Stress Procedure Research Articles

Error consciousness predicts physiological response to an acute psychosocial stressor in men

There are substantial individual differences in the response towards acute stressor. The aim of the current study was to examine how the neural activity after an error response during a non-stressful state, prospectively predicts the magnitude of physiological stress response (e.g., cortisol response and heart rate) and negative affect elicited by a laboratory stress induction procedure in nonclinical participants. Thirty-seven healthy young male adults came to the laboratory for the baseline neurocognitive measurement on the first day during which they performed a Go/Nogo task with their electroencephalogram recorded. On the second day, they came again to be tested on their stress response using an acute psychosocial stress procedure (i.e., the Trier Social Stress Test, the TSST). Results showed that the amplitude of error positivity (Pe) significantly predicted both the heart rate and cortisol response towards the TSST. Our results suggested that baseline cognitive neural activity reflecting error consciousness could be used as a biological predictor of physiological response to an acute psychological stressor in men.

Evaluation of the effectiveness of chronic antidepressant drug treatments in the hippocampal mitochondria – A proteomic study in an animal model of depression

Several lines of evidence indicate that adverse experience in early life may be a triggering factor for disturbances in the brain mitochondrial proteins and lead to the development of depression in adulthood. On the other hand, little is known about the impact of chronic administration of various antidepressant drugs on the brain mitochondria, as a target for the pharmacotherapy of depression.The purpose of our study was to compare the impact of chronic treatment with two antidepressant drugs with different mechanisms of action, a tricyclic antidepressant (TCA), imipramine, and an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class, fluoxetine, on the mitochondria-enriched subproteome profile in the hippocampus of 3-month-old male rats following a prenatal stress procedure (an animal model of depression).We clearly confirmed that chronic imipramine and fluoxetine administration not only normalized depression-like disturbances evoked by the prenatal stress procedure but also modulated the mitochondria-enriched subproteome profile in the hippocampus of adult offspring rats. In line with this, two-dimensional electrophoresis coupled with mass spectrometry showed a statistically significant down-regulation of 14-3-3 and cytochrome bc1 proteins and an up-regulation of COP9 signalosome expression after chronic imipramine treatment in the hippocampus of prenatally stressed offspring. Fluoxetine administration strongly up-regulated the expression of cathepsin D, one of the key proteins involved in the prevention of the development of neurodegenerative processes. Furthermore, this antidepressant treatment enhanced expression of proteins engaged in the improvement of learning and memory processes (STMN1, Dnm-1) as well as in mitochondrial biogenesis and defense against oxidative stress (DJ-1).These findings provide new evidence that chronic administration of antidepressants exerts a varied impact on the mitochondria-enriched subproteome in the hippocampus of adult rats following a prenatal stress procedure. In particular, the effect of fluoxetine requires additional experiments to elucidate the possible beneficial biological consequences underlying the effects mediated by this antidepressant.

Systemic N-terminal fragments of adrenocorticotropin reduce inflammation- and stress-induced anhedonia in rats

Emerging evidence implicates impaired self-regulation of the hypothalamic–pituitary–adrenal (HPA) axis and inflammation as important and closely related components of the pathophysiology of major depression. Antidepressants show anti-inflammatory effects and are suggested to enhance glucocorticoid feedback inhibition of the HPA axis. HPA axis activity is also negatively self-regulated by the adrenocorticotropic hormone (ACTH), a potent anti-inflammatory peptide activating five subtypes of melanocortin receptors (MCRs). There are indications that ACTH-mediated feedback can be activated by noncorticotropic N-terminal ACTH fragments such as a potent anti-inflammatory MC1/3/4/5R agonist α-melanocyte-stimulating hormone (α-MSH), corresponding to ACTH(1-13), and a MC3/5R agonist ACTH(4-10). We investigated whether intraperitoneal administration of rats with these peptides affects anhedonia, which is a core symptom of depression. Inflammation-related anhedonia was induced by a single intraperitoneal administration of a low dose (0.025mg/kg) of lipopolysaccharide (LPS). Stress-related anhedonia was induced by the chronic unpredictable stress (CUS) procedure. The sucrose preference test was used to detect anhedonia. We found that ACTH(4-10) pretreatment decreased LPS-induced increase in serum corticosterone and tumor necrosis factor (TNF)-α, and a MC3/4R antagonist SHU9119 blocked this effect. Both α-MSH and ACTH(4-10) alleviated LPS-induced anhedonia. In the CUS model, these peptides reduced anhedonia and normalized body weight gain. The data indicate that systemic α-MSH and ACTH(4-10) produce an antidepressant-like effect on anhedonia induced by stress or inflammation, the stimuli that trigger the release of ACTH and α-MSH into the bloodstream. The results suggest a counterbalancing role of circulating melanocortins in depression and point to a new approach for antidepressant treatment.

Effects of escitalopram and paroxetine on mTORC1 signaling in the rat hippocampus under chronic restraint stress

BackgroundRecent studies have suggested that the activation of mammalian target of rapamycin (mTOR) signaling may be related to antidepressant action. Therefore, the present study evaluated whether antidepressant drugs would exert differential effects on mTOR signaling in the rat hippocampus under conditions of chronic restraint stress. Male Sprague–Dawley rats were subjected to restraint stress for 6 h/days for 21 days with either escitalopram (10 mg/kg) or paroxetine (10 mg/kg) administered after the chronic stress procedure. Western blot analyses were used to assess changes in the levels of phospho-Ser2448-mTOR, phospho-Thr37/46-4E-BP-1, phospho-Thr389-p70S6 K, phospho-Ser422-eIF4B, phospho-Ser240/244-S6, phospho-Ser473-Akt, and phospho-Thr202/Tyr204-ERK in the hippocampus.ResultsChronic restraint stress significantly decreased the levels of phospho-mTOR complex 1 (mTORC1), phospho-4E-BP-1, phospho-p70S6 K, phospho-eIF4B, phospho-S6, phospho-Akt, and phospho-ERK (p < 0.05); the administration of escitalopram and paroxetine increased the levels of all these proteins (p < 0.05 or 0.01). Additionally, chronic restraint stress reduced phospho-mTORC1 signaling activities in general, while escitalopram and paroxetine prevented these changes in phospho-mTORC1 signaling activities.ConclusionThese findings provide further data that contribute to understanding the possible relationships among mTOR activity, stress, and antidepressant drugs.

Stimulatory effect of desipramine on lung metastases of adenocarcinoma MADB 106 in stress highly-sensitive and stress non-reactive rats

The effect of antidepressant drugs on tumor progress is very poorly recognized. The aim of the present study was to examine the effect of individual reactivity to stress and 24-day desipramine (DES) administration on the metastatic colonization of adenocarcinoma MADB 106 cells in the lungs of Wistar rats. Wistar rats were subjected to stress procedure according to the chronic mild stress (CMS) model of depression for two weeks and stress highly-sensitive (SHS) and stress non-reactive (SNR) rats were selected. SHS rats were more prone to cancer metastasis than SNR ones and chronic DES treatment further increased the number of lung metastases by 59% and 50% in comparison to vehicle-treated appropriate control rats. The increase in lung metastases was connected with DES-induced skew macrophage activity towards M2 functional phenotype in SHS and SNR rats. Moreover, during 24h after DES injection in healthy rats, the decreased number of TCD8+ and B cells in SHS and SNR rats as well as NK cell cytotoxic activity in SNR rats could be attributed to the lowered capacity to defend against cancer metastasis observed in chronic DES treated and tumor injected rats.

Gender differences in automatic thoughts and cortisol and alpha-amylase responses to acute psychosocial stress in patients with obsessive-compulsive personality disorder

IntroductionObsessive-compulsive personality disorder (OCPD) has a pervasive pattern of preoccupation with orderliness, perfection, and mental and interpersonal control at the expense of flexibility, openness, and efficiency. The aims of the present study were to explore the relationship between OCPD and psychological stress and psychological tests. MethodsWe evaluated 63 OCPD patients and 107 healthy controls (HCs). We collected saliva samples from patients and controls before and after a social stress procedure, the Trier Social Stress Test (TSST), to measure the concentrations of salivary alpha-amylase (sAA) and salivary cortisol. The Childhood Trauma Questionnaire (CTQ), Profile of Mood State (POMS), State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), Social Adaptation Self-Evaluation Scale (SASS), and Depression and Anxiety Cognition Scale (DACS) were administered to patients and HCs. ResultsFollowing TSST exposure, the salivary amylase and cortisol levels were significantly decreased in male patients compared with controls. Additionally, OCPD patients had higher CTQ, POMS, STAI, and BDI scores than HCs and exhibited significantly higher anxiety and depressive states. OCPD patients scored higher on future denial and threat prediction as per the DACS tool. According to a stepwise regression analysis, STAI, POMS, and salivary cortisol responses were independent predictors of OCPD. ConclusionsOur results suggested that attenuated sympathetic and parasympathetic reactivity in male OCPD patients occurs along with attenuated salivary amylase and cortisol responses to the TSST. In addition, there was a significant difference between OCPD patients and HCs in child trauma, mood, anxiety, and cognition. The finding support the modeling role of cortisol (20min) on the relationships between STAI trait and depression among OCPD.

Activation of cannabinoid receptors elicits antidepressant-like effects in a mouse model of social isolation stress.

Social isolation stress (SIS) paradigm is a chronic stress procedure able to induce profound behavioral and neurochemical changes in rodents and evokes depressive and anxiety-like behaviors. Recent studies demonstrated that the cannabinoid system plays a key role in behavioral abnormalities such as depression through different pathways; however, there is no evidence showing a relation between SIS and the cannabinoid system. This study investigated the role of the cannabinoid system in depressive-like behavior and anxiety-like behavior of IC animals. For this purpose, NMRI mice were treated with WIN55, 212-2 (non-selective cannabinoid receptor agonist) and AM-251 (cannabinoid receptor type 1 antagonist) and AM-630 (cannabinoid receptor type 2 antagonist). We found that behavioral abnormality followed by SIS was mitigated after administration of WIN55, 212-2. Also, depressive-like effects induced by SIS were significantly increased following administration of AM-251 and AM-630. Co-administration of cannabinoid receptor antagonists (AM-251 and AM-630), significantly reversed the antidepressant effect of WIN55, 212-2 in IC animals. Our findings suggest that the cannabinoid system is involved in depressive-like behaviors induced by SIS. We showed that activation of cannabinoid receptors (type 1 and 2) could mitigate depression-like behavior induced by SIS in a mouse model.

RADIATION EXPOSURE TO OPERATORS PERFORMING PHARMACOLOGIC STRESS TESTING IN 99mTc MYOCARDIAL PERFUSION IMAGING: A PROSPECTIVE STUDY.

This prospective study investigated radiation exposure dose (RED) to main operator (MO) and supervisory operator (SO) performing dypiridamole stress testing in a 1-d rest/stress 99mTc tetrofosmin single-photon emission computed tomography (SPECT) of consecutive 42 patients. MO was instructed to be close to the patients during the entire procedures including the vasodilator and radiotracer injection. SO mainly recorded the data on the procedures apart from the patients. RED, procedure time (PT) and internal radioactivity (IR) of patients were measured before and after a secondary tracer injection for stress SPECT, respectively. RED was significantly greater to MO than to SO (6.2 ± 2.7 vs 2.5 ± 2.1 μSV per stress procedure, p < 0.0001). Multivariate analyses revealed that IR and PT were significantly independent factors to predict RED to both operators. Operators performing pharmacologic stress procedure should be aware that IR and PT are independent factors for RED in 99mTc myocardial perfusion imaging.

Blunted cortisol response to psychosocial stress in atopic patients is associated with decrease in salivary alpha-amylase and aldosterone: Focus on sex and menstrual cycle phase

A decreased responsiveness of the hypothalamic-pituitary-adrenocortical axis to stress stimuli in patients with atopy is well documented. The aim of this study was to investigate personality traits, salivary alpha-amylase activity and the aldosterone response to psychosocial stress procedure based on public speech in atopic patients with respect to sex and the menstrual cycle (MC) phase. The study was performed in 106 subjects of both sexes, 53 atopic patients suffering from allergic rhinitis, allergic asthma or atopic dermatitis and 53 age-, sex-, the MC phase- and BMI- matched healthy controls. Substantially attenuated activity of alpha-amylase and reduced secretion of aldosterone during the psychosocial stress were observed in the whole sample of patients with atopy. Higher activity of alpha-amylase observed in the follicular compared to the luteal phase in healthy women was not present in atopic patients. In both males and females, atopy was associated with blunted cortisol response but no changes in the heart rate. Psychological characterization revealed a significantly higher trait anxiety and higher preference for avoidance-oriented coping strategy in female but not male atopic patients. These findings provide evidence that patients with atopy exhibit insufficient alpha-amylase and aldosterone responsiveness to psychosocial stress, thus suggesting decreased sympathetic activity. Potential disturbances in sex hormone status during the MC in female patients with atopy have to be considered in future research. Changes in personality traits were demonstrated in female atopic patients, but not in male patients.

Sonographic Findings of Chondral Avulsion Fractures of the Lateral Ankle Ligaments in Children.

In this series, we aimed to describe the sonographic findings of chondral avulsion fractures that develop concomitant with lateral ankle ligament injury in children. We performed stress sonography during a manual anterior drawer stress procedure of the ankle in 9 skeletally immature patients who had recently had a lateral ankle sprain. Echo videos were obtained through the course of treatment, and all videos were reviewed. We elucidated the common features of chondral avulsion fractures of the lateral ankle ligaments in the children. The features of avulsion fractures on conventional sonography included absence of a fracture with hyperechoic spots (sonographic occult fracture type), cortical discontinuity with hyperechoic spots (cortical disruption fracture type), fracture line in the cortical bone (double-line fracture type), and a step-off deformity of the cortical bone with cartilage (displaced fracture type). In contrast, the features of chondral fractures on stress sonography included abnormal motion of the chondral lesions and mobility/fluidity of hyperechoic spots along the chondral fracture site. The presence of hyperechoic spots around the chondral lesion is an important sonographic sign for diagnosing chondral fractures concomitant with ankle lateral ligament injury. Hence, we believe that stress sonography should be considered for the detection of chondral fractures concomitant with radiographically negative ankle lateral ligament injuries in skeletally immature patients with lateral ankle pain and ankle sprains, if hyperechoic spots are present in the cartilage of the distal fibula.

Regulation of insulin receptor phosphorylation in the brains of prenatally stressed rats: New insight into the benefits of antidepressant drug treatment

A growing body of evidence supports the involvement of disturbances in the brain insulin pathway in the pathogenesis of depression. On the other hand, data concerning the impact of antidepressant drug therapy on brain insulin signaling remain scare and insufficient. We determinated the influence of chronic treatment with antidepressant drugs (imipramine, fluoxetine and tianeptine) on the insulin signaling pathway of the brain of adult prenatally stressed rats. 3-month-old prenatally stressed and control rats were treated for 21 days with imipramine, fluoxetine or tianeptine (10mg/kg/day i.p.).The impact of chronic antidepressant administration was examined in forced swim test. In the frontal cortex and hippocampus, the mRNA and protein expression of insulin, insulin receptor, insulin receptor substrates (IRS-1,IRS-2) and adaptor proteins (Shc1, Grb2) before and after drugs administration were measured.Rats exposed prenatally to stressful stimuli displayed depressive-like disturbances, which were attenuated by antidepressant drug administration. We did not reveal the impact of prenatal stress or antidepressant treatment on insulin and the insulin receptor expression in the examined structures. We revealed that diminished insulin receptor phosphorylation evoked by the prenatal stress procedure was attenuated by drugs treatment. We demonstrated that the favorable effect of antidepressans on insulin receptor phosphorylation in the frontal cortex was mainly related with the normalization of serine312 and tyrosine IRS-1 phosphorylation, while in the hippocampus, it was related with the adaptor proteins Shc1/Grb2. It can be suggested that the behavioral effectiveness of antidepressant drug therapy may be related with the beneficial impact of antidepressant on insulin receptor phosphorylation pathways.

Mechanisms Underlying the Antidepressant Response of Acupuncture via PKA/CREB Signaling Pathway.

Protein kinase A (PKA)/cAMP response element-binding (CREB) protein signaling pathway, contributing to impaired neurogenesis parallel to depressive-like behaviors, has been identified as the crucial factor involved in the antidepressant response of acupuncture. However, the molecular mechanisms associated with antidepressant response of acupuncture, neurogenesis, and depressive-like behaviors ameliorating remain unexplored. The objective was to identify the mechanisms underlying the antidepressant response of acupuncture through PKA signaling pathway in depression rats by employing the PKA signaling pathway inhibitor H89 in in vivo experiments. Our results indicated that the expression of hippocampal PKA-α and p-CREB was significantly downregulated by chronic unpredicted mild stress (CUMS) procedures. Importantly, acupuncture reversed the downregulation of PKA-α and p-CREB. The expression of PKA-α was upregulated by fluoxetine, but not p-CREB. No significant difference was found between Acu and FLX groups on the expression of PKA-α and p-CREB. Interestingly, H89 inhibited the effects of acupuncture or fluoxetine on upregulating the expression of p-CREB, but not PKA-α. There was no significant difference in expression of CREB among the groups. Conclusively, our findings further support the hypothesis that acupuncture could ameliorate depressive-like behaviors by regulating PKA/CREB signaling pathway, which might be mainly mediated by regulating the phosphorylation level of CREB.

Association of attachment disorganization, attachment-related emotion regulation, and cortisol response after standardized psychosocial stress procedure: A pilot study

Attachment representations are related to maintaining biological homeostasis, including physiological stress and emotional regulation. Therefore, recent research has focused on attachment stress regulation and hypothalamus pituitary adrenal (HPA) axis reactivity. However, the attachment disorganization underlying emotion regulation associated with the HPA axis response has not yet been investigated. In our study, the attachment representation and the HPA-axis reactivity by cortisol level before and after the Trier Social Stress Test were assessed in a sample of 98 healthy non-clinical subjects. As expected, approximately 30% of this sample showed a disorganized attachment representation. The subjects? unresolved attachment (breakdown of emotional regulation) showed a prolonged cortisol recovery. No differences were found between the attachment patterns in the increase and the delta of the cortisol response. However, the cortisol reactivity differed significantly for the occurrence of emotional regulation. The subjects with a high occurrence of attachment-related emotion regulation showed a higher cortisol response than the subjects with an unresolved attachment and the ones with a low occurrence of attachment-related emotion regulation. Regulating the negative emotions of stressful situations may require more attention as it might lead to an increased activation of the physiological system.

Differential heart rate variability and physiological responses associated with accumulated short- and long-term stress in rodents

In this study, we tested the hypothesis that chronic stress has cumulative effects over time on heart rate variability (HRV) and physiological responses in a rodent model of chronic mild stress. Rats were exposed to either short-term (2weeks) or long-term (4weeks) stress, followed by a 1-week recovery period. Controls were normally housed rats that did not undergo the stress procedure. For electrocardiogram recordings, transmitters were implanted in all rats 10days before the onset of the experiment to allow recovery from surgery. To investigate physiological responses, body weight, temperature, sucrose preference, and serum corticosterone levels were measured weekly. Rats exposed to both short- and long-term stress showed significant reductions in body weight, which did not normalize after the recovery period. A significant difference was observed between short- and long-term stress groups in serum corticosterone levels, with long-term stress significantly increasing serum corticosterone levels, which remained elevated after the recovery period (P<0.05). HRV analysis indicated that long-term stress significantly decreased time-domain indexes, whereas significantly increased frequency-domain indexes were observed in the low-frequency range (0.1–1Hz). These results may represent dysfunction in parasympathetic/vagal modulation with hyperactivation of the sympathetic nervous system after long-term exposures to stress. In addition, prolonged Q-to-T wave (QT) intervals were observed in rats exposed to long-term stress, which did not return to baseline levels after the recovery period. These findings are consistent with the view that chronic stress is associated with cardiac autonomic disorders and emphasize the importance of monitoring stress in our daily life since the effects of even mild stress may be cumulative.

The ROCK Inhibitor Fasudil Prevents Chronic Restraint Stress-Induced Depressive-Like Behaviors and Dendritic Spine Loss in Rat Hippocampus.

Background:Dendritic arbor simplification and dendritic spine loss in the hippocampus, a limbic structure implicated in mood disorders, are assumed to contribute to symptoms of depression. These morphological changes imply modifications in dendritic cytoskeleton. Rho GTPases are regulators of actin dynamics through their effector Rho kinase. We have reported that chronic stress promotes depressive-like behaviors in rats along with dendritic spine loss in apical dendrites of hippocampal pyramidal neurons, changes associated with Rho kinase activation. The present study proposes that the Rho kinase inhibitor Fasudil may prevent the stress-induced behavior and dendritic spine loss.Methods:Adult male Sprague-Dawley rats were injected with saline or Fasudil (i.p., 10 mg/kg) starting 4 days prior to and maintained during the restraint stress procedure (2.5 h/d for 14 days). Nonstressed control animals were injected with saline or Fasudil for 18 days. At 24 hours after treatment, forced swimming test, Golgi-staining, and immuno-western blot were performed.Results:Fasudil prevented stress-induced immobility observed in the forced swimming test. On the other hand, Fasudil-treated control animals showed behavioral patterns similar to those of saline-treated controls. Furthermore, we observed that stress induced an increase in the phosphorylation of MYPT1 in the hippocampus, an exclusive target of Rho kinase. This change was accompanied by dendritic spine loss of apical dendrites of pyramidal hippocampal neurons. Interestingly, increased pMYPT1 levels and spine loss were both prevented by Fasudil administration.Conclusion:Our findings suggest that Fasudil may prevent the development of abnormal behavior and spine loss induced by chronic stress by blocking Rho kinase activity.

Antidepressant-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in chronically stressed rats

The present study aimed to examine the molecular and cellular mechanisms underlying the antidepressant-like effect of YL-IPA08, a novel TSPO ligand designed and synthesized at our institute. We firstly used the chronic unpredictable stress (CUS) procedure of rats, a well validated stress-related animal model of depression, to further determine the antidepressant-like of YL-IPA08. And we found that YL-IPA08 caused significant suppression of inhibiting of locomotor activity, reducing the sucrose preference and increasing the latency to eat induced by CUS. In addition, YL-IPA08 treatment increased the levels of progesterone and allopregnanolone in the hippocampus and prefrontal cortex of post- CUS rats. Furthermore, long-term YL-IPA08 administration reversed dendritic shrinkage, down-regulation of neurotrophic signaling pathway within the hippocampus, as well as HPA dysfunctions simultaneously observed in the CUS rats. Collectively, the evidence presented above supports the notion that binding to TSPO and the subsequent synthesis of neurosteroid, maintenance of hippocampal morphologic and functional plasticity, and preventing HPA axis dysfunction, may account for the profound molecular and cellular mechanism underlying the antidepressant-like effect of YL-IPA08.

Chronic restraint stress causes a delayed increase in responding for palatable food cues during forced abstinence via a dopamine D1-like receptor-mediated mechanism

Relapse to unhealthy eating habits in dieters is often triggered by stress. Animal models, moreover, have confirmed a causal role for acute stress in relapse. The role of chronic stress in relapse vulnerability, however, has received relatively little attention. Therefore, in the present study, we used an abstinence-based relapse model in rats to test the hypothesis that exposure to chronic stress increases subsequent relapse vulnerability. Rats were trained to press a lever for highly palatable food reinforcers in daily 3-h sessions and then tested for food seeking (i.e., responding for food associated cues) both before and after an acute or chronic restraint stress procedure (3h/day×1day or 10days, respectively) or control procedure (unstressed). The second food seeking test was conducted either 1day or 7days after the last restraint. Because chronic stress causes dopamine D1-like receptor-mediated alterations in prefrontal cortex (a relapse node), we also assessed dopaminergic involvement by administering either SCH-23390 (10.0μg/kg; i.p.), a dopamine D1-like receptor antagonist, or vehicle prior to daily treatments. Results showed that chronically, but not acutely, stressed rats displayed increased food seeking 7days, but not 1day, after the last restraint. Importantly, SCH-23390 combined with chronic stress reversed this effect. These results suggest that drugs targeting D1-like receptors during chronic stress may help to prevent future relapse in dieters.

Questioning the benefits of current screening protocols for common cancers

Screening is the application of a diagnostic test to a population of patients without suspicious clinical signs or symptoms of a disease. Applying screening protocols to detect cancer is especially attractive as cancer is a growing burden and earlier detection of malignancies can lead to better outcomes. While the initial excitement over screening for cancers has caused protocols to be put into practice, data analysis has cast doubt on the net benefit. Prostate-specific antigen (PSA) blood testing has been used as a screening test for prostate cancer. The harms of a positive PSA screen include invasive investigations and treatments with side effects such as infection and incontinence. The poor sensitivity and specificity of PSA screening caused the Canadian Task Force on Preventive Health Care to recommend against PSA as a screening tool. Similarly, mammography and ultrasound for detecting breast cancer lesions in asymptomatic women suffer from relatively low sensitivity and specificity. The harms of screening include emotional stress and invasive surgical procedures. Meta-analyses reveal that the risks outweigh the benefits for some age groups, but there may be a role in screening asymptomatic patients with a family history of breast cancer with more sensitive but more expensive modalities, such as magnetic resonance imaging (MRI). Finally, colonoscopy, which is the gold standard to diagnose colorectal cancers, has failed to show net benefit in screening. While screening protocols thus far have provided underwhelming results, the key in screening in the future may lie in using tests with high specificity and sensitivity, as in next generation screening modalities that rely on molecular markers and analytics.

3-D local mesh refinement XFEM with variable-node hexahedron elements for extraction of stress intensity factors of straight and curved planar cracks

A novel local mesh refinement approach for fracture analysis of three-dimensional (3-D) linear elastic solids is developed, considering both 3-D straight and curved planar cracks. The present local mesh refinement formulation is a combination of the extended finite element method (XFEM), variable-node hexahedron elements, and a posteriori error indicator. Our 3-D formulation using hexahedron elements rigorously embraces a posteriori error estimation scheme, a structural coupling scale-meshes strategy and an enrichment technique. Local mesh refinement is only performed where it is needed, e.g., a vicinity of crack, through an error estimator based on the recovery stress procedure. To treat the mismatching problem induced by different scale-meshes in the domain, a structural coupling scheme employing variable-node transition hexahedron elements based on the generic point interpolation with an arbitrary number of nodes on each of their faces is presented. The 3-D finite element approximations of field variables are enhanced by enrichments so that the mesh is fully independent of the crack geometry. The displacement extrapolation method is taken for the evaluation of linear elastic fracture parameters (e.g., stress intensity factors—SIFs). To show the accuracy and performance of our proposed 3-D formulation, six numerical examples of planar 3-D straight and curved shaped cracks with single and mixed-mode fractures and different configurations are considered and analyzed. The SIFs computed by the developed method are validated with respect to analytical solutions and the ones derived from the conventional XFEM. Associated with an adaptive process, the present 3-D formulation allows the analysts to gain a desirable accuracy with a few trials, which is suited for practices purpose.

Investigation of the effects of vanilloids in chronic fatigue syndrome.

To assess the effectiveness of TRPV1 modulators in animal model of Chronic fatigue syndrome (CFS). To assess central and peripheral behavioral activity of TRPV1 modulators. CFS was induced by forcing the rats to swim for 10min for 21 consecutive days. The rats were treated with capsaicin (TRPV1 agonist, 2.5mg/kg) and n-tert-butylcyclohexanol (TRPV1 antagonist, 10mg/kg) for 21days 30min before the exposure to stress procedure. The behavioral consequence of CFS was measured in terms of immobility time, grip strength, locomotor activity, and anxiety level using Rota rod, Actophotometer, and Elevated plus maze model respectively. The other parameters include Plasma corticosterone, adrenal gland and spleen weight, complete blood count, blood urea niterogen (BUN), Lactate dehydrogenase (LDH), Lipid peroxidation, catalase and reduced glutathione (GSH). TRPV1 modulators reversed (p<0.05) the increase in immobility period, anxiety, spleen weight, BUN and LDH levels, and MDA levels along with decrease in grip strength, locomotor activity, plasma corticosterone, adrenal gland weight, catalase, and GSH. There was also significant increase in total WBC count when compared with the disease control group. The reversal was attributed to modulation of HPA axis, oxidative stress, anaerobic respiration product, muscle degradation product. The present study reveals the effectiveness of n-tert-butylcyclohexanol and capsaicin against chronic fatigue syndrome. The mechanism of action can be attributed to inhibition of TRPV1 channel and thereby modulating pain perception, neuroendocrine function, oxidative stress and immune function.