein, which collectively suggest reduced autophagic signaling. Exercise training had little effect on autophagy-related signaling factors in LV; however, exercise training increased (p<0.05) proteasome activity but reduced (p<0.05) caspase-3 and calpain activity. Our results suggest that autophagic signaling is altered in skeletal and cardiac muscle of hypertensive animals. Regular aerobic exercise can effectively alter the proteolytic environment in both cardiac and skeletal muscle, as well as influence several autophagy-related factors in skeletal muscle of normotensive and hypertensive rats.     

The Impact of Trachomatous Trichiasis on Quality of Life: A Case Control Study

Background

Trachomatous trichiasis is thought to have a profound effect on quality of life (QoL), however, there is little research in this area. We measured vision and health-related QoL in a case-control study in Amhara Region, Ethiopia.

Methodology/Principal Findings

We recruited 1000 adult trichiasis cases and 200 trichiasis-free controls, matched to every fifth trichiasis case on age (+/- two years), sex and location. Vision-related quality of life (VRQoL) and health-related quality of life (HRQoL) were measured using the WHO/PBD-VF20 and WHOQOL-BREF questionnaires. Comparisons were made using linear regression adjusted for age, sex and socioeconomic status. Trichiasis cases had substantially lower VRQoL than controls on all subscales (overall eyesight, visual symptom, general functioning and psychosocial, p<0.0001), even in the sub-group with normal vision (p<0.0001). Lower VRQoL scores in cases were associated with longer trichiasis duration, central corneal opacity, visual impairment and poor contrast sensitivity. Trichiasis cases had lower HRQoL in all domains (Physical-health, Psychological, Social, Environment, p<0.0001), lower overall QoL (mean, 34.5 v 64.6; p<0.0001) and overall health satisfaction (mean, 38.2 v 71.7; p<0.0001). This association persisted in a sub-group analysis of cases and controls with normal vision. Not having a marriage partner (p<0.0001), visual impairment (p = 0.0068), daily labouring (p<0.0001), presence of other health problems (p = 0.0018) and low self-rated wealth (p<0.0001) were independently associated with lower overall QoL scores in cases. Among cases, trichiasis caused 596 (59%) to feel embarrassed, 913 (91.3%) to worry they may lose their remaining eyesight and 681 (68.1%) to have sleep disturbance.

Conclusions/Significance

Trachomatous trichiasis substantially reduces vision and health related QoL and is disabling, even without visual impairment. Prompt trichiasis intervention is needed both to prevent vision loss and to alleviate physical and psychological suffering, social exclusion and improve overall well-being. Implementation of the full SAFE strategy is needed to prevent the development of trachomatous trichiasis.     

Comparison of Visceral Fat Measures with Cardiometabolic Risk Factors in Healthy Adults

We aimed to evaluate the associations of visceral adiposity with cardiometabolic risk factors in normal subjects with integrated ¹⁸F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT). A total of 58 normal subjects who underwent ¹⁸F-FDG PET/CT scan for cancer screening were included in this study. Volume and average Hounsfield unit (HU) of visceral adipose tissue (VAT) was measured from CT components of integrated PET/CT. Standardized uptake values (SUVmax) of liver, spleen, lumbar spine and ascending aorta (AA) were measured from PET components of integrated PET/CT. Body mass index (coefficient 78.25, p = 0.0259), glucose (37.62, p<0.0001), insulin (348.90, p = 0.0011), logarithmic transformation of homeostatic model assessment index-insulin resistance (-2118.37, p = 0.0007), and VAT HU (-134.99, p<0.0001) were independently associated with VAT volume. Glucose (0.1187, p = 0.0098) and VAT volume (-0.004, p<0.0001) were found to be associated with VAT HU. Both VAT volume and VAT HU of whole abdominal cavity is significantly associated with cardiometabolic risk factors.     

Research Activity and the Association with Mortality

IntroductionThe aims of this study were to describe the key features of acute NHS Trusts with different levels of research activity and to investigate associations between research activity and clinical outcomes.MethodsNational Institute for Health Research (NIHR) Comprehensive Clinical Research Network (CCRN) funding and number of patients recruited to NIHR Clinical Research Network (CRN) portfolio studies for each NHS Trusts were used as markers of research activity. Patient-level data for adult non-elective admissions were extracted from the English Hospital Episode Statistics (2005-10). Risk-adjusted mortality associations between Trust structures, research activity and, clinical outcomes were investigated.ResultsLow mortality Trusts received greater levels of funding and recruited more patients adjusted for size of Trust (n = 35, 2,349 £/bed [95% CI 1,855–2,843], 5.9 patients/bed [2.7–9.0]) than Trusts with expected (n = 63, 1,110 £/bed, [864–1,357] p<0.0001, 2.6 patients/bed [1.7–3.5] p<0.0169) or, high (n = 42, 930 £/bed [683–1,177] p = 0.0001, 1.8 patients/bed [1.4–2.1] p<0.0005) mortality rates. The most research active Trusts were those with more doctors, nurses, critical care beds, operating theatres and, made greater use of radiology. Multifactorial analysis demonstrated better survival in the top funding and patient recruitment tertiles (lowest vs. highest (odds ratio & 95% CI: funding 1.050 [1.033–1.068] p<0.0001, recruitment 1.069 [1.052–1.086] p<0.0001), middle vs. highest (funding 1.040 [1.024–1.055] p<0.0001, recruitment 1.085 [1.070–1.100] p<0.0001).ConclusionsResearch active Trusts appear to have key differences in composition than less research active Trusts. Research active Trusts had lower risk-adjusted mortality for acute admissions, which persisted after adjustment for staffing and other structural factors.     

S-100 B Concentrations Are a Predictor of Decreased Survival in Patients with Major Trauma,Independently of Head Injury

Background

Major trauma remains one of the principle causes of disability and death throughout the world. There is currently no satisfactory risk assessment to predict mortality in patients with major trauma. The aim of our study is to examine whether S-100 B protein concentrations correlate with injury severity and survival in patients with major trauma, with special emphasis on patients without head injury.

Methods

Our retrospective data analysis comprised adult patients admitted to our emergency department between 1.12. 2008 and 31.12 2010 with a suspected major trauma. S-100 B concentrations were routinely assessed in major trauma patients.

Results

A total of 27.7% (378) of all patients had major trauma. The median ISS was 24.6 (SD 8.4); 16.6% (63/378) of the patients died. S-100 B concentrations correlated overall with the ISS (p<0.0001). Patients who died had significantly higher S-100 B concentrations than survivors (8.2 μg/l versus 2.2 μg/l, p<0.0001). Polytraumatised patients with and without head trauma did not differ significantly with respect to S-100 B concentration (3.2 μg/l (SD 5.3) versus 2.9 μg/l (SD 3.8), respectively, p = 0.63) or with respect to Injury Severity Score (24.8 (SD 8.6) versus 24.2 (SD 8.1), respectively, p = 0.56). S-100 B concentrations correlated negatively with survival (p<0.0001) in all patients and in both subgroups (p = 0.001 and p = 0.006, respectively)

Conclusions

S-100 concentrations on admission correlate positively with greater injury severity and decreased survival in major trauma patients, independently of the presence of a head injury. S-100 B protein levels at admission in patients with major trauma may therefore be used to assess outcome in all polytraumatised patients. These measurements should be subject to further evaluation.     

Increase in Dickkopf-1 Serum Level in Recent Spondyloarthritis. Data from the DESIR Cohort

Objectives

To investigate DKK-1 and SOST serum levels among patients with recent inflammatory back pain (IBP) fulfilling ASAS criteria for SpA and associated factors.

Methods

The DESIR cohort is a prospective, multicenter French cohort of 708 patients with early IBP (duration >3 months and <3 years) suggestive of AxSpA. DKK-1 and SOST serum levels were assessed at baseline and were compared between the subgroup of patients fulfilling ASAS criteria for SpA (n = 486; 68.6%) and 80 healthy controls.

Results

Mean SOST serum levels were lower in ASAS+ patients than healthy controls (49.21 ± 25.9 vs. 87.8 ± 26 pmol/L; p<0.0001). In multivariate analysis, age (p = 5.4 10⁻⁹), CRP level (p<0.0001) and serum DKK-1 level (p = 0.001) were associated with SOST level. Mean DKK-1 serum levels were higher in axial SpA patients than controls (30.03 ± 15.5 vs. 11.6 ± 4.2 pmol/L; p<0.0001). In multivariate analysis, DKK-1 serum levels were associated with male gender (p = 0.03), CRP level (p = 0.006), SOST serum level (p = 0.002) and presence of sacroiliitis on radiography (p = 0.05). Genetic association testing of 10 SNPs encompassing the DKK-1 locus failed to demonstrate a significant contribution of genetics to control of DKK-1 serum levels.

Conclusions

DKK-1 serum levels were increased and SOST levels were decreased among a large cohort of patients with early axial SpA compared to healthy controls. DKK-1 serum levels were mostly associated with biological inflammation and SOST serum levels.     

The effect of uphill stride manipulation on race walking gait

Stride length analysis represents an easy method for assessing race walking kinematics. However, the stride parameters emerging from such an analysis have never been used to design a training protocol aimed at increasing stride length. With this aim, we investigated the effects of stride frequency manipulation during three weeks of uphill (2%) training on stride length at iso-efficiency speed. Twelve male race walkers were randomly allocated to one of two training groups: stride frequency manipulation (RWM, n=6) and free stride frequency (RWF, n=6). Results. Kinematic parameters measured before and after the 3-week training in RWM showed increased stride length (4.54%; p<0.0001) and contact time (4.58%; p<0.001); inversely, a decreased stride frequency (4.44%; p<0.0001) and internal work (7.09%; p<0.05) were found. In RWF the effect of the training showed a decrease in stride length (1.18%; p<0.0001) and contact time (<1%; p<0.0001) with respect to baseline conditions and an increased stride frequency and internal work of 1.19% (p<0.0001). These results suggest that using slopes (2%) as RWM could help coaches to provide some training methods that would improve an athlete''s performance, through increasing stride length without altering his or her race walking technique or metabolic demands.     

Optical Coherence Tomography in Alzheimer’s Disease: A Meta-Analysis

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder, which is likely to start as mild cognitive impairment (MCI) several years before the its full-blown clinical manifestation. Optical coherence tomography (OCT) has been used to detect a loss in peripapillary retina nerve fiber layer (RNFL) and a reduction in macular thickness and volume of people affected by MCI or AD. Here, we performed an aggregate meta-analysis combining results from different studies.

Methods and Findings

Data sources were case-control studies published between January 2001 and August 2014 (identified through PubMed and Google Scholar databases) that examined the RNFL thickness by means of OCT in AD and MCI patients compared with cognitively healthy controls.

Results

11 studies were identified, including 380 patients with AD, 68 with MCI and 293 healthy controls (HC). The studies suggest that the mean RNFL thickness is reduced in MCI (weighted mean differences in μm, WMD = -13.39, 95% CI: -17.34 to -9.45, p = 0.031) and, even more so, in AD (WMD = -15.95, 95% CI: -21.65 to -10.21, p<0.0001) patients compared to HC. RNFL in the 4 quadrants were all significantly thinner in AD superior (superior WMD = -24.0, 95% CI: -34.9 to -13.1, p<0.0001; inferior WMD = -20.8, 95% CI: -32.0 to -9.7, p<0.0001; nasal WMD = -14.7, 95% CI: -23.9 to -5.5, p<0.0001; and temporal WMD = -10.7, 95% CI: -19.9 to -1.4, p<0.0001); the same significant reduction in quadrant RNFL was observed in MCI patients compared with HC (Inferior WMD = -20.22, 95% CI: -30.41 to -10.03, p = 0.0001; nasal WMD = -7.4, 95% CI: -10.08 to -4.7, p = 0.0000; and temporal WMD = -6.88, 95% CI: -12.62 to -1.13, p = 0.01), with the exception of superior quadrant (WMD = -19.45, 95% CI: -40.23 to 1.32, p = 0.06).

Conclusion

Results from the meta-analysis support the important role of OCT for RNFL analysis in monitoring the progression of AD and in assessing the effectiveness of purported AD treatments.     

Relevance of Distinct Monocyte Subsets to Clinical Course of Ischemic Stroke Patients

Background and Purpose

The most common strategy for treating patients with acute ischemic stroke is thrombolytic therapy, though only a few patients receive benefits because of the narrow time window. Inflammation occurring in the central nervous system (CNS) in association with ischemia is caused by immune cells including monocytes and involved in lesion expansion. If the specific roles of monocyte subsets in stroke can be revealed, they may become an effective target for new treatment strategies.

Methods

We performed immunological examinations of 36 consecutive ischemic stroke patients within 2 days of onset and compared the results with 24 age-matched patients with degenerative disorders. The stroke patients were repeatedly tested for the proportions of monocyte subsets in blood, and serum levels of pro- and anti-inflammatory cytokines immediately after admission, on days 3-7 and 12-16 after stroke onset, and on the day of discharge. In addition, immunological measurements were analyzed for relationships to stroke subtypes and complications, including progressive infarction (PI) and stroke-associated infection (SAI).

Results

Monocyte count was significantly increased from 0–16 days after stroke as compared to the controls (p<0.05). CD14^highCD16^- classical and CD14^highCD16⁺ intermediate monocytes were significantly increased from 0-7 and 3-16 days after stroke, respectively (p<0.05), whereas CD14 ^dimCD16^high non-classical monocytes were decreased from 0–7 days (p<0.05). Cardioembolic infarction was associated with a persistent increase in intermediate monocytes. Furthermore, intermediate monocytes were significantly increased in patients with PI (p<0.05), while non-classical monocytes were decreased in those with SAI (p<0.05). IL-17A levels were positively correlated with monocyte count (r=0.485, p=0.012) as well as the percentage of non-classical monocytes (r=0.423, p=0.028), and negatively with that of classical monocytes (r=-0.51, p=0.007) during days 12-16.

Conclusions

Our findings suggest that CD14^highCD16⁺ intermediate monocytes have a role in CNS tissue damage during acute and subacute phases in ischemic stroke especially in relation to cardioembolism.     

Differential effects of low-magnitude high-frequency vibration on reloading hind-limb soleus and gastrocnemius medialis muscles in 28-day tail-suspended rats

Objectives:Low-magnitude high-frequency vibration (LMHFV) was reported beneficial to muscle contractile functions in clinical and preclinical studies. This study aims to investigate the effects of LMHFV on myofibers, myogenic cells and functional properties of disused soleus (Sol) and gastrocnemius medialis (GM) during reloading.Methods:Sprague Dawley rats were hind-limb unloaded for 28 days and assigned to reloading control (Ctrl) or LMHFV group (Vib). Sol and GM of both groups were harvested for fiber typing, proliferating myogenic cell counting and in vitro functional assessment.Results:Myogenic cells proliferation was promoted by LMHFV in both Sol and GM (p<0.001 and p<0.05 respectively). Force generating capacity was not much affected (Vib=Ctrl, p>0.05) but fast-fiber favorable changes in fiber type switching (more type IIA but lower type I in Vib; p<0.05 and 0.01 respectively) and fiber hypertrophy (type I, Vib<Ctrl; p<0.01) were observed mainly in GM.Conclusion:LMHFV was not detrimental to reloading muscles but the outcomes were muscle dependent. The unique fiber type composition and anatomical differences between Sol and GM might render the differential muscle responses to LMHFV. Further investigations on myofibers type specific responses to different LMHFV regimes and myogenic cell interaction with associated myofiber were proposed.     

Insulin Growth Factor 1 Receptor Expression Is Associated with NOTCH1 Mutation,Trisomy 12 and Aggressive Clinical Course in Chronic Lymphocytic Leukaemia

IGF1R is emerging as an important gene in the pathogenesis of many solid and haematological cancers and its over-expression has been reported as frequently associated with aggressive disease and chemotherapy resistance. In this study we performed an investigation of the role of IGF1R expression in a large and representative prospective series of 217 chronic lymphocytic leukaemia (CLL) patients enrolled in the multicentre O-CLL1 protocol (clinicaltrial.gov #NCT00917540). High IGF1R gene expression was significantly associated with IGHV unmutated (IGHV-UM) status (p<0.0001), high CD38 expression (p<0.0001), trisomy 12 (p<0.0001), and del(11)(q23) (p=0.014). Interestingly, higher IGF1R expression (p=0.002) characterized patients with NOTCH1 mutation (c.7541_7542delCT), identified in 15.5% of cases of our series by next generation sequencing and ARMS-PCR. Furthermore, IGF1R expression has been proven as an independent prognostic factor associated with time to first treatment in our CLL prospective cohort. These data suggest that IGF1R may play an important role in CLL biology, in particular in aggressive CLL clones characterized by IGHV-UM, trisomy 12 and NOTCH1 mutation.     

Area-Level Socioeconomic Gradients in Overweight and Obesity in a Community-Derived Cohort of Health Service Users – A Cross-Sectional Study

Background

Overweight and obesity lead to higher probability of individuals accessing primary care but adiposity estimates are rarely available at regional levels to inform health service planning. This paper analyses a large, community-derived clinical database of objectively measured body mass index (BMI) to explore relationships with area-level socioeconomic disadvantage for informing regional level planning activities.

Materials and Methods

The study included 91776 adults who had BMI objectively measured between 1 July 2009 and 30 June 2011 by a single pathology provider. Demographic data and BMI were extracted and matched to 2006 national census socioeconomic data using geocoding. Adjusted odds-ratios for overweight and obesity were calculated using sex-stratified logistic regression models with socioeconomic disadvantage of census collection district of residence as the independent variable.

Results

The prevalence of overweight or obesity was 79.2% (males) and 65.8% (females); increased with age to 74 years; and was higher in rural (74%) versus urban areas (71.4%) (p<0.001). Increasing socioeconomic disadvantage was associated with increasing prevalence of overweight (p<0.0001), obesity (p<0.0001) and overweight or obesity (p<0.0001) in women and obesity (p<0.0001) in men. Socioeconomic disadvantage was unrelated to overweight (p = 0.2024) and overweight or obesity (p = 0.4896) in males.

Conclusion

It is feasible to link routinely-collected clinical data, representative of a discrete population, with geographic distribution of disadvantage, and to obtain meaningful area-level information useful for targeting interventions to improve population health. Our results demonstrate novel area-level socioeconomic gradients in overweight and obesity relevant to regional health service planning.