Role of hypothalamic-pituitary adrenal-axis, toll-like receptors, and macrophage polarization in pre-atherosclerotic changes induced by social isolation stress in mice.

It has been well documented that chronic stress can induce atherosclerotic changes, however, the underlying mechanisms is yet to be established. In this regard, this study aimed to elucidate the relation between hypothalamic-pituitary adrenal-axis (HPA-axis), toll-like receptors (TLRs), as well as M1/M2 macrophage ratio and pre-atherosclerotic changes in social isolation stress (SIS) in mice. We used small interfering RNA against the glucocorticoid receptor (GR) to evaluate the relation between HPA-axis and TLRs. C57BL/6J mice were subjected to SIS and RT-PCR, ELISA, flow cytometry, and immunohistochemistry were used to assess the relations between pre-atherosclerotic changes and TLRs, macrophage polarization, pro-inflammatory cytokines, and cell adhesion molecules in aortic tissue. We used TAK-242 (0.3 mg/kg, intraperitoneally), a selective antagonist of TLR4, as a possible prophylactic treatment for atherosclerotic changes induced by SIS. We observed that isolated animals had higher serum concentration of corticosterone and higher body weight in comparison to normal animals. In isolated animals, results of in vitro study showed that knocking-down of the GR in bone marrow-derived monocytes significantly decreased the expression of TLR4. In vivo study suggested higher expression of TLR4 on circulating monocytes and higher M1/M2 ratio in aortic samples. Pathological study showed a mild pre-atherosclerotic change in isolated animals. Finally, we observed that treating animals with TAK-242 could significantly inhibit the pre-atherosclerotic changes. SIS can possibly increase the risk of atherosclerosis through inducing abnormal HPA-axis activity and subsequently lead to TLR4 up-regulation, vascular inflammation, high M1/M2 ratio in intima. Thus, TLR4 inhibitors might be a novel treatment to decrease the risk of atherosclerosis induced by chronic stress.

Impact of a High-protein Nutritional Intake on the Clinical Outcome of the Neurocritical Patients.

Disease-related malnutrition of neurocritical illness harms its treatment, which increases the mortality rate. The aim of this study was evaluating the effect of a high protein diet on the dietary factors, clinical outcome, and mortality rate of neurocritical patients. In a randomized controlled trial, 15 neurocritical patients were recruited in each group. The patients in the intervention and control groups received high protein and conventional protein regimens, respectively. The Clinical Extended Glasgow Outcome Scale (GOSE) measured at one, two, and three months later. Acute Physiology and Chronic Health Evaluation II (APACHE-II) score, Glasgow Coma Scale, the serum level of transthyretin (TTR) on the first, 3rd and fifth days of admission, and nitrogen balance (NB) at the baseline and fifth day of the study were recorded. Thirty patients, 15 in each group, entered into the study. There was no statistically significant difference in the baseline characteristics of the patients between the two groups of the study. The 28-days-mortality rate in the intervention and control group were 33.3% (n = 5) and 73.3% (n = 11), P-value = 0.034, respectively. The GOSE scores were higher in the patients who received a high protein diet, and lower in the patients with lower baseline TTR, higher APACHE-II score, older age, and a baseline negative nitrogen balance. The high protein diet may decrease the mortality rate, and improve the clinical outcome of neurocritical patients. The baseline TTR level, APACHE II score, and NB are prognostic factors for the prediction of the GOSE in neurocritical patients.

The potential role of very small embryonic-like stem cells in the neuroinflammation induced by social isolation stress: Introduction of a new paradigm.

Lack of social contacts could induce psychiatric features and lead to various behavioral and neurochemical abnormalities in rodents. Social isolation stress (SIS) is a valid paradigm of depressive- and anxiety-like behaviors in animals. It has demonstrated that psychiatric disorder could affect the peripheral blood population of very small embryonic-like stem cells (VSELs). The aim of the current study is to evaluate the role of VSELs in behavioral impairments induced by SIS through neuroinflammation in mice. Behavioral experiments were evaluated by using forced swimming test (FST), open field test (OFT), and splash test in male NMRI mice. In addition, plasma and bone marrow samples, as well as hippocampus, were collected to evaluate the population of VSELs, nitrite level, and inflammatory cytokines by using flow cytometry and ELISA. Behavioral tasks showed that SIS could induce depressive- and anxiety-like behaviors in mice. Data obtained from flow cytometry showed that VSELs significantly increased in socially isolated animals in bone marrow, peripheral blood, and hippocampus. Also, TNF-α, IL-1ß, and IL-6 significantly increased in hippocampal and plasma samples in socially isolated animals. Correlation analysis indicated that mice with higher VSELs counts have better results in behavioral tasks, and lower pro-inflammatory cytokines as well as nitrite level in mice. In conclusion, VSELs could be used as a biological marker to enhance diagnostic accuracy as well as predicting the prognosis. Also, increment in the VSELs counts might decrease the neuro-inflammation and subsequently improve the behavioral impairments induced by SIS.

Epidemiology of facial fractures: incidence, prevalence and years lived with disability estimates from the Global Burden of Disease 2017 study.

BACKGROUND: The Global Burden of Disease Study (GBD) has historically produced estimates of causes of injury such as falls but not the resulting types of injuries that occur. The objective of this study was to estimate the global incidence, prevalence and years lived with disability (YLDs) due to facial fractures and to estimate the leading injurious causes of facial fracture. METHODS: We obtained results from GBD 2017. First, the study estimated the incidence from each injury cause (eg, falls), and then the proportion of each cause that would result in facial fracture being the most disabling injury. Incidence, prevalence and YLDs of facial fractures are then calculated across causes. RESULTS: Globally, in 2017, there were 7 538 663 (95% uncertainty interval 6 116 489 to 9 493 113) new cases, 1 819 732 (1 609 419 to 2 091 618) prevalent cases, and 117 402 (73 266 to 169 689) YLDs due to facial fractures. In terms of age-standardised incidence, prevalence and YLDs, the global rates were 98 (80 to 123) per 100 000, 23 (20 to 27) per 100 000, and 2 (1 to 2) per 100 000, respectively. Facial fractures were most concentrated in Central Europe. Falls were the predominant cause in most regions. CONCLUSIONS: Facial fractures are predominantly caused by falls and occur worldwide. Healthcare systems and public health agencies should investigate methods of all injury prevention. It is important for healthcare systems in every part of the world to ensure access to treatment resources.

Protective effect of minocycline on LPS-induced mitochondrial dysfunction and decreased seizure threshold through nitric oxide pathway.

Lipopolysaccharide (LPS) increases inflammatory cytokines of the brain and deregulates the mitochondrial function, thus could increase the seizure susceptibility. Studies have shown that minocycline has neuroprotective and antioxidant properties. In this study, we aimed to evaluate the anticonvulsant properties of minocycline in LPS-treated animals and the possible involvement of nitric oxide and mitochondrial pathways. In a PTZ model of seizure in mice, minocycline was administrated to LPS-treated mice. Then followed by co-injection of its sub-effective dose and NOS inhibitors including 7-Nitroindazole (7-NI), aminoguanidine (AG) and L-NG-Nitroarginine methyl ester (L-NAME) to evaluate the changes in seizure threshold and the possible involvement of nitrergic system. Molecular assessments were used to evaluate the effects of each treatment on inflammation and mitochondrial function in the brain. LPS-treated animals had lower seizure threshold compared to intact animals; injection of minocycline (80 mg/kg) to LPS-treated mice reversed this effect. Co-injection of sub-effective doses of minocycline (40 mg/kg) and L-NAME to LPS-treated animals significantly increased seizure threshold. We observed that co-treatment of minocycline and AG dissimilar to 7-NI could increase the seizure threshold of LPS-treated animals. L-arginine reversed the anticonvulsant effect of minocycline. Also, molecular evaluations showed that LPS could increase the ATP levels, GSH levels, and reactive oxygen species formation. However, minocycline at both doses significantly reversed the effect of LPS. Minocycline counteracts the proconvulsant effects of LPS through regulating of mitochondrial function and decreasing of neuro-inflammation. Also, co-administration of minocycline and i-NOS inhibitors could intensify anticonvulsant effects of minocycline.

Activation of ATP-sensitive K-channel promotes the anticonvulsant properties of cannabinoid receptor agonist through mitochondrial ATP level reduction.

Cannabinoid receptor (CBR) agonist could act as a protective agent against seizure susceptibility in animal models of epilepsy. Studies have shown that potassium channels could play a key role in ameliorating neuronal excitability. In this study, we attempted to evaluate how CBRs and Adenosine Tri-Phosphate (ATP)-sensitive potassium channels collaborate to affect seizure susceptibility by changing the clonic seizure threshold (CST). We used male Naval Medical Research Institute (NMRI) mice and treated them with the following drugs: cromakalim (a potassium channel opener, 10 µg/kg), glibenclamide (a potassium channel blocker, 0.03 and 1 mg/kg), 0.5 mg/kg of AM-251 (a selective CB1 antagonist), AM-630 (a selective CB2 antagonist), and 0.5, 3, and 10 mg/kg of WIN 55,212-2 (a nonselective agonist of CBRs); and CST was appraised after each type of administration. Also, we evaluated the ATP level of the hippocampus in each treatment to clarify the interaction between the cannabinoid system and potassium channel. Our results showed that administration of WIN 55,212-2 at 10 mg/kg significantly increased CST (P < 0.001). This change could be reversed by using AM-251(P < 0.001) but not AM-630. Also, either cromakalim (10 µg/kg) or glibenclamide (0.03 and 1 mg/kg) could not significantly affect the CST. In addition, glibenclamide (1 mg/kg) could reverse the anticonvulsant effect of WIN 55,212-2 (10 mg/kg) on CST (P < 0.001). However, the anticonvulsant effect was observed when cromakalim (10 µg/kg) was added to WIN 55,212-2 at its subeffective dose (3 mg/kg) in comparison to single-treated animals. Interestingly, we observed that CB1 agonist could significantly decrease ATP level. In conclusion, CB1 agonist accomplishes at least a part of its anticonvulsant actions through ATP-sensitive potassium channels, probably by decreasing the mitochondrial ATP level to open the potassium channel to induce its anticonvulsant effect.

Involvement of opioid system in behavioral despair induced by social isolation stress in mice.

Social isolation stress (SIS) as a type of chronic stress could induce depressive- and anxiety-like behaviors. Our study evaluates the role of opioid system on negative behavioral impacts of SIS in male NMRI mice. We investigated effects of morphine, a nonselective opioid receptor (OR) agonist, naltrexone (NLX), an OR antagonist, naltrindole (NLT), a delta opioid receptor (DOR) antagonist, SNC80, a DOR agonist, U-69593, a kappa opioid receptor (KOR) agonist, nor-Binaltorphimine, a selective KOR antagonist and cyprodime hydrochloride a selective mu opioid receptor (MOR) antagonist on depressive- and anxiety-like behaviors. Using RT-PCR we evaluated ORs gene expression in mice brain. Our findings showed that SIS induced anxiety- and depressive-like behavior in the forced swimming test, open field test, splash test and hole-board test. Moreover, administration of SNC-80 significantly mitigated anxiety- and depressive-like behaviors. NLT decreased grooming-activity in the splash test. Excitingly, administration of agents affecting KOR failed to alter the negative effects of SIS. RT-PCR demonstrated that MOR and KOR gene expression decreased in socially isolated mice; however, SIS did not affect DORs expression. Our findings suggest that SIS at least in part, probably via altering endogenous opioids particularly MORs and KORs but not DORs mediated negative impacts on behavior; also, it could be concluded that DORs might be considered as a novel target for studying depression and anxiety.

Involvement of NO/NMDA-R pathway in the behavioral despair induced by amphetamine withdrawal.

Abrupt discontinuation of chronic amphetamine consumption leads to withdrawal symptoms including depression, anhedonia, dysphoria, fatigue, and anxiety. These irritating symptoms may result in continuing to take the drug or can lead to suicidal behavior. Past studies have shown the involvement of various biologic systems in depression induced following amphetamine withdrawal (AW). However, there is no evidence about the relation between nitric oxide (NO) with NMDA receptors on depression following AW. In this study, we examined the involvement of the NO/NMDA pathways on depressive-like behaviors after 24 h withdrawal following 5 continuous days of amphetamine administration in male NMRI mice. Behavioral tasks used for depression assessment included the forced swimming test (FST), the Splash test and the open field test (OFT). In order to evaluate the role of NO/NMDA pathways animals treated with MK-801 (NMDA-R antagonist), Aminoguanidine (AG), a selective iNOS inhibitor, Nω-Nitro-l-arginine (L-NNA), a non-selective NOS inhibitor and 7-Nitro indazole (7-NI), a selective nNOS inhibitor. We also measured the level of nitrite in the hippocampus. Our data showed that AW induced the depressive-like effect in the FST and the Splash test. We showed that administration of AG, L-NNA, and MK-801 mitigated AW induced depression, however, 7-NI was failed to decrease depressive-like behaviors. Also, the antidepressant-like effect of co-injection of sub-effective doses of MK-801 with AG suggested that inducible nitric oxide synthase (iNOS) is associated with NMDA-R in AW induced depression. In conclusion, both NO and NMDA-R pathways are involved and related to each other in depression induced following AW.