Severity-dependent Manner Research Articles

Risk Factors Associated with Childhood Strabismus: The Multi-Ethnic Pediatric Eye Disease and Baltimore Pediatric Eye Disease Studies

To investigate risk factors associated with esotropia or exotropia in infants and young children. Population-based cross-sectional prevalence study. Population-based samples of 9970 children 6 to 72 months of age from California and Maryland. Participants were preschool African-American, Hispanic, and non-Hispanic white children participating in the Multi-Ethnic Pediatric Eye Disease Study and the Baltimore Eye Disease Study. Data were obtained by parental interview and ocular examination. Odd ratios and 95% confidence intervals were calculated to evaluate the association of demographic, behavioral, and clinical risk factors with esotropia and exotropia. Odds ratios (ORs) for various risk factors associated with esotropia or exotropia diagnosis based on cover testing. In multivariate logistic regression analysis, esotropia was associated independently with prematurity, maternal smoking during pregnancy, older preschool age (48-72 months), anisometropia, and hyperopia. There was a severity-dependent association of hyperopia with the prevalence of esotropia, with ORs increasing from 6.4 for 2.00 diopters (D) to less than 3.00 D of hyperopia, to 122.0 for 5.00 D or more of hyperopia. Exotropia was associated with prematurity, maternal smoking during pregnancy, family history of strabismus, female sex, astigmatism (OR, 2.5 for 1.50 to <2.50 D of astigmatism, and 5.9 for ≥2.5 D of astigmatism), and anisoastigmatism in the J0 component (OR, ≥2 for J0 anisoastigmatism of ≥0.25 D). Prematurity and maternal smoking during pregnancy are associated with a higher risk of having esotropia and exotropia. Refractive error is associated in a severity-dependent manner to the prevalence of esotropia and exotropia. Because refractive error is correctable, these risk associations should be considered when developing guidelines for the screening and management of refractive error in infants and young children. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Transcriptomic response of murine liver to severe injury and hemorrhagic shock: a dual-platform microarray analysis

Trauma-hemorrhagic shock (HS/T) is a complex process that elicits numerous molecular pathways. We hypothesized that a dual-platform microarray analysis of the liver, an organ that integrates immunology and metabolism, would reveal key pathways engaged following HS/T. C57BL/6 mice were divided into five groups (n = 4/group), anesthetized, and surgically treated to simulate a time course and trauma severity model: 1) nonmanipulated animals, 2) minor trauma, 3) 1.5 h of hemorrhagic shock and severe trauma (HS/T), 4) 1.5 h HS/T followed by 1 h resuscitation (HS/T+1.0R), 5) 1.5 h HS/T followed by 4.5 h resuscitation (HS/T+4.5R). Liver RNA was hybridized to CodeLink and Affymetrix mouse whole genome microarray chips. Common genes with a cross-platform correlation >0.6 (2,353 genes in total) were clustered using k-means clustering, and clusters were analyzed using Ingenuity Pathways Analysis. Genes involved in the stress response and immunoregulation were upregulated early and remained upregulated throughout the course of the experiment. Genes involved in cell death and inflammatory pathways were upregulated in a linear fashion with elapsed time and in severe injury compared with minor trauma. Three of the six clusters contained genes involved in metabolic function; these were downregulated with elapsed time. Transcripts involved in amino acid metabolism as well as signaling pathways associated with glucocorticoid receptors, IL-6, IL-10, and the acute phase response were elevated in a severity-dependent manner. This is the first study to examine the postinjury response using dual-platform microarray analysis, revealing responses that may enable novel therapies or diagnostics.

Regulation of AKT Phosphorylation at Ser473 and Thr308 by Endoplasmic Reticulum Stress Modulates Substrate Specificity in a Severity Dependent Manner

Endoplasmic reticulum (ER) stress is a common factor in the pathophysiology of diverse human diseases that are characterised by contrasting cellular behaviours, from proliferation in cancer to apoptosis in neurodegenerative disorders. Coincidently, dysregulation of AKT/PKB activity, which is the central regulator of cell growth, proliferation and survival, is often associated with the same diseases. Here, we demonstrate that ER stress modulates AKT substrate specificity in a severity-dependent manner, as shown by phospho-specific antibodies against known AKT targets. ER stress also reduces both total and phosphorylated AKT in a severity-dependent manner, without affecting activity of the upstream kinase PDK1. Normalisation to total AKT revealed that under ER stress phosphorylation of Thr308 is suppressed while that of Ser473 is increased. ER stress induces GRP78, and siRNA-mediated knock-down of GRP78 enhances phosphorylation at Ser473 by 3.6 fold, but not at Thr308. Substrate specificity is again altered. An in-situ proximity ligation assay revealed a physical interaction between GRP78 and AKT at the plasma membrane of cells following induction of ER stress. Staining was weak in cells with normal nuclear morphology but stronger in those displaying rounded, condensed nuclei. Co-immunoprecipitation of GRP78 and P-AKT(Ser473) confirmed the immuno-complex consists of non-phosphorylated AKT (Ser473 and Thr308). The interaction is likely specific as AKT did not bind to all molecular chaperones, and GRP78 did not bind to p70 S6 kinase. These findings provide one mechanistic explanation for how ER stress contributes to human pathologies demonstrating contrasting cell fates via modulation of AKT signalling.

Heart failure severity, as determined by loop diuretic dosages, predicts the risk of developing diabetes after myocardial infarction: a nationwide cohort study

Heart failure (HF) is associated with increased insulin resistance, but the consequences of HF for development of diabetes are not well studied. The aim of the present study was to investigate the relationship between HF severity and risk of developing diabetes in a nationwide cohort of patients with myocardial infarction (MI). Patients discharged from first-time MI during 1997-2006 and not previously treated with glucose-lowering medications (GLM) or loop diuretics were identified from Danish nationwide registers. Heart failure severity was determined by loop diuretic dosage after discharge. Patients were followed until first claimed prescription of GLM, death, or until the end of 2006. The cohort comprised 50 874 patients. A total of 3006 (6%) had mild (loop-diuretic dosage≤40 mg/day), 5383 (11%) moderate (>40-120 mg/day), and 1127 (2%) severe (>120 mg/day) HF. During follow-up, 2531 (5%) patients developed diabetes. Increasing HF severity was associated with increased risk of diabetes, but the use of renin-angiotensin system inhibitors (RASi) attenuated the risk (P-value for interaction between the HF group and RASi<0.05). Compared with no HF, the adjusted hazard ratios (95% confidence interval) for the development of diabetes were 1.34 (1.11-1.63), 1.63 (1.40-1.90), and 1.68 (1.25-2.25) for mild, moderate, and severe HF with RASi treatment; and 1.45 (1.13-1.88), 1.90 (1.56-2.33), and 3.02 (2.01-4.54) for mild, moderate, and severe HF without RASi treatment. Heart failure predicts the development of diabetes in a severity-dependent manner among patients with MI. Focus on increased predisposition to diabetes is warranted and needs further investigations.

Relationship between injury severity and serum tau protein levels in traumatic brain injured rats

Background Although serum tau protein levels increase following TBI, the time course is unknown. The aim of the present study was to determine whether serum tau protein levels increased in both a severity-dependent and time-dependent manner in an experimental model of rat traumatic brain injury (TBI). Methods A total of 24 Sprague-Dawley rats were subjected to varying grades of TBI using a contusion injury model on the right parietal cortex. Enzyme-linked Immunoabsorbent Assay (ELISA) analysis for serum was performed at 15 min pre-injury, 1, 6, 24, 48, and 168 h post-injury. Immunoblotting for serum tau protein, neurological evaluation and histological observation were also performed. Results Tau protein levels rapidly increased after 1 h in both mild and severe TBI groups ( p < 0.001), and declined after 6 h. In the sham-operated group, tau protein levels did not change significantly after TBI. Tau protein levels were severity-dependent at 1 and 6 h after TBI. The levels were higher in the severe TBI group than in the mild TBI group at 1 h ( p < 0.001) and 6 h ( p < 0.001). Conclusions Serum tau protein levels were severity-dependent and time-dependent at 1 and 6 h after TBI. However, the serum tau protein may not be a useful marker 24 h after TBI.

A Possible Association Between Suspected Restrictive Pattern as Assessed by Ordinary Pulmonary Function Test and the Metabolic Syndrome

Impaired restrictive pulmonary function has been reported to be associated with insulin resistance and metabolic abnormalities. However, the possible association of restrictive pulmonary defect with metabolic syndrome (MetS) is not well understood. We examined the association in comparison with C-reactive protein (CRP), which is a predictor for MetS. We recruited 2,396 apparently healthy adults and investigated the associations among pulmonary function, metabolic abnormality, and MetS, as defined by three different criteria. Abnormal pulmonary function was evaluated by both continuous pulmonary function variables including the percentage of predicted FVC (%PFVC) and a clinical category defined according to the American Thoracic Society/European Respiratory Society guidelines. CRP and %PFVC, but not FEV1/FVC ratio, were significantly correlated with metabolic abnormalities even after adjustment for confounders including waist circumference. After adjustment for age, sex, and height, the odds ratios (ORs) of a restrictive pattern (RP), as defined by a reduced FVC and a normal FEV1/FVC ratio using the lower limit of normal and RP substitutively defined by reduced FVC and an FEV1/FVC ratio of > or = 85% for MetS, were 1.76 to 2.52 (p < 0.05 to < 0.0001) and 1.87 to 2.28 (p < 0.05 to < 0.01), respectively. The obstructive pattern (OP) was not significantly associated with any MetS criteria. A moderate-to-severe RP, but not a high CRP level (> 3.0 mg/L), was consistently associated with the three MetS criteria (OR, 2.08 to 3.57; p < 0.05 to < 0.01), even after adjustment for confounders. Impaired restrictive pulmonary function, but not OP, might be associated with metabolic disorders and MetS in a severity-dependent manner.

Delayed Neutrophil Apoptosis in Patients with Sleep Apnea

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia/reoxygenation (IHR), is associated with atherosclerosis. Polymorphonuclear leukocytes (PMNs) are implicated in atherogenesis by producing oxidizing radicals and proteolytic enzymes during PMN-endothelium interactions. PMN apoptosis is a fundamental, injury-limiting mechanism, which prevents their destructive potential. To determine whether PMN apoptosis and expression of adhesion molecules are affected by OSA and IHR in vitro. Apoptosis and expression of adhesion molecules were assessed in whole blood PMNs by flow cytometry, verified by various culture conditions, and morphology. These were complemented by exposing whole blood and purified PMNs to IHR and to sustained hypoxia in vitro. This study demonstrates for the first time that, in patients with moderate to severe OSA, PMN apoptosis is delayed. Apoptosis was attenuated in patients with an apnea-hypopnea index (AHI) of more than 15, determined by decreased expression of low-CD16/annexin-V-positive PMNs, by lowered caspase-3 activity and nuclear condensation. Concomitantly, selectin-CD15 expression was increased in a severity-dependent manner in patients with moderate to severe OSA having an AHI greater than 15. The percentage of apoptotic PMNs was negatively correlated with OSA severity, determined by AHI, and positively with CD15 expression. In nasal continuous positive airway pressure-treated patients, CD15 expression was attenuated and low CD16 was increased, whereas omitting nasal continuous positive airway pressure for a single night increased CD15 expression and decreased the percentage of low CD16. IHR in vitro delayed PMN apoptosis as well. Decreased apoptosis and increased expression of adhesion molecules were noted in OSA PMNs. Although adhesion molecules may facilitate increased PMN-endothelium interactions, decreased apoptosis may further augment these interactions and facilitate free radical and proteolytic enzyme release.

17β-Estradiol extends ischemic thresholds and exerts neuroprotective effects in cerebral subcortex against transient focal cerebral ischemia in rats

Neuroprotective effects of estrogens are demonstrated consistently in the cerebral cortex, but not in subcortical areas. In the present study, transient middle cerebral artery occlusions (MCAO) were induced for various duration, and protective effects of estrogen treatment on the cerebral cortex and subcortex were evaluated. MCAO was induced for 30, 40 or 60 min in ovariectomized rats. Animals were treated with 17β-estradiol (E2) or vehicle (OVX) 2 h before MCAO and sacrificed 24 h after the indicated duration of MCAO. Ischemic lesion was evaluated by 2,3,5-triphenyltetrazolium chloride staining, hematoxylin and eosin staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. E2 treatment reduced the magnitude and delayed the appearance of the total ischemic lesion area and largely prevented TUNEL staining in the cortex. In the subcortex, E2 treatment prevented the ischemic lesion in the 30-min group, reduced lesion area in the 40-min group, but had no effect on ischemic lesion area in the 60-min group. E2 treatment significantly decreased apoptotic cell number in the subcortical area at 30 and 40 min, but not at 60 min of MCAO. This study demonstrated that estrogen treatment can protect the cerebral subcortex in a severity-dependent manner, suggesting that the lack of protective effects of estrogen treatment in the subcortex is not due to the lack of estrogen receptors. Further, this study indicates that estrogens could be used as a neuroprotectant to prolong the therapeutic window of thrombolysis and prolong the time of cerebral circulation intervention for neurosurgical procedure.

Increased adenosine in cerebrospinal fluid after severe traumatic brain injury in infants and children: association with severity of injury and excitotoxicity.

To measure adenosine concentration in the cerebrospinal fluid of infants and children after severe traumatic brain injury and to evaluate the contribution of patient age, Glasgow Coma Scale score, mechanism of injury, Glasgow Outcome Score, and time after injury to cerebrospinal fluid adenosine concentrations. To evaluate the relationship between cerebrospinal fluid adenosine and glutamate concentrations in this population. Prospective survey. Pediatric intensive care unit in a university-based children's hospital. Twenty-seven critically ill infants and children who had severe traumatic brain injury (Glasgow Coma Scale < 8), who required placement of an intraventricular catheter and drainage of cerebrospinal fluid as part of their neurointensive care. None. Patients ranged in age from 2 months to 14 yrs. Cerebrospinal fluid samples (n = 304) were collected from 27 patients during the first 7 days after traumatic brain injury. Control cerebrospinal fluid samples were obtained from lumbar puncture on 21 infants and children without traumatic brain injury or meningitis. Adenosine concentration was measured by using high-pressure liquid chromatography. Adenosine concentration was increased markedly in cerebrospinal fluid of children after traumatic brain injury vs. controls (p < .001). The increase in cerebrospinal fluid adenosine was independently associated with Glasgow Coma Scale < or = 4 vs. > 4 and time after injury (both p < .005). Cerebrospinal fluid adenosine concentration was not independently associated with either age (< or = 4 vs. > 4 yrs), mechanism of injury (abuse vs. other), or Glasgow Outcome Score (good/moderately disabled vs. severely disabled, vegetative, or dead). Of the 27 patients studied, 18 had cerebrospinal fluid glutamate concentration previously quantified by high-pressure liquid chromatography. There was a strong association between increases in cerebrospinal fluid adenosine and glutamate concentrations (p < .005) after injury. Cerebrospinal fluid adenosine concentration is increased in a time- and severity-dependent manner in infants and children after severe head injury. The association between cerebrospinal fluid adenosine and glutamate concentrations may reflect an endogenous attempt at neuroprotection against excitotoxicity after severe traumatic brain injury.

Soluble E-selectin and eosinophil cationic protein are distinct serum markers that differentially represent clinical features of atopic dermatitis.

The serum levels of eosinophil cationic protein (ECP), soluble E-selectin (sE-selectin), soluble CD14 (sCD14) and interleukin (IL)-4 are known to be elevated in patients with atopic dermatitis (AD). However, little is known of the mutual relationship between these factors. To elucidate the clinical and mutual relevance of these markers, we examined the serum levels of ECP, sE-selectin, sCD14 and IL-4 as compared with eruption scores, itch scores, total IgE and numbers of peripheral eosinophils in patients with AD (n = 43), non-atopic eczema (n = 24) and urticaria (n = 13) and in normal individuals (n = 45). In 27 patients with AD the levels of these markers were compared before and after treatment. Levels of ECP were elevated only in the patients with AD, whereas the sE-selectin levels were higher not only in AD but also in non-atopic eczema in a severity-dependent manner. The levels of both markers significantly diminished after treatment. Significant correlations existed between ECP levels and numbers of eosinophils, sE-selectin levels and itch scores, and sE-selectin levels and IgE levels. No significant changes were observed in the sCD14 and IL-4 levels. Taken together, sE-selectin and ECP are good but distinct serum markers that reflect different clinical features of AD.