CD14 Expression in the First 24h of Sepsis: Effect of −260C>T CD14 SNP

Sepsis is defined as systemic inflammation caused by infection. The membrane bound CD14 (mCD14) or the soluble form (sCD14) play a crucial role facing Gram-negative and Gram-positive sepsis since they are pattern recognition receptors of the innate immune response enabling cells to produce inflammatory cytokines against bacterial infections. A ?260C>T single nucleotide polymorphism (SNP) was detected in the promoter modulating the CD14 gene expression. We hypothesized that the CD14 expression depends of the genetic inheritance of ?260C>T CD14 SNP and it is modulated by sepsis condition. We investigated human CD14 expression on early sepsis diagnosis (in vivo) and after LPS stimulation (in vitro), and determined the ?260C>T CD14 SNP. We found that TT homozygotes showed higher mCD14 density (p?=?0.0207), but not different sCD14 levels when compared to the CT+CC genotypes. Monocyte mCD14 density and sCD14 serum levels in our sample of early 14 septic patients were significantly higher than normal 30 controls (p<0.0001). Our results suggest that the ?260TT CD14 genotype is associated with higher monocyte mCD14, but not sCD14 expression, and that in the first 24 h after sepsis diagnosis, both monocyte mCD14 density and sCD14 levels are elevated, similarly to what is observed in vitro upon challenge with LPS.     

Phenotypic changes in the composition of muscular fibres in rat soleus motor units after 14 days of hindlimb unloading

The main goal of this study was to identify the different fibre types of the motor units (MUs) contained in the soleus muscles from control (CONT) rats and from rats submitted to 14 days of hindlimb unloading (HU). The MU types were classified according to their contractile properties and also using glycogen depletion followed by adenosine triphosphatase (ATPase) staining. In CONT rats, the soleus muscle contained two MU types identified as slow and fast types. After HU, the MU distribution showed three populations: slow, intermediate and fast. All the MUs from HU soleus were heterogeneous in terms of fibre type composition, indicating a complex remodelling of the muscle.     

Electrophysiological correlates of word meanings in 14‐month‐old human infants

Two studies were conducted in a preliminary attempt to determine whether electrophysiological procedures could be used to study early word learning in young infants. In Experiment 1, auditory evoked responses (AERs) were recorded from the frontal, temporal, and parietal scalp regions of a group of 14‐month‐old infants while they listened to a series of words. The brain responses reliably discriminated between words the infants were thought (by their parents and two independent raters) to understand versus those that they did not appear to know. A second experiment was conducted with a different group of infants to determine whether familiarity with the sounds alone could produce similar brainwave differences. This study, although showing that the brain‐wave patterns could discriminate familiar from novel speech‐sound sequences, did not demonstrate findings identical to those reported for differences in word understanding. These data are the first indication that AERs can be used to detect differences in word meanings in infants.     

Predictors of maximal short-term power outputs in basketball players 14-16 years

Relationships between growth, maturation and maximal short-term power outputs were investigated in 94 youth basketball players aged 14–16 years. Data included chronological age (CA), skeletal age (SA), years of training; body dimensions, estimated thigh volume, a running based short-term exercise assessed by the line drill test (LDT), the Bangsbo sprint test (BST) and short-term muscle power outputs with the Wingate anaerobic test (WAnT). Multiple linear regression analyses were used to estimate the effects of CA, skeletal maturity (SA/CA), years of training experience, body size and lower-limb volume on short-term performance in the LDT, BST and WAnT, respectively. Explained variances differed between cycle-ergometry outputs (52–54%) and running test performances (23–46%). The independent effects of predictors were small in the fatigue scores of the WAnT (4%) and the BST (11%). Skeletal maturity, body mass and leg length were primary predictors for all maximal short-term power output measures. Leg length was more relevant as a predictor than stature in the WAnT outputs, while stature and body mass appeared in the model with the running tests as dependent variable. Maximal short-term running abilities were also sensitive to years of training. In summary, skeletal maturation, body size and thigh muscle mass explained moderate to large proportions of the variance on maximal short-term performances of adolescent basketball players. The results highlight the importance of considering maturity status in evaluating the maximal short-term power outputs of adolescent athletes.     

Association of 14-3-3 ε gene haplotype with completed suicide in Japanese

Genetic factors have been suggested to be involved in suicide. Although some genetic factors, such as serotonergic transduction, have been associated with suicide, the results are inconsistent. There is a possibility that various signaling anomalies are involved in the biological vulnerability to suicide. We carried out a genome-wide gene-expression study in the brains of suicide victims using DNA microarrays;14-3-3 , which is related to neurogenesis, was one of the genes upregulated in the brains of suicide victims in the microarray analysis. This was confirmed by Western blot analysis. To examine the possibility of the involvement of 14-3-3 in the pathogenesis of suicide, we investigated the association of the 14-3-3 gene and completed suicide. We used three high-frequency SNPs (rs1532976, rs3752826, and rs9393) and found a significant association of two alleles (rs1532976 and rs3752826) with completed suicide (p < 0.05). Moreover, the distribution of haplotype revealed a more significant difference between completed suicide and controls (p=0.0005). This finding suggests that 14-3-3 is a potential suicide susceptibility gene and implies that dysregulation of neurogenesis may be involved in suicide.     

Seasonal and weather variation of sleep and physical activity in 12–14-year-old children

Background: Understanding variation in physical activity (PA) and sleep is necessary to develop novel intervention strategies targeting adolescents’ health behaviors. We examined the extent to which PA and sleep vary by aspects of the physical environment. Participants: We performed a cross-sectional analysis of 669 adolescents in the Project Viva cohort. Methods: We estimated total PA, sleep duration, sleep efficiency, and sleep midpoint timing from wrist accelerometers. We used multivariable linear regression models and generalized estimated equations to assess associations of PA and sleep with season and daily weather conditions obtained from the National Oceanic and Atmospheric Administration archive. Results: Mean age was 12.9 (SD 0.6) years; 51% were female and 68% were white. Mean sleep duration was 466 (SD 42) min per night and total PA was 1,652 (SD 431) counts per min per day. Sleep midpoint time was 41 (95% CI: 27 to 54) min later in summer, 28 (95% CI: ?41 to ?14) min earlier in spring, and 29 (95% CI: ?43 to ?15) min earlier in autumn compared to winter. Higher temperature and longer day length both were associated with small reductions of nightly sleep duration. Adolescents were less physically active during winter and on rainy and short sunlight days. There was an inverse U-shaped relationship between PA and mean temperature. Conclusions: Season was associated with large changes in sleep timing, and smaller changes in other sleep and PA measurements. Given the importance of sleep and circadian alignment, future health behavioral interventions may benefit by targeting “season-specific” interventions.     

Gains of 12q13–14 and overexpression of mdm2 are frequent findings in intimal sarcomas of the pulmonary artery

The characterization of clinical, histopathological, immunohistochemical, and genetic features of intimal sarcomas arising in the pulmonary artery is presented in this study. Four resected lungs, one endarterectomy specimen and three biopsies from eight patients (four males and four females; median age 41 years) suffering from intimal sarcomas of the pulmonary artery using conventional stains, immunohistochemistry, and comparative genomic hybridization (CGH) were analyzed. The predominant clinical presentation was dyspnea (all eight patients) and febrile pulmonary disease (six of eight). Signs of embolic lung disease were present in all patients. One patient died postoperatively, six patients died of disease 8-35 months after presentation, and one patient was alive 6 months after surgery. Histopathological examination of the submitted material showed spindle cell, partially myxoid and pleomorphic sarcomas. Metastases were histologically confirmed in three patients (lung, pleura, and skull). Immunohistochemically, vimentin was strongly expressed in all tumors. Focal positivity was observed for alpha smooth muscle actin, CD117, CD68, p53, and bcl2. No reaction could be obtained for endothelial markers. The proliferation index Ki-67 was between 5% and 80%. Six examined tumors were positive for mdm2. In the CGH analysis, gains and amplifications in the 12q13-14 region were found in six of eight tumors (75%). Other, less consistent alterations, were losses on 3p, 3q, 4q, 9p, 11q, 13q, Xp, and Xq, gains on 7p, 17p, and 17q, and amplifications on 4q, 5p, 6p, and 11q. Intimal sarcomas of the pulmonary artery are tumors with an unfavorable prognosis and poorly differentiated morphology. A majority of tumors show a consistent genetic alteration (gains and amplifications in the 12q13-14 region) and overexpression of mdm2, implicating the mdm2/p53 pathway as a possible mechanism in the tumor pathogenesis.     

Age of onset of pubertal characteristics in boys aged 6–14 years of the Province of L’Aquila (Abruzzo,Italy)

Background:?Previous results on growth patterns of children from central-southern Italy (Abruzzo region) showed an increasing tendency to obesity and suggested that the secular trend was still in progress in this region. However, data on pubertal development was lacking.

Objective:?The objective of the study was to provide population data on pubertal development in a sample of 535 boys aged 6–14 years as a contribution to the ongoing debate on earlier onset of pubertal traits and on the slowing down of the secular trend.

Methods:?A cross-sectional survey was used. Data for genital and pubic hair development (GD and PHD) were analysed by probit analysis.

Results:?The boys start developing sexual characteristics at age 9: 13.3% had entered stage 2 of GD and 8.9% showed PHD. At 13 years of age, 5% and 7.4% were still in stage 1 of GD and PHD, respectively, whereas almost one-third had attained stage 5 for both sexual characteristics. The median age for attainment of stage 2 was 11.2 years for GD, 11.5 years for PHD and 11 years for one or both of them.

Conclusions:?These results are in line with those for several European and industrialized countries and do not show a significantly earlier onset of sexual maturation.     

Profiles of metabolic gene expression in the white adipose tissue,liver and hypothalamus in leptin knockout (LepΔI14/ΔI14 ) rats

Leptin deficiency is principally linked to metabolic disorders. Leptin knockout (LepΔI14/ΔI14) Sprague Dawley rats created by CRISPR/Cas9 is a new model to study metabolic disorders. We used a whole rat genome oligonucleotide microarray to obtain tissue-specific gene expression profiles of the white adipose tissue, liver and hypothalamus in LepΔI14/ΔI14 and wild-type (WT) rats. We found 1,651 differentially expressed (enriched) genes in white adipose tissue, 916 in the liver, and 306 in the hypothalamus in the LepΔI14/ΔI14 rats compared to WT. Gene ontology category and KEGG pathway analysis of the relationships among differentially expressed genes showed that these genes were represented in a variety of functional categories, including fatty acid metabolism, molecular transducers and cellular processes. The reliability of the data obtained from microarray was verified by quantitative real-time PCR on 14 representative genes. These data will contribute to a greater understanding of different metabolic disorders, such as obesity and diabetes.     

Does the developmental status of Valpha14i NKT cells play a role in disease?

CD1d-restricted natural killer T (NKT) cells that express an invariant Valpha14 T-cell receptor (TCR) represent a subset of T cells implicated in the regulation of several immune responses, including autoimmunity, infectious diseases, and cancer. Their immunoregulatory functions are defined by their ability to rapidly and abundantly produce cytokines when activated. Unlike conventional T cells, Valpha14i NKT cells appear unique in their tendency to simultaneously produce both Th1 and Th2 cytokines, and whereas they enhance immunity in some disease models, they are reported to suppress immunity in others. This makes their effect on immune responses unpredictable. We reported recently that several important changes in gene expression occur in the course of Valpha14i NKT cell development. Immature and mature Valpha14i NKT cells differ in their expression of cytokines and chemokines, their cytotoxicity, and their expression of diverse chemokine receptors important for their migration. These results suggest that functionally distinct and developmentally linked subsets of Valpha14i NKT cells exist. Although mature NKT cells make up the majority of the peripheral NKT cells, a steady and sizable number of immature NKT cells migrate from the thymus into the periphery each day. These immature NKT cells, contrary to their name, are functional but are likely to behave quite differently from their mature counterparts. To what extent the developmental status of Valpha14i NKT cells plays a role in the outcome of any given immune response remains to be determined. Here we review the current knowledge of Valpha14i NKT cell development and propose that different developmental intermediates might be responsible for the various effects that have been observed in the many models where Valpha14i NKT cells have been implicated.     

Overexpression of 14-3-3ε predicts tumour metastasis and poor survival in hepatocellular carcinoma

Ko B‐S, Chang T‐C, Hsu C, Chen Y‐C, Shen T‐L, Chen S‐C, Wang J, Wu K K, Jan Y‐J & Liou J‐Y
(2011) Histopathology 58 , 705–711
Overexpression of 14‐3‐3ε predicts tumour metastasis and poor survival in hepatocellular carcinoma Aims: The results of our earlier studies suggested that 14‐3‐3ε is involved in cancer cell survival and growth. However, it is not clear whether 14‐3‐3ε plays a role in tumour metastasis and patient outcome. The aim of this study was to determine whether 14‐3‐3ε is a marker for predicting hepatocellular carcinoma (HCC) metastasis and survival. Methods and results: One hundred and fourteen patients with tissue‐diagnosed primary HCC were followed for an average of 58.6 months. 14‐3‐3ε in liver tissues was analysed by immunohistochemistry, and quantified by a Quick score system. Correlation of 14‐3‐3ε with patient survival and metastasis was analysed with a Wilcoxon signed rank test, Kaplan–Meier survival curves, and Cox proportional hazard regression. Seventy‐one of 114 patients (62.3%) had a significant increase of 14‐3‐3ε expression in HCC tissues, whereas normal tissues expressed weak or undetectable 14‐3‐3ε. Elevated 14‐3‐3ε expression was significantly associated with shortened overall survival and progression‐free survival. Furthermore, 14‐3‐3ε overexpression increased the risk of metastasis 4.6‐fold. Conclusions: Overexpression of 14‐3‐3ε in primary HCC tissues predicts a high risk of extrahepatic metastasis and worse survival, and is a potential therapeutic target.     

Is a duplication of 14q32 a new recurrent chromosomal alteration in B-cell non-Hodgkin lymphoma?

Identification of clonal chromosomal abnormalities involving 14q32 and its association with specific histological subtypes of non-Hodgkin lymphoma (NHL) has provided substantial insight to the genetic events leading to the disease. However, in some cases with inferior morphology of tumor cell chromosomes, the additional segment on chromosome 14 remains unidentified by cytogenetic banding techniques alone. To elucidate the origin of the additional chromosomal segment and to correlate the newly determined alterations with histology, metaphases from 15 NHL patients with add(14)(q32) were examined using fluorescence in situ hybridization (FISH) techniques after cytogenetic analysis had been performed. We found the duplication of 14q involving the q32 region in 6 cases with a dup(14) (q32) in 4 cases and a dup(14)(q24q32) in 2 cases. In 8 cases, FISH unveiled known NHL associated translocations; a t(14;18)(q32;q21) in 4 cases, a t(11;14)(q13;q32) in 2 cases, a t(8;14)(q24;q32) and a t(9;14)(p13;q32) in 1 case each. We also noted a t(14;17)(q32;q21) in 1 case. The use of FISH was a valuable asset in determining the origin of the additional material on chromosome 14q32, and helped resolve a group of B-cell NHLs with involvement of a duplicated 14q32 region.     

Growth status of indigenous school children 6–14 years in the Tarahumara Sierra,Northern Mexico,in 1990 and 2007

Aims: The study evaluated the growth status and secular change in body size of indigenous Tarahumara children in northern Mexico.

Methods: Heights and weights of Tarahumara children 6–14 years were measured in 1990 (n = 601) and 2007 (n = 583); the BMI was calculated. International criteria defined weight status while United States reference data defined stunting.

Results: Estimated secular gains in height from 1990 to 2007 were greatest in 6–7 year-old boys and declined with age to a small, non-significant secular decline in boys 12–14 years. Among girls secular gains in height were similar at 6–7 and 8–9 years, largest at 10–11 years and small and non-significant at 12–14 years. Secular gains in weight were similar among 6–7 and 8–9 year-old boys and girls, were greater in girls than in boys at 10–11 years and showed a small, non-significant secular decline in boys and girls 12–14 years. Secular change in the BMI paralleled those for weight. The prevalence of stunting declined from 1990 to 2007 in both sexes and all age groups except 12–14 year youth. Overweight was more prevalent in girls than boys in both years and increased from 4% to 7% in boys and 9% to 13% in girls. Obesity was not common among boys and girls in each age group and in both years. Stunting and overweight/obesity were not related in either 1990 or 2007.

Conclusion: Positive secular changes in growth status have occurred in Tarahumara children 6–11 years in contrast to negligible changes among children 12–14 years. The results suggest recent improvements in health and nutrition sufficient to support a positive secular trend in younger children.     

Role of SIRPα in regulation of mucosal immunity in the intestine

Mononuclear phagocytes such as dendritic cells (DCs) and macrophages in the lamina propria (LP) are thought to be important for both induction of inflammatory responses and maintenance of immunologic tolerance in the mammalian intestine. The molecular mechanisms by which these cells regulate intestinal immunity have remained poorly understood, however. Signal regulatory protein α (SIRPα) is a transmembrane protein that is specifically expressed in DCs, macrophages and neutrophils. Here, we show that SIRPα is abundant in CD11c(+) CD11b(+) LP cells of the mouse intestine. Whereas SIRPα did not appear to be important for the steady-state homeostasis of mucosal immunity in the intestine, the flagellin-stimulated production of IL-17 or interferon (IFN)-γ by LP cells of SIRPα mutant (MT) mice that lack the cytoplasmic region of the protein was markedly decreased compared with that observed with wild-type cells. Moreover, the flagellin-induced production of IL-6 by LP cells from SIRPα MT mice was also greatly reduced. SIRPα MT mice were also resistant to the development of colitis induced by IL-10 deficiency. Our data thus suggest that SIRPα expressed on CD11c(+) LP cells is important for the production of IL-17 or IFN-γ in the LP as well as for the development of colitis induced by IL-10 deficiency.     

Exercise training-induced lowering of inflammatory (CD14+CD16+) monocytes: a role in the anti-inflammatory influence of exercise?

Exercise training or higher levels of physical activity are known to exert anti-inflammatory effects. CD14+CD16+ monocytes are potent producers of inflammatory proteins, and elevated levels of these "inflammatory" monocytes have been implicated in disease development. Little is known about the influence of exercise training on this cell population. On the basis of their physical activity pattern, male and female subjects, 65-80 years old, were assigned to a physically active (PA; n=15) or inactive (PI; n=15) group. The PI group performed 12 weeks (3 days/week) of endurance (20 min at 70-80% heart-rate reserve) and resistance exercise training (eight exercises, two sets at 70-80% of one repetition maximum). Subjects in the PA group maintained their habitual activity level. Flow cytometry was used to determine monocyte phenotype and monocyte TLR4 expression. ELISAs were used to measure whole blood, LPS-stimulated TNF-alpha production, and serum C-reactive protein (CRP). At baseline, the PA group had a lower percentage of CD14+CD16+ monocytes and lower unstimulated production of TNF-alpha than the PI group. CD14+CD16+ monocyte percentage and 1 ng/ml LPS-stimulated TNF-alpha production were reduced after the PI group underwent 12 weeks of exercise training. PI subjects also had higher TLR4 expression on classical monocytes, but there were no significant exercise training-induced changes in monocyte TLR4 expression. The PA group had significantly lower serum CRP than the PI group. Physical activity was associated with lower CD14+CD16+ monocyte percentage and LPS-stimulated TNF-alpha production. Exercise training-induced reductions in CD14+CD16+ monocytes may contribute to the anti-inflammatory effects of exercise training.     

The Influences of CD14 −260C>T Polymorphism on Survival in ICU Critically Ill Patients

In order to analyze the effect of the two different versions of the cluster of differentiation 14 (CD14) receptor recognizing gene on survival, we determined the ?260C>T single nucleotide polymorphism (SNP) frequencies in 514 critically ill patients. We compared the ?260TT homozygotes with ?260C allele carriers (?260CC and ?260CT genotypes) and we demonstrated—260TT patients had the highest survival rate (82% vs 64%; p < 0.001; OR = 2.52, 95% CI = 1.43–4.46). We performed binary logistic regression, incorporating both ?260C>T genotype groups and the main clinical predictors to exclude other risk factors that could influence the outcome from critical illness: higher age, APACHE II score, and length of stay at hospital, and the occurrence of sepsis and septic shock were risk factors to Intensive Care Unit (ICU) patient's mortality, but the ?260TT genotype was protective factor toward survival (p = 0.001; OR = 3.08 95%CI = 1.54–5.98). Among septic and septic shock patients, ?260TT genotype was also protective factor toward survival (p = 0.001; OR = 3.11 95%CI = 1.63–6.66 to septic patients, and p = 0.001; OR = 3.80 95%CI = 1.68–8.58 to patients with septic shock). Our results and our hypothesis suggest that the higher ?260TT genotype frequency in ICU survivor patients is possibly explained by a beneficial effect on innate immunity signaling.