Doxycycline-Mediated Protective Effect Against Focal Cerebral Ischemia–Reperfusion Injury Through the Modulation of Tight Junctions and PKCδ Signaling in Rats

The strategy for the development of effective and safe neuroprotective agents has great potential to reduce cerebral ischemia–reperfusion injury and improve the functional outcome in stroke patients. Recently, doxycycline, a tetracycline antibiotic, has been shown to have neuroprotective efficiency in reduction of a variety of ischemia–reperfusion injuries as well as ischemic brain damage. We used the rat models of middle cerebral artery occlusion (MCAO) and reperfusion to investigate the effects of treatments with doxycycline against the blood-brain barrier (BBB) leakage at 3, 12, 72, and 120 h of reperfusion. Male Sprague–Dawley rats were subjected to MCAO for 2 h followed by reperfusion for 3, 12, 72, and 120 h and received either doxycycline (45 mg/kg) or saline. The results showed that the treatment of doxycycline significantly reduced the BBB leakage and cerebral infarct volume, which were proved by Evans blue assay and TTC staining. Real-time PCR, immunohistochemistry, and western blot assay verified that the administration of doxycycline significantly up-regulated the expression of tight junction claudin-5, occludin, and ZO-1 from 3 to 120 h after reperfusion. The results of real-time PCR, western blot, and gelatin zymography analyses revealed that the gene and protein expression and activities of matrix metalloproteinases (MMPs) MMP-2 and MMP-9 were significantly elevated in a different time-dependent manner after ischemia–reperfusion but significantly inhibited by doxycycline treatment. Moreover, doxycycline could also significantly down-regulate the expression of PKCδ mRNA and protein after ischemia–reperfusion. These results suggested that the protective effects of doxycycline against BBB damage induced by reperfusion might be related to the up-regulation of tight junction proteins and inhibition of MMP-2, MMP-9, and PKCδ.     

Gemfibrozil Pretreatment Affecting Antioxidant Defense System and Inflammatory, but not Nrf-2 Signaling Pathways Resulted in Female Neuroprotection and Male Neurotoxicity in the Rat Models of Global Cerebral Ischemia–Reperfusion

Two important pathophysiological mechanisms involved during cerebral ischemia are oxidative stress and inflammation. In pathological conditions such as brain ischemia the ability of free radicals production is greater than that of elimination by endogenous antioxidative systems, so brain is highly injured due to oxidation and neuroinflammation. Fibrates as peroxisome proliferator-activated receptor (PPAR)-α ligands, are reported to have antioxidant and anti-inflammatory actions. In this study, gemfibrozil, a fibrate is investigated for its therapeutic potential against global cerebral ischemia–reperfusion (I/R) injury of male and female rats. This study particularly has focused on inflammatory and antioxidant signaling pathways, such as nuclear factor erythroid-related factor (Nrf)-2, as well as the activity of some endogenous antioxidant agents. It was found that pretreatment of animals with gemfibrozil prior to I/R resulted in a sexually dimorphic outcome. Within females it proved to be protective, modulating inflammatory factors and inducing antioxidant defense system including superoxide dismutase (SOD), catalase, as well as glutathione level. However, Nrf-2 signaling pathway was not affected. It also decreased malondialdehyde level as an index of lipid peroxidation. In contrast, gemfibrozil pretreatment was toxic to males, enhancing the expression of inflammatory factors such as tumor necrosis factor-α, nuclear factor-κB, and cyclooxygenase-2, and decreasing Nrf-2 expression and SOD activity, leading to hippocampal neurodegeneration. Considering that gemfibrozil is a commonly used anti-hyperlipidemic agent in clinic, undoubtedly more investigations are crucial to exactly unravel its sex-dependent neuroprotective/neurodegenerative potential.     

Symptom Complaints Following Reports of Blast Versus Non-Blast Mild TBI: Does Mechanism of Injury Matter?

Patients with a reported history of mild traumatic brain injury (mild TBI) due to blast (n?=?298) or non-blast (n?=?92) mechanisms were asked to complete the Neurobehavioral Symptom Inventory (NSI) and the Post-traumatic Stress Disorder Checklist (PCL). Mechanism of injury did not account for a significant amount of variance in post-concussion symptom reporting overall, nor did severity of mild TBI (i.e., brief loss of consciousness versus only an alteration of consciousness). Symptom reporting was greater in those injured more than 1 month ago compared to those injured less than 1 month ago and in those reporting higher levels versus lower levels of PTSD symptoms. When examining specific symptoms, the only symptom that significantly varied between groups was hearing difficulty (with the blast-injured group reporting more severe difficulty with hearing). Findings suggest that greater symptom reporting is most strongly related to emotional distress.     

Depression and Disordered Gaming: Does Culture Matter?

The dearth of evidence related to cultural and gender variations of established associations between Internet Gaming Disorder (IGD) and other psychopathologies has been highlighted. Accordingly, the present study examined the association between depression and disordered gaming behaviors, while considering cultural perspectives of vertical individualism (independence and hierarchy) and gender as potentially variating factors. To achieve this, an ethnically diverse online sample of internet gamers from multicultural societies (N?=?1032; Australia?=?738; 71.5%; USA?=?222; 21.5%; other multicultural countries?=?72; 13.3%; M_age?=?24 years; males?=?503 [48.7%], females?=?529 [51.3%]) completed the Internet Gaming Disorder Scale–Short-Form (IGDS9-SF); the Depression, Anxiety and Stress Scale (DASS-21) and the Individualism and Collectivism Scale (ICS). Regression, moderation and moderated moderation analyses were conducted. Results demonstrated that gamers presenting concurrently with symptoms of depression and vertically individualistic inclinations reported higher levels of disordered gaming behaviors, with no significant gender differences. The findings obtained imply that practitioners globally, and especially in multicultural societies (e.g., Australia, USA), should consider cultural differences when developing prevention and intervention strategies for disordered gaming.

     

Inattention and Disordered Gaming: Does Culture Matter?

Psychiatric Quarterly - Problematic gaming has emerged as a contemporary concern, leading to the introduction of the diagnostic term ‘Internet Gaming Disorder’ (IGD; American...     

The Relationship Between Change in Therapeutic Alliance Ratings and Improvement in Youth Symptom Severity: Whose Ratings Matter the Most?

This paper presents the psychometric evaluation of brief measures of therapeutic alliance (TA) for youths, clinicians and caregivers and a longitudinal analysis of relationships between changes in TA and changes in youth symptom and functioning severity. Psychometric analyses using methods from Classical Test Theory, Item Response Theory, and Factor Analysis indicate that the measures of TA used in this study offer something new for both practice and research. The measures have variability, sensitivity to change over time, brevity and can be used with multiple parties through parallel forms. The longitudinal analyses, employing hierarchical linear modeling with time-varying covariates, found that TA ratings of the clinician correlated with symptom improvement as rated by the clinician, caregiver and youth. Additional analyses showed that decreases in clinician-rated youth TA was most important in predicting a lower rate of youth improvement. Implications for future research and clinical practice are discussed.     

Does the Sunset of Mental Health Parity Really Matter?

The 1996 Mental Health Parity Act (MHPA), which became effective in January 1998, is scheduled to expire in September 2001. This article provides an overview of what the MHPA intended to do and what it actually has accomplished. We summarize state legislature actions through the end of 2000 and report on their effects on employer-sponsored mental health coverage using a national survey fielded in 1999–2000. We then discuss possible amendments to the MHPA and reforms beyond full parity that might be considered.     

Formal Volunteering and Mental Health in South Korea: Does Age Matter?

Extensive research shows a positive association between formal volunteering and mental health and this association is stronger for older adults compared to their younger peers. The purpose of our study is to re-examine the link between formal volunteering, age, and mental health in a non-western society, South Korea. We employ two recent waves—years 2012-13 -- of nationally representative data from the Korea Welfare Panel Survey to test the extent to which the relationship between formal volunteering and mental health, as measured by depression, varies across two non-elderly age groups—young adults (18–35) and those middle-aged (36–55). Findings reveal that being a formal volunteer is psychologically more beneficial to young adults compared to their middle-aged counterparts. Understanding the age differential in the link between formal volunteering and depression in South Korea is crucial, given the different economic and sociocultural contexts, at current time, for young adults and their middle-aged peers.     

Does the Co-occurrence of FGFR3 Gene Mutation in Hypochondroplasia,Medial Temporal Lobe Dysgenesis,and Focal Epilepsy Suggest a Syndrome?

BackgroundHypochondroplasia is a rare skeletal dysplasia characterized by disproportionately short stature, lumbar lordosis, and limited extension of the elbow caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene that plays a role in controlling nervous system development. Hypochondroplasia with FGFR3 mutation associated with bilateral medial temporal lobe anomalies and focal epilepsy was previously reported in several patients.PatientWe report clinical, electroclinical, and neuroradiological findings of one patient affected by hypochondroplasia.ResultsClinical diagnosis was confirmed by molecular analysis of the FGFR3 gene, which showed a N540 K mutation. The patient had normal psychomotor development and showed early-onset focal seizures with left temporal localization on interictal and ictal electroencephalograph. The seizures were well controlled, and the patient has been seizure-free since infancy. Magnetic resonance imaging showed abnormal anteriorly posteriorly infolding in the hippocampus and abnormally oriented parahippocampus sulci, and additional cortical rim dysplasia with gray-white matter junction blurring in the hippocampus.ConclusionsThe present case of hypochondroplasia and FGFR3 mutation in Asn540Lys associated with characteristic abnormalities involving bilaterally medial temporal lobe structures, probable hippocampal cortex focal dysplasia, and early onset of focal epilepsy underscores the possibility of a rare syndrome.     

Modulation of the endocannabinoid system: Neuroprotection or neurotoxicity?

There is now a large volume of data indicating that compounds activating cannabinoid CB₁ receptors, either directly or indirectly by preventing the breakdown of endogenous cannabinoids, can protect against neuronal damage produced by a variety of neuronal “insults”. Given that such neurodegenerative stimuli result in increased endocannabinoid levels and that animals with genetic deletions of CB₁ receptors are more susceptible to the deleterious effects of such stimuli, a case can be made for an endogenous neuroprotective role of endocannabinoids. However, this is an oversimplification of the current literature, since (a) compounds released together with the endocannabinoids can contribute to the neuroprotective effect; (b) other proteins, such as TASK-1 and PPARα, are involved; (c) the CB₁ receptor antagonist/inverse agonist rimonabant has also been reported to have neuroprotective properties in a number of animal models of neurodegenerative disorders. Furthermore, the CB₂ receptor located on peripheral immune cells and activated microglia are potential targets for novel therapies. In terms of the clinical usefulness of targeting the endocannabinoid system for the treatment of neurodegenerative disorders, data are emerging, but important factors to be considered are windows of opportunity (for acute situations such as trauma and ischemia) and the functionality of the target receptors (for chronic neurodegenerative disorders such as Alzheimer's disease).     

Family Ties and Mental Health of Orphans in Ouagadougou (Burkina Faso). Does the Gender of the Dead Parent Matter?

In sub-Saharan Africa, families represent a type of social safety net for individuals in difficulty, thus making up for the absence of social programs and public institutions for orphaned youth. Yet the past decades have witnessed an erosion of the mechanisms of solidarity and health inequalities between orphans and non-orphaned children. This study aims to understand the family dynamics that lead to mental disorders among orphans in Burkina Faso, a landlocked and resource-limited country. A unique set of key informant interviews with 43 orphans and in-depth direct observations in informal neighborhoods were conducted from September to December 2012, transcribed and analyzed using thematic analysis techniques (Corbin and Strauss 2014). The findings reveal the assumptions concerning children’s belonging to their father’s extended family are misplaced and shed light on the unintended effects of intra-family divisions, mistrust, and harsh economic conditions of widows on the mental health of orphans, described as uprooted.     

Specific Role of Tight Junction Proteins Claudin-5, Occludin,and ZO-1 of the Blood–Brain Barrier in a Focal Cerebral Ischemic Insult

Blood–brain barrier (BBB) leakage plays a key role in cerebral ischemia–reperfusion injury. It is quite necessary to further explore the characteristic and mechanism of BBB leakage during stroke. We induced a focal cerebral ischemia model by transient middle cerebral artery occlusion in male rats for defining the time course of BBB permeability within 120 h following reperfusion and evaluate the specific role of tight junction (TJ) associated proteins claudin-5, occludin, and ZO-1 as well as protein kinase C delta (PKCδ) pathway in BBB leakage induced by reperfusion injury. We verified a bimodal increase in the permeability of the BBB following focal ischemia by Evans blue assay. Two peaks of BBB permeability appeared at 3 h and 72 h of reperfusion after 2 h focal ischemia, respectively. The leak at the endothelial cell was represented at the level of transmission electron microscopy. TTC staining results showed increased infarct size with time after cerebral ischemia reperfusion. The mRNA and protein expression levels of these three TJ associated proteins were significantly decreased compared with the sham-operated group within 120 h of reperfusion, corresponding to the time-dependent change of the biphasic pattern in BBB leakage. The redistribution of claudin-5, occludin, and ZO-1 in ischemia brain microvascular endothelial cells was observed at the same time points. In addition, Western blot assay revealed PKCδ level was also significantly increased in a similar biphasic pattern to above results within 120 h after cerebral ischemia–reperfusion. This study demonstrates the timing of TJ associated proteins claudin-5, occludin, and ZO-1 in light of BBB permeability associated with cerebral ischemia reperfusion, and suggests PKCδ pathway may participate in TJ barrier open and BBB leakage during reperfusion injury in a time-dependent manner.     

Mind-Reading in Young Adults with ASD: Does Structure Matter?

This study further elaborates on the mind-reading impairments of young adults with autism spectrum disorder (ASD). The hypothesis is that differences in mind-reading abilities between subjects with ASD and control subjects become more apparent when they have to infer thoughts and feelings of other persons in a less structured or more chaotic conversation, than when they have to do so in a more structured conversation. Conform to the empathic accuracy design, subjects viewed two videotaped interactions depicting two strangers and attempted to infer thoughts and feelings. One of the videotaped conversations was less structured than in the other. The results underscore the significance of structure to the mind-reading abilities of young adults with ASD.