Spatial clusters, social determinants of health and risk of COVID-19 mortality in Brazilian children and adolescents: A nationwide population-based ecological study.

Background: Data regarding the geographical distribution of cases and risk factors for COVID-19 death in children and adolescents are scarce. We describe the spatial distribution of COVID-19 cases and deaths in paediatric population and their association with social determinants of health in Brazil. Methods: This is a population-based ecological study with a spatial analysis of all cases and deaths due to COVID-19 in Brazil among children and adolescents aged 0-19 years from March 2020 to October 2021. The units of analysis were the 5570 municipalities. Data on COVID-19 cases and deaths, social vulnerability, health inequities, and health system capacity were obtained from publicly available databases. Municipalities were stratified from low to very high COVID-19 incidence and mortality using K-means clustering procedures, and spatial clusters and relative risks were estimated using spatial statistics with Poisson probability models. The relationship between COVID-19 estimates and social determinants of health was explored by using multivariate Beta regression techniques. Findings: A total of 33,991 COVID-19 cases and 2424 deaths among children and adolescents aged 0-19 years were recorded from March 2020 to October 2021. There was a spatial dependence for the crude mortality coefficient per 100,000 population in the paediatric population aged 0-19 years (I Moran 0·10; P < 0·001). Forty municipalities had higher mortality rates, of which 20 were in states from the Northeast region. Seven spatial clusters were identified for COVID-19 mortality, with four clusters in the Northeast region and three in the North region. Municipalities with higher social inequality and vulnerability had higher COVID-19 mortality in the paediatric population. Interpretation: The main clusters of risk for mortality among children and adolescents were identified in municipalities in the North and Northeast regions, which are the regions with the worst socioeconomic indicators and greatest health disparities in the country. Our findings confirmed the higher burden of COVID-19 for Brazilian paediatric population in municipalities with higher social inequality and vulnerability and worse socioeconomic indicators. To reduce the burden of COVID-19 on children, mass immunisation is necessary. Funding: None.

Pathophysiological mechanisms involved in the relationship between diabetes and major depressive disorder.

Diabetes mellitus (DM) and major depressive disorder (MDD) are diseases that are expanding globally. Separately, each presents with several comorbidities for patients. When the two diseases present simultaneously in the same subject, there is a drastic worsening in the quality of life of the patient. This study reviewed the literature relating to the relationship between MDD and DM, bringing forward studies showing that DM develops due to MDD, and others that report the opposite. According to the studies reviewed, DM and MDD are both debilitating conditions that are associated with significant morbidity, mortality, and healthcare costs. When these two diseases coexist, the association results in a decreased adherence to treatment, poor metabolic control, higher rates of complications, a decrease in the quality of life for the patient, increased healthcare use and cost, increased disability and lost productivity, and an increased risk of death. Therefore, it becomes essential that there are larger studies targeting the association of these two diseases, as for the patient, preventing even one of them will ensure improvements in their quality of life.

Human brucellosis in Portugal-Retrospective analysis of suspected clinical cases of infection from 2009 to 2016.

Brucellosis is a zoonosis that is emerging in some regions of the world. Although brucellosis is a disease of obligatory declaration and is not eradicated in Portugal, no prevalence data is available in this country. In this study, we retrospectively analyzed the data available at the Reference Laboratory at the Portuguese National Institute of Health during the past 7 years (2009-2016) in order to get insight into the epidemiological scenario of brucellosis in Portugal. A total of 2313 biological samples from patients with clinical suspicion of brucellosis were subjected to immunological techniques for laboratory diagnosis. From 2010 to 2015, a subset of 259 samples was subjected to molecular methods. According to the available data, 167 out of 2313 (7.2%) samples had positive serology for Brucella spp. and 43 out of 259 samples (16.6%) were positive for B. melitensis by real time PCR, being classified as biovar 1 and 3. This study draws attention to the importance of integrating clinical and laboratory data of human cases in order to increase the efficacy of the response measures in case of outbreaks.

Effects of ketamine administration on mTOR and reticulum stress signaling pathways in the brain after the infusion of rapamycin into prefrontal cortex.

Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists. A relationship between mTOR kinase and the endoplasmic reticulum (ER) stress pathway, also known as the unfolded protein response (UPR) has been shown. We evaluate the effects of ketamine administration on the mTOR signaling pathway and proteins of UPR in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens, after the inhibiton of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol), or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). The immunocontent of mTOR, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), eukaryotic elongation factor 2 kinase (eEF2K) homologous protein (CHOP), PKR-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1) - alpha were determined in the brain. The mTOR levels were reduced in the rapamycin group treated with saline and ketamine in the PFC; p4EBP1 levels were reduced in the rapamycin group treated with ketamine in the PFC and nucleus accumbens; the levels of peEF2K were increased in the PFC in the vehicle group treated with ketamine and reduced in the rapamycin group treated with ketamine. The PERK and IRE1-alpha levels were decreased in the PFC in the rapamycin group treated with ketamine. Our results suggest that mTOR signaling inhibition by rapamycin could be involved, at least in part, with the mechanism of action of ketamine; and the ketamine antidepressant on ER stress pathway could be also mediated by mTOR signaling pathway in certain brain structures.

Ketamine Exhibits Different Neuroanatomical Profile After Mammalian Target of Rapamycin Inhibition in the Prefrontal Cortex: the Role of Inflammation and Oxidative Stress.

Studies indicated that mammalian target of rapamycin (mTOR), oxidative stress, and inflammation are involved in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been identified as a novel MDD therapy; however, the antidepressant mechanism is not fully understood. In addition, the effects of ketamine after mTOR inhibition have not been fully investigated. In the present study, we examined the behavioral and biochemical effects of ketamine in the prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens after inhibition of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol) or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). Immobility was assessed in forced swimming tests, and then oxidative stress parameters and inflammatory markers were evaluated in the brain and periphery. mTOR activation in the PFC was essential to ketamine's antidepressant-like effects. Ketamine increased lipid damage in the PFC, hippocampus, and amygdala. Protein carbonyl was elevated in the PFC, amygdala, and NAc after ketamine administration. Ketamine also increased nitrite/nitrate in the PFC, hippocampus, amygdala, and NAc. Myeloperoxidase activity increased in the hippocampus and NAc after ketamine administration. The activities of superoxide dismutase and catalase were reduced after ketamine administration in all brain areas studied. Inhibition of mTOR signaling pathways by rapamycin in the PFC was required to protect against oxidative stress by reducing damage and increasing antioxidant enzymes. Finally, the TNF-α level was increased in serum by ketamine; however, the rapamycin plus treatment group was not able to block this increase. Activation of mTOR in the PFC is involved in the antidepressant-like effects of ketamine; however, the inhibition of this pathway was able to protect certain brain areas against oxidative stress, without affecting inflammation parameters.

Depressive disorders and comorbidities among the elderly: a population-based study / Transtornos depressivos e algumas comorbidades em idosos: um estudo de base populacional

Objective The present study assessed the prevalence of depressive disorders and associated factors in a sample of elderly persons in the south of Santa Catarina. Methods A cross-sectional study based on population data was performed, evaluating 1021 elderly individuals aged between 60 and 79 years. Home interviews were carried out using the Portuguese version of the Mini International Neuropsychiatric Interview (MINI), in order to collect demographic data, information on hypertension and reports of acute myocardial infarction. The disorders studied were current depressive episode, dysthymia and a comorbidity of a depressive episode and dysthymia, representing double depression. The comparison of mean age and prevalence was made with the t-test and other associations were analyzed using the Chi-squared test. Results The prevalence of depression was 26.2%, while 5.5% of the sample suffered from dysthymia and 2.7% experienced double depression. Risk factors for depression were: nine or more years of schooling [PR = 1.44 (1.17 to 1.77); p <0.05] and being a current smoker [OR = 1.63 (1.30-2.05); p <0.05]. Dysthymia was associated with the male gender [OR = 6.46 (3.29 to 12.64); p <0.05], reports of hypertension [OR = 2.55 (1.53 to 4.24); p <0.05] and being either a current [OR = 1.86 (1.02 to 3.42); p <0.05] or past or former [OR = 2.89 (1.48 to 5.65); p <0.05] smoker. The same risk factors as for dysthymia were found for double depression: male [OR = 4.21 (1.80 to 9.81); p <0.05], reports of hypertension [OR = 8.11 (3.32 to 19.80); p <0.05], and being either a current [OR = 5.72 (1.64 to 19.93); p <0.05] or past [PR = 13.11 (3.75 to 45.86); p <0.05] smoker. Conclusions The present study shows that depressive disorders are a common phenomenon among the elderly. The results not only corroborated with other studies, but found slightly higher levels of depressive disorders among the elderly population.

Objetivo Avaliar a prevalência de transtornos depressivos e fatores associados em uma amostra de idosos no Sul de Santa Catarina. Método Estudo transversal com base de dados populacional, que avaliou 1.021 indivíduos idosos entre 60 e 79 anos. Foram realizadas entrevistas domiciliares com a versão em português do Mini International Neuropsychiatric Interview (MINI), coleta de dados sociodemográficos, informações sobre hipertensão arterial sistêmica, infarto agudo do miocárdio e tabagismo. Os transtornos estudados foram episódio depressivo atual, distimia e comorbidade entre episódio depressivo e distimia, caracterizando depressão dupla. A comparação das médias de idade e prevalências foi feita com o teste t Student, as demais associações foram analisadas pelo teste Qui-quadrado. Resultados A prevalência de depressão foi de 26,2%; distimia, 5,5%; e depressão dupla, 2,7%. Fatores de risco para depressão: nove anos ou mais de estudo [RP=1,44(1,17-1,77); p<0,05] e tabagismo atual [RP=1,63(1,30-2,05); p<0,05]. A distimia foi associada ao gênero masculino [RP=6,46(3,29-12,64); p<0,05], relato de hipertensão arterial [RP=2,55(1,53-4,24);p<0,05] e tabagismo, tanto atual [RP=1,86(1,02-3,42),p<0,05] quanto passado ou ex-tabagistas [RP=2,89(1,48-5,65); p<0,05]. Para a depressão dupla, repetiram os mesmos fatores de risco da distimia: gênero masculino [RP=4,21(1,80-9,81); p<0,05], relato de hipertensão arterial [RP=8,11(3,32-19,80); p<0,05], tabagismo atual [RP=5,72(1,64-19,93); p<0,05] e passado [RP=13,11(3,75-45,86); p<0,05]. Conclusão Os dados demonstram que quadros depressivos são fenômenos frequentes e atingem um percentual significativo de idosos. Adicionalmente, os transtornos depressivos foram associados a fatores sociodemográficos e doenças crônicas, como nível de escolaridade, tabagismo e hipertensão arterial.

Antioxidant Therapy Alters Brain MAPK-JNK and BDNF Signaling Path-ways in Experimental Diabetes Mellitus.

This study was designed to investigate the effects of treatment with the antioxidants N-acetylcysteine (NAC) and deferoxamine (DFX) in intracellular pathways in the brain of diabetic rats. To conduct this study we induced diabetes in Wistar rats with a single injection of alloxan, and afterwards rats were treated with NAC or DFX for 14 days. Following treatment completion, the immunocontent of c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase-38 (MAPK38), brain-derived neurotrophic factor (BDNF), and protein kinases A and C (PKA and PKC) were determined in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens (NAc). DFX treatment increased JNK content in the PFC and NAc of diabetic rats. In the amygdala, JNK was increased in diabetics treated with saline or NAC. MAPK38 was decreased in the PFC of control and in diabetic rats treated with NAC or DFX; and in the NAc in all groups. PKA was decreased in the PFC with DFX treatment. In the amygdala, PKA content was increased in diabetic rats treated with either saline or NAC, compared to controls; and it was decreased in either NAC or DFX-treated groups, compared to saline-treated diabetic animals. In the NAc, PKA was increased in NAC-treated diabetic rats. PKC was increased in the amygdala of NAC-treated diabetic rats. In the PFC, the BDNF levels were decreased following treatment with DFX in diabetic rats. In the hippocampus of diabetic rats the BDNF levels were decreased. However, treatment with DFX reversed this effect. In the amygdala the BDNF increased with DFX in non-diabetic rats. In the NAc DFX treatment increased the BDNF levels in diabetic rats. In conclusion, both diabetes and treatment with antioxidants were able to alter intracellular pathways involved in the regulation of cell survival in a brain area and treatment-dependent fashion.

Effects of ketamine administration on the phosphorylation levels of CREB and TrKB and on oxidative damage after infusion of MEK inhibitor.

BACKGROUND: Ketamine, an antagonist of N-methyl-d-aspartate (NMDA) receptors, has presented antidepressant effects in basic and clinical studies. The MAPK kinase (MEK) signaling pathway could be a target for novel antidepressant drugs and an important pathway involved in neuronal plasticity. Thus, this study evaluated the effects of the administration of ketamine on the phosphorylation of TrKB and CREB, and oxidative stress parameters in the prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens (NAc) rats, after the inhibition of MAPK pathway (PD184161). METHODS: Male adult Wistar rats were submitted to a surgical procedure to receive a single dose of a pharmacological inhibitor of MAPK (PD184161) at a dose of (0.1µg/µl) or vehicle. Then, they were divided: 1) vehicle+saline; 2) inhibitor PD184161+saline; 3) vehicle+ketamine 15mg/kg; and 4) inhibitor PD184161+ketamine 15mg/kg. RESULTS: MEK inhibitor and ketamine increased the phosphorylation of the transcription factor cAMP response element-binding protein (pCREB) and neurotrophic factor/tropomyosin related kinase B receptor (pTrKB) in the PFC, and decreased pCREB in the hippocampus. The MEK inhibitor abolished ketamine's effects in the hippocampus. In the amygdala, pCREB was decreased, and pTrKB was increased after MEK inhibitor plus ketamine. Ketamine increased the thiobarbituric acid reactive species (TBARS) in the PFC, hippocampus, amygdala, and NAc; MEK inhibitor antagonized these effects. The carbonyl was increased in the PFC by both ketamine and MEK inhibitor, but inhibitor infusion plus ketamine administration reduced this effect. In the amygdala, MEK inhibitor increased carbonyl. CONCLUSION: Ketamine's effects on pCREB, pTrKB, and oxidative stress are mediated, at least in part, by a mechanism dependent of MAPK signaling inhibition.

Dental disorders in brown howler monkeys (Alouatta guariba clamitans) maintained in captivity.

BACKGROUND: The aim of this study was to investigate dental disorders of brown howler monkeys maintained in captivity. The hypothesis is that the identification and diagnosis of the lesions may contribute to control and prevention. METHODS: Sixteen intact brown howler monkeys (Alouatta guariba clamitans), eight females and eight males, weighing from 3.9 to 6.8 kg, were studied. Under general anesthesia, the teeth were evaluated by visual inspection, probing, palpation, and intra-oral radiographic exam. The findings were registered on a dental chart specific for primates. RESULT: Of the 16 monkeys evaluated in the present study, 94% (n = 15) had some type of dental disorder. The lesions observed were dental calculus (88%), dental wear (81%), missing teeth (38%), gingivitis (19%), gingival recession (6%), dental fracture (19%), pulp exposure (19%), and dental staining (25%). CONCLUSIONS: Alouatta guariba clamitans maintained in captivity have a high rate of dental problems.

Enriched Flavonoid Fraction from Cecropia pachystachya Trécul Leaves Exerts Antidepressant-like Behavior and Protects Brain Against Oxidative Stress in Rats Subjected to Chronic Mild Stress.

The purpose of this study was to assess the effect of an enriched C-glycosyl flavonoids fraction (EFF-Cp) from Cecropia Pachystachya leaves on behavior, mitochondrial chain function, and oxidative balance in the brain of rats subjected to chronic mild stress. Male Wistar rats were divided into experimental groups (saline/no stress, saline/stress, EFF-Cp/no stress, and EFF-Cp/stress). ECM groups were submitted to stress for 40 days. On the 35th ECM day, EFF-Cp (50 mg/kg) or saline was administrated and the treatments lasted until the 42nd day. On the 41st and 42nd days, the animals were submitted to the splash test and the forced swim test. After these behavioral tests, the enzymatic activity of mitochondrial chain complexes and oxidative stress were analyzed. EFF-Cp reversed the depressive-like behavior induced by ECM. It also reversed the increase in thiobarbituric acid reactive species, myeloperoxidase activity, and nitrite/nitrate concentrations in some brain regions. The reduced activities of the antioxidants superoxide dismutase and catalase in some brain regions were also reversed by EFF-Cp. The most pronounced effect of EFF-Cp on mitochondrial complexes was an increase in complex IV activity in all studied regions. Thus, it is can be concluded that EFF-Cp exerts an antidepressant-like effect and that oxidative balance may be an important physiological process underlying these effects.

Antioxidant treatment ameliorates experimental diabetes-induced depressive-like behaviour and reduces oxidative stress in brain and pancreas.

Studies have shown a relationship between diabetes mellitus (DM) and the development of major depressive disorder. Alterations in oxidative stress are associated with the pathophysiology of both diabetes mellitus and major depressive disorder. This study aimed to evaluate the effects of antioxidants N-acetylcysteine and deferoxamine on behaviour and oxidative stress parameters in diabetic rats. To this aim, after induction of diabetes by a single dose of alloxan, Wistar rats were treated with N-acetylcysteine or deferoxamine for 14 days, and then depressive-like behaviour was evaluated. Oxidative stress parameters were assessed in the prefrontal cortex, hippocampus, amygdala, nucleus accumbens and pancreas. Diabetic rats displayed depressive-like behaviour, and treatment with N-acetylcysteine reversed this alteration. Carbonyl protein levels were increased in the prefrontal cortex, hippocampus and pancreas of diabetic rats, and both N-acetylcysteine and deferoxamine reversed these alterations. Lipid damage was increased in the prefrontal cortex, hippocampus, amygdala and pancreas; however, treatment with N-acetylcysteine or deferoxamine reversed lipid damage only in the hippocampus and pancreas. Superoxide dismutase activity was decreased in the amygdala, nucleus accumbens and pancreas of diabetic rats. In diabetic rats, there was a decrease in catalase enzyme activity in the prefrontal cortex, amygdala, nucleus accumbens and pancreas, but an increase in the hippocampus. Treatment with antioxidants did not have an effect on the activity of antioxidant enzymes. In conclusion, animal model of diabetes produced depressive-like behaviour and oxidative stress in the brain and periphery. Treatment with antioxidants could be a viable alternative to treat behavioural and biochemical alterations induced by diabetes.

Anxious phenotypes plus environmental stressors are related to brain DNA damage and changes in NMDA receptor subunits and glutamate uptake.

This study aimed at investigating the effects of chronic mild stress on DNA damage, NMDA receptor subunits and glutamate transport levels in the brains of rats with an anxious phenotype, which were selected to represent both the high-freezing (CHF) and low-freezing (CLF) lines. The anxious phenotype induced DNA damage in the hippocampus, amygdala and nucleus accumbens (NAc). CHF rats subjected to chronic stress presented a more pronounced DNA damage in the hippocampus and NAc. NMDAR1 were increased in the prefrontal cortex (PC), hippocampus and amygdala of CHF, and decreased in the hippocampus, amygdala and NAc of CHF stressed. NMDAR2A were decreased in the amygdala of the CHF and stressed; and increased in CHF stressed. NMDRA2A in the NAc was increased after stress, and decreased in the CLF. NMDAR2B were increased in the hippocampus of CLF and CHF. In the amygdala, there was a decrease in the NMDAR2B for stress in the CLF and CHF. NMDAR2B in the NAc were decreased for stress and increased in the CHF; in the PC NMDAR2B increased in the CHF. EAAT1 increased in the PC of CLF+stress. In the hippocampus, EAAT1 decreased in all groups. In the amygdala, EAAT1 decreased in the CLF+stress and CHF. EAAT2 were decreased in the PC for stress, and increased in CHF+control. In the hippocampus, the EAAT2 were increased for the CLF and decreased in the CLF+stress. In the amygdala, there was a decrease in the EATT2 in the CLF+stress and CHF. These findings suggest that an anxious phenotype plus stress may induce a more pronounced DNA damage, and promote more alterations in the glutamatergic system. These findings may help to explain, at least in part, the common point of the mechanisms involved with the pathophysiology of depression and anxiety.

Ketamine treatment partly reverses alterations in brain derived- neurotrophic factor, oxidative stress and energy metabolism parameters induced by an animal model of depression.

Studies have suggested that ketamine, a nonselective NMDA receptor antagonist, could be a new drug in the treatment of major depression, but the way ketamine presents such effects remains to be elucidated. Therefore, the objective of this paper was to evaluate the effects of ketamine treatment on parameters related to depression in the brain of adult rats subjected to an animal model of depression. The animals were divided into: non-deprived + saline; non-deprived + ketamine; deprived + saline; deprived + ketamine. Treatments involving ketamine (15 mg/kg) were administered once a day during 14 days in the animal's adult phase. After treatment, the brain derived-neurotrophic factor (BDNF) levels, oxidative stress and energy metabolism activity were evaluated in brain structures of rats involved in the circuit of depression. In the amygdala, hippocampus and nucleus accumbens (NAc), a reduction in BDNF levels was observed in deprived rats, but the animals treated with ketamine reversed the effects of this animal model only in the amygdala and NAc. In addition to this, the complex I activity, in deprived rats, was diminished in the prefrontal cortex (PFC) and amygdala; in the PFC and hippocampus, the complex II-III was diminished in deprived rats; still the administration of ketamine increased the complex IV activity in the PFC and amygdala of rats submitted to the maternal deprivation. In deprived rats, the creatine kinase activity was reduced in the PFC and amygdala, however the administration of ketamine reversed this decrease in the amygdala. The malondialdehyde (MDA) equivalents were increased in non-deprived rats treated with ketamine in the PFC and NAc. Carbonyl levels in the PFC were diminished in control rats that received saline. Though ketamine treatment reversed this effect in deprived rats in the PFC and hippocampus. Still, in NAc, the carbonyl levels were diminished in deprived rats. The superoxide dismutase (SOD) activity was increased in control rats that received ketamine in the PFC and NAc, and were diminished in deprived rats that received saline or ketamine in the PFC and hippocampus. These findings may help to explain that dysfunctions involving BDNF, oxidative stress and energy metabolism within specific brain areas, may be linked with the pathophysiology of depression, and antidepressant effects of ketamine can be positive, at least partially due to the control of these pathways.

Minocycline protects against oxidative damage and alters energy metabolism parameters in the brain of rats subjected to chronic mild stress.

Studies have been suggested that minocycline can be a potential new agent for the treatment of depression. In addition, both oxidative stress and energy metabolism present an important role in pathophysiology of depression. So, the present study was aimed to evaluate the effects of minocycline on stress oxidative parameters and energy metabolism in the brain of adult rats submitted to the chronic mild stress protocol (CMS). After CMS Wistar, both stressed animals as controls received twice ICV injection of minocycline (160 µg) or vehicle. The oxidative stress and energy metabolism parameters were assessed in the prefrontal cortex (PF), hippocampus (HIP), amygdala (AMY) and nucleus accumbens (Nac). Our findings showed that stress induced an increase on protein carbonyl in the PF, AMY and NAc, and mynocicline injection reversed this alteration. The TBARS was increased by stress in the PF, HIP and NAc, however, minocycline reversed the alteration in the PF and HIP. The Complex I was incrased in AMY by stress, and minocycline reversed this effect, however reduced Complex I activity in the NAc; Complex II reduced in PF and AMY by stress or minocycline; the Complex II-III increased in the HIP in stress plus minocycline treatment and in the NAc with minocycline; in the PF and HIP there were a reduced in Complex IV with stress and minocycline. The creatine kinase was reduced in AMY and NAc with stress and minocycline. In conclusion, minocycline presented neuroprotector effects by reducing oxidative damage and regulating energy metabolism in specific brain areas.

Ketamine ameliorates depressive-like behaviors and immune alterations in adult rats following maternal deprivation.

A growing body of evidence points toward an association between the glutamatergic system, as well as immune system dysregulation and major depression. So, the present study was aimed at evaluating the behavioral and molecular effects of the ketamine, an antagonist of the N-methyl-D-aspartate (NMDA) receptor of glutamate in maternally deprived adult rats. In deprived rats treated with saline, we observed an increase in the immobility time; however, ketamine treatment reversed this effect, decreasing immobility time. In addition, maternal deprivation induced an increase in cytokines: TNF-α and IL-1 in serum, and in IL-6 in serum and cerebrospinal fluid (CSF). Interestingly, ketamine treatment reduced the levels of all the cytokines in deprived rats. In conclusion, these findings further support a relationship between immune activation and depression. Considering the action of ketamine, this study suggested that antagonists of the NMDA receptor, such as ketamine, could exert their effects by modulation of the immune system.

Anxiety disorders are associated with quality of life impairment in patients with insulin-dependent type 2 diabetes: a case-control study

Objective: To assess the presence of anxiety disorders and quality of life in patients with insulin-dependent type 2 diabetes. Methods: Case-control study of 996 patients with type 2 diabetes and 2,145 individuals without diabetes. The sole inclusion criterion for the case group was insulin-dependent type 2 diabetes. We compared the case and control groups for sociodemographic variables, laboratory and clinical data, and presence of anxiety disorders. Quality of life was evaluated using the WHOQOL-BREF instrument, and the prevalence of anxiety disorder was evaluated by the Mini International Neuropsychiatric Interview (MINI). Results: Patients with diabetes had a higher prevalence of generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder. The presence of these disorders in combination with type 2 diabetes was associated with worse quality of life in the physical, social, psychological, and environmental domains. Conclusions: This study demonstrates the importance of diagnosing and treating anxiety disorders in patients with diabetes, so as to prevent more serious complications associated with these comorbidities. .

Animal models of social anxiety disorder and their validity criteria.

Anxiety disorders pose one of the largest threats to global mental health, and they predominantly emerge early in life. Social anxiety disorder, also known as social phobia, is the most common of all anxiety disorders. Moreover, it has severe consequences and is a disabling disorder that can cause an individual to be unable to perform the tasks of daily life. Social anxiety disorder is associated with the subsequent development of major depression and other mental diseases, as well as increased substance abuse. Although some neurobiological alterations have been found to be associated with social anxiety disorder, little is known about this disorder. Animal models are useful tools for the investigation of this disorder, as well as for finding new pharmacological targets for treatment. Thus, this review will highlight the main animal models of anxiety associated with social phobia.

Anxiety disorders are associated with quality of life impairment in patients with insulin-dependent type 2 diabetes: a case-control study.

OBJECTIVE: To assess the presence of anxiety disorders and quality of life in patients with insulin-dependent type 2 diabetes. METHODS: Case-control study of 996 patients with type 2 diabetes and 2,145 individuals without diabetes. The sole inclusion criterion for the case group was insulin-dependent type 2 diabetes. We compared the case and control groups for sociodemographic variables, laboratory and clinical data, and presence of anxiety disorders. Quality of life was evaluated using the WHOQOL-BREF instrument, and the prevalence of anxiety disorder was evaluated by the Mini International Neuropsychiatric Interview (MINI). RESULTS: Patients with diabetes had a higher prevalence of generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder. The presence of these disorders in combination with type 2 diabetes was associated with worse quality of life in the physical, social, psychological, and environmental domains. CONCLUSIONS: This study demonstrates the importance of diagnosing and treating anxiety disorders in patients with diabetes, so as to prevent more serious complications associated with these comorbidities.

MAPK signaling correlates with the antidepressant effects of ketamine.

Studies have pointed to a relationship between MAPK kinase (MEK) signaling and the behavioral effects of antidepressant drugs. So, in the present study we examined the behavioral and molecular effects of ketamine, an antagonist of the N-methyl-d-aspartate receptor (NMDA), which has been shown to have an antidepressant effect after the inhibition of MEK signaling in Wistar rats. Our results showed that acute administration of the MEK inhibitor PD184161, produced depressive-like behavior and stopped antidepressant-like effects of ketamine in the forced swimming test. The phosphorylation of extracellular signal-regulated kinase 1/2 (pERK 1/2) was decreased by PD184161 in the amygdala and nucleus accumbens, and the effects of ketamine on pERK 1/2 in the prefrontal cortex and hippocampus were inhibited by PD184161. The ERK 2 levels were decreased by PD184161 in the nucleus accumbens; and the effects of ketamine were blocked in this brain area. The p38 protein kinase (p38MAPK) and proBDNF were inhibited by PD184161, and the MEK inhibitor prevented the effects of ketamine in the nucleus accumbens. In addition, ketamine increased pro-BDNF levels in the hippocampus. In conclusion, our findings demonstrated that an acute blockade of MAPK signaling lead to depressive-like behavior and stopped the antidepressant response of ketamine, suggesting that the effects of ketamine could be mediated, at least in part, by the regulation of MAPK signaling in these specific brain areas.

Ketamine and imipramine in the nucleus accumbens regulate histone deacetylation induced by maternal deprivation and are critical for associated behaviors.

Studies indicate that histone deacetylation is important for long term changes related to stress and antidepressant treatment. The present study aimed to evaluate the effects of the classic antidepressant imipramine, and of an antagonist of the N-methyl-d-asparte (NMDA) receptor, ketamine, on behavior and histone deacetylase (HDAC) activity in the brains of maternally deprived adult rats. To this aim, deprived and non-deprived (control) male Wistar rats were divided into the following groups: non-deprived+saline; non-deprived+imipramine (30 mg/kg); non-deprived+ketamine (15 mg/kg); deprived+saline; deprived+imipramine (30 mg/kg); and deprived+ketamine (15 mg/kg). The drugs were administrated once a day for 14 days during their adult phase. Their behavior were then assessed using the forced swimming and open field tests. In addition, the HDAC activity was evaluated in the prefrontal cortex, hippocampus, amygdala and nucleus accumbens using the kit ELISA-sandwich test. In deprived rats treated with saline, we observed an increase in the immobility time, but treatments with imipramine and ketamine were able to reverse this alteration, decreasing the immobility time. Also, there was a decrease on number of crossings with imipramine treatment in non-deprived rats, and an increase on number of crossings with ketamine treatment in deprived rats. The HDAC activity did not alter in the prefrontal cortex, hippocampus and amygdala by deprivation or via treatment with imipramine or ketamine. However, in the nucleus accumbens we observed an increase of HDAC activity in the deprived rats, and interestingly, imipramine and ketamine treatments were able to decrease HDAC activity in this brain area. These findings provide a novel insight into the epigenetic regulation of histone deacetylase in the nucleus accumbens caused by imipramine and ketamine, and indicate that molecular events are necessary to reverse specific stress-induced behavior.