Spatiotemporal trends of Chagas disease-related mortality in the Northeast of Brazil, 2007-2017.

Chagas disease (CD) is a neglected disease and endemic in Brazil. In the Brazilian Northeast Region, it affects millions of people. Therefore, it is necessary to identify the spatiotemporal trends of CD mortality in the Northeast of Brazil. This ecological study was designed, in which the unit of analysis was the municipality of the Brazilian northeast. The data source was the Information System of Mortality. It was calculated relative risk from socioeconomic characteristics. Mortality rates were smoothed by the Local Empirical Bayes method. Spatial dependency was analysed by the Global and Local Moran Index. Scan spatial statistics were also used. A total of 11 287 deaths by CD were notified in the study. An expressive parcel of this number was observed among 70-year-olds or more (n = 4381; 38.8%), no schooling (n = 4381; 38.8%), mixed-race (n = 4381; 62.3%), male (n = 6875; 60.9%). It was observed positive spatial autocorrelation, mostly in municipalities of the state of Bahia, Piauí (with high-high clusters), and Maranhão (with low-low clusters). The spatial scan statistics has presented a risk of mortality in 24 purely spatial clusters (P < 0.05). The study has identified the spatial pattern of CD mortality mostly in Bahia and Piauí, highlighting priority areas in planning and control strategies of the health services.

Mortality and survival of COVID-19.

This study aims to identify the risk factors associated with mortality and survival of COVID-19 cases in a state of the Brazilian Northeast. It is a historical cohort with a secondary database of 2070 people that presented flu-like symptoms, sought health assistance in the state and tested positive to COVID-19 until 14 April 2020, only moderate and severe cases were hospitalised. The main outcome was death as a binary variable (yes/no). It also investigated the main factors related to mortality and survival of the disease. Time since the beginning of symptoms until death/end of the survey (14 April 2020) was the time variable of this study. Mortality was analysed by robust Poisson regression, and survival by Kaplan-Meier and Cox regression. From the 2070 people that tested positive to COVID-19, 131 (6.3%) died and 1939 (93.7%) survived, the overall survival probability was 87.7% from the 24th day of infection. Mortality was enhanced by the variables: elderly (HR 3.6; 95% CI 2.3-5.8; P < 0.001), neurological diseases (HR 3.9; 95% CI 1.9-7.8; P < 0.001), pneumopathies (HR 2.6; 95% CI 1.4-4.7; P < 0.001) and cardiovascular diseases (HR 8.9; 95% CI 5.4-14.5; P < 0.001). In conclusion, mortality by COVID-19 in Ceará is similar to countries with a large number of cases of the disease, although deaths occur later. Elderly people and comorbidities presented a greater risk of death.

Clinical Evolution of Patients Using Ventricular Assist Devices as a Bridge for Transplantation.

OBJECTIVE: To evaluate the clinical evolution of patients with implantation of ventricular assist device (VAD) and identify the intervening factors for death. METHODS: This analytical, retrospective study was carried out in a public reference hospital in cardiopulmonary diseases located in northeastern Brazil. The study population encompassed the medical records of 16 patients who underwent VAD implantation. Data collection took place from January to August 2016, through the consultation of medical records. Descriptive analysis, odds ratio, and the Fisher's Exact, Wilcoxon, Friedman and t-tests were used to analyze the data. RESULTS: All patients experienced complications during the use of the device, with bleeding being the main cause (11 [68.8%]). There was a significant decrease in noradrenaline (P = .025), milrinone (Primacor; P = .007), and dobutamine (P = .046) flow rates with the clinical evolution of patients. Regarding hematologic parameters, the use of VAD promoted a significant improvement in hemoglobin (P < .001), hematocrit (P = .003), activated partial thromboplastin time (P = .013), and fibrinogen (P = .049) values at the 3 time points analyzed. Regarding the clinical outcome of the patients, the majority (10 [62.5%]) underwent cardiac transplantation. CONCLUSIONS: This study allowed for better knowledge of the clinical evolution of patients with VAD implantation, highlighting the benefits of this type of device as a bridge for heart transplantation.

Memory impairment induced by an interfering task is reverted by pre-frontal cortex lesions: a possible role for an inhibitory process in memory suppression in mice.

Interference theory refers to the idea that forgetting occurs because the recall of certain items interferes with the recall of other items. Recently, it has been proposed that interference is due to an inhibitory control mechanism, triggered by competing memories, that ultimately causes forgetting [Anderson MC (2003) Rethinking interference theory: Executive control and the mechanisms of forgetting. J Mem Lang 49:415-4453]. In the present research we study the interference process by submitting CD1 mice to two different hippocampal-dependent tasks: a place object recognition task (PORT) and a step-through inhibitory avoidance task (IA). Our results show a mutual interference between PORT and IA. To elucidate the possible neural mechanism underlying the interference process, we submit hippocampus- and prefrontal cortex-lesioned mice to PORT immediately before IA training. Results from these experiments show that prefrontal cortex lesions completely revert the impairing effect exerted by PORT administration on IA memory, while hippocampus lesions, that as expected impair memory for both PORT and IA, increase this effect. Altogether our results suggest that interference-induced forgetting is driven by an inhibitory control mechanism through activation of hippocampus-prefrontal cortex circuitry. The hippocampus seems to be crucial for storing information related to both behavioral tasks. Competition between memories triggers the inhibitory control mechanism, by activating prefrontal cortex, and induces memory suppression.

A role for ERK2 in reconsolidation of fear memories in mice.

Recent studies have shown that consolidated fear memories, when reactivated, return to a labile state that requires a new protein synthesis for reconsolidation. Post-retrieval infusion of an inhibitor of protein synthesis blocks memory reconsolidation processes. In a previous research, the role of MAPKs in memory consolidation has been shown in emotional tasks, such as passive and active avoidance. In particular, mice knockout for ERK1 had a better performance in comparison to wild type mice in both passive and active avoidance tasks. In the present study, in order to investigate the involvement of MAPKs in memory reconsolidation processes we administered immediately after retrieval, different doses of SL327 (an inhibitor of MEK, a kinase that activates both ERK1 and ERK2) both in C57BL/6 (C57) mice and ERK1 mutant mice tested in a fear conditioning task. Systemic administration of SL327 dose-dependently reduced the memory reconsolidation of fear memories in C57 mice. Moreover, SL327 administration impaired memory reconsolidation also in ERK1 mutant mice. Altogether, these results clearly indicate a central role for ERK2 protein in memory reconsolidation processes in mice.

NMDA receptors and learning and memory processes.

In the first part of this review studies are considered in which pre- or post-training peripheral or intracerebroventricular administrations of competitive or noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists were carried out in a variety of animal species tested in different experimental conditions, in order to investigate the effects of these drugs on acquisition and memory processes. In particular, post-training treatments, which are known to affect memory consolidation, ruling out the possible "aspecific effects" linked to the pre-training administrations, show that the NMDA receptor antagonists impair memory in animals tested in various tasks. Memory impairments are also evident when the NMDA antagonists (in particular AP5) are injected into different brain structures, including amygdala and hippocampus. In a second part of this review some recent studies are considered showing the existence of: a) cholinergic-glutamatergic interactions; b) interactions between NMDA receptors and opioid system, and c) interactions between NMDA receptor antagonists (MK-801) and cocaine, in the modulation of memory processes of laboratory animals. The results of some studies showing the involvement of glutamatergic mechanisms in Alzheimer's disease are finally reported, and the therapeutic efficacy of glutamatergic drugs in the treatment of this disease is considered.

Effects of MK-801 and nicotine combinations on memory consolidation in CD1 mice.

RATIONALE: Recent experiments have shown that pre-trial administrations of nicotine to rats tested in a 16-arm radial maze attenuated the MK-801-induced deficit in both working and reference memory performance. Memory consolidation can be influenced in laboratory animals, by post-training administration of drugs. OBJECTIVE: In the present study we have investigated the effects on memory consolidation of CD1 mice exerted by: a) the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclo-hepten-5, 10-imine-maleate] b) nicotine, and c) combinations of MK-801 and nicotine. METHODS: Different groups of mice were injected intraperitoneally (IP) with the single drugs and with their combinations, immediately after training in a passive avoidance task. Additional groups of animals were also injected 2 h post-training with the highest effective dose of MK-801 (0.3 mg/kg), with the highest effective dose of nicotine (0.5 mg/kg) or with the combination of an otherwise ineffective dose of MK-801 (0.1 mg/kg) with the highest effective dose of nicotine, respectively. Their performances were compared with those of mice injected with saline, with the vehicle of nicotine and with the other treatment combinations, respectively RESULTS: The results showed that MK-801 exerted deleterious effects, while nicotine exerted facilitatory effects on mice performances. Further, an otherwise ineffective dose of MK-801 (0.1 mg/kg) antagonized the facilitatory effects of nicotine (0.25 and 0.5 mg/kg). In the 2 h post-training injected groups the treatments were ineffective, showing that the immediate post-training drug administrations affected memory consolidation processes. CONCLUSIONS: In conclusion, from the present research, it is evident that NMDA glutamate and nicotinic acetylcholine receptor systems interact in modulating memory consolidation in CD I mice.

In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: correction of neuropathology and protection against learning impairments in affected mice.

Metachromatic leukodystrophy (MLD) is a lipidosis caused by deficiency of arylsulfatase A (ARSA). Although the genetics of MLD are known, its pathophysiology is not understood. The disease leads to progressive demyelination and early death and no effective treatment is available. We used lentiviral vectors to deliver a functional ARSA gene (human ARSA) into the brain of adult mice with germ-line inactivation of the mouse gene encoding ARSA, As2. We report sustained expression of active enzyme throughout a large portion of the brain, with long-term protection from development of neuropathology and hippocampal-related learning impairments. We show that selective degeneration of hippocampal neurons is a central step in disease pathogenesis, and provide evidence that in vivo transfer of ARSA by lentiviral vectors reverts the disease phenotype in all investigated areas. Therefore, in vivo gene therapy offers a unique option for MLD and other storage diseases affecting the central nervous system.

Strain-dependent interactions between MK-801 and cocaine on retention of C57BL/6 and DBA/2 mice tested in a one-trial inhibitory avoidance task: involvement of dopaminergic mechanisms.

Two sets of experiments were carried out with C57BL/6 (C57) and DBA/2 (DBA) mice tested in a one-trial inhibitory avoidance task. In the first set C57 and DBA mice were injected posttraining with saline or with the D1 DA receptor antagonist SCH 23390 and then with saline, cocaine (5 mg/kg), MK-801 (0.1 mg/kg), or with a combination of these two drugs. Cocaine enhanced retention in the C57 strain and impaired it in the DBA strain, and MK-801 potentiated the effects of cocaine in both strains. Furthermore, pretreatment with SCH 23390 completely antagonized the potentiation of the effects of cocaine exerted by MK-801. In the second set of experiments mice belonging to these same two strains were injected posttraining with vehicle or with the D2 DA receptor antagonist (-)-sulpiride and then with saline, cocaine (5 mg/kg), MK-801 (0.1 mg/kg), or with a combination of these two drugs. Pretreatment with the D2 DA receptor antagonist completely antagonized in both strains the potentiation of the effect of cocaine exerted by MK-801. The results of the present research show that the noncompetitive NMDA receptor antagonist MK-801 enhances the effect of cocaine on retention performance in C57 and DBA mice and that dopaminergic mechanisms are involved in this potentiation.

Essential role for TrkB receptors in hippocampus-mediated learning.

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB regulate both short-term synaptic functions and long-term potentiation (LTP) of brain synapses, raising the possibility that BDNF/TrkB may be involved in cognitive functions. We have generated conditionally gene targeted mice in which the knockout of the trkB gene is restricted to the forebrain and occurs only during postnatal development. Adult mutant mice show increasingly impaired learning behavior or inappropriate coping responses when facing complex and/or stressful learning paradigms but succeed in simple passive avoidance learning. Homozygous mutants show impaired LTP at CA1 hippocampal synapses. Interestingly, heterozygotes show a partial but substantial reduction of LTP but appear behaviorally normal. Thus, CA1 LTP may need to be reduced below a certain threshold before behavioral defects become apparent.

MK-801-induced disruptions of one-trial inhibitory avoidance are potentiated by stress and reversed by naltrexone.

Five experiments were carried out to investigate opioid and NMDA receptor-mediated responses to one-trial inhibitory avoidance training in CD1 mice. In the first experiment immediate posttraining intraperitoneal administration of the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 impaired the performance of mice. The effects of MK-801 were time-dependent (they were absent in mice injected with the drug starting 120 min after training). No effect was evident in no-foot-shock groups, showing lack of proactive influence of the treatment on performance. In the second experiment preexposure of the mice to the testing apparatus decreased the effects of MK-801. In the the third experiment naltrexone antagonized the effects of MK-801, suggesting an involvement of opioid neurons. In the fourth experiment immediate posttraining immobilization stress exerted a potentiating effect on the performance of MK-801-injected animals. In the fifth experiment the potentiation of the impairing effect of MK-801 induced by immobilization stress was antagonized by naltrexone.

Strain-dependent effects of MK-801 on passive avoidance behaviour in mice: interactions with morphine and immobilization stress.

RATIONALE: Post-training treatments (drugs, stress, ECS) influence retention performance of laboratory animals, sometimes in a strain-dependent way. In a previous study, an interaction between the effects of morphine and of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 on retention performance was observed, in random bred mice. OBJECTIVE: In the present research, we have investigated the effects on retention of C57BL/6 (C57) and DBA/2 (DBA) mice exerted by a) morphine, b) MK-801 and c) naltrexone. Further, we have studied in both strains the effects exerted on retention by combinations of morphine and MK-801, and of MK-801 and immobilization stress. Finally, the naltrexone-reversibility of the interaction between immobilization stress and MK-801 was also assessed. METHODS: All treatments were administered immediately after training in mice tested in a passive avoidance task. Drugs were injected IP. RESULTS: The results of our experiments showed that morphine and the non-competitive NMDA receptor antagonist MK-801 exerted dose- and time-dependent facilitatory effects on retention performance in C57 mice, and dose- and time-dependent impairments in DBA mice. Further, dose- and time-dependent deleterious effects on retention performance, in the C57 strain, and dose- and time-dependent enhancing effects, in the DBA strain, were observed following post-training IP naltrexone administration. MK-801 enhanced, in both strains, the effects of morphine. Finally, immobilization stress enhanced in both strains the effects of MK-801 and these effects were naltrexone-reversible. CONCLUSIONS: In conclusion, the results of this study show that the genetic make-up of the mice played an important role in all the effects observed, and, in particular, in the interaction between the opioid and the glutamatergic systems. Further, the naltrexone reversibility of the interaction between MK-801 and immobilization stress suggests that opioid mechanisms were involved.

[Surgical wound infection. Review of the guidelines and results of a prevalence study by the Presidio Ospedaliero de Voghera]. / Infezione della ferita chirurgica. Revisione delle linee guida e risultato di una indagine di prevalenza nel Presidio Ospedaliero di Voghera.

BACKGROUND: A prevalence study regarding hospital acquired infections and particularly surgical wound infections was performed from 17-4-1995 to 17-7-1995 in the Voghera hospital, a large one in Northern Italy. METHODS: The records of all subjects who have operated since at least 24 hours have been checked and the surgical wounds have been classified according to the guidelines of CDC (Atlanta). RESULTS: The prevalence rate of surgical wound infections was 13.73% of operated patients, confirming the seriousness of the problem of nosocomial infections surveillance. Pseudonomas aeruginosa (31.27%) and Staphylococcus aureus (21.92%) were the most frequently isolated organisms. CONCLUSIONS: Finally, behaviour guideline have been reproposed to try to reduce surgical wound infections for a best Quality of care in the light of a Regional credit.

The dorsal hippocampus is essential for context discrimination but not for contextual conditioning.

The authors describe how (a) the timing of hippocampal lesions and (b) the behavioral-representational demands of the task affect the requirement for the hippocampus in contextual fear conditioning. Post- but not pretraining lesions of the hippocampus greatly reduced contextual fear conditioning. In contrast, pretraining lesions of the hippocampus abolished context discrimination, a procedure in which mice are trained to discriminate between 2 similar chambers (shock context vs. no-shock context). Whereas either contextual- or cue-based strategies can be used to recognize an aversive context, discrimination between similar contexts is optimally acquired by contextual (hippocampal)-based strategies. In keeping with the lesion results, Nf1(+/-)/Nmdar1(+/-) mutant mice, which have spatial learning deficits, are impaired in context discrimination but not in contextual conditioning. Together, these data dissociate hippocampal and nonhippocampal contributions to contextual conditioning, and they provide direct evidence that the hippocampus plays an essential role in the processing of contextual stimuli.

A role for the Ras signalling pathway in synaptic transmission and long-term memory.

Members of the Ras subfamily of small guanine-nucleotide-binding proteins are essential for controlling normal and malignant cell proliferation as well as cell differentiation. The neuronal-specific guanine-nucleotide-exchange factor, Ras-GRF/CDC25Mm, induces Ras signalling in response to Ca2+ influx and activation of G-protein-coupled receptors in vitro, suggesting that it plays a role in neurotransmission and plasticity in vivo. Here we report that mice lacking Ras-GRF are impaired in the process of memory consolidation, as revealed by emotional conditioning tasks that require the function of the amygdala; learning and short-term memory are intact. Electrophysiological measurements in the basolateral amygdala reveal that long-term plasticity is abnormal in mutant mice. In contrast, Ras-GRF mutants do not reveal major deficits in spatial learning tasks such as the Morris water maze, a test that requires hippocampal function. Consistent with apparently normal hippocampal functions, Ras-GRF mutants show normal NMDA (N-methyl-D-aspartate) receptor-dependent long-term potentiation in this structure. These results implicate Ras-GRF signalling via the Ras/MAP kinase pathway in synaptic events leading to formation of long-term memories.

MK-801 potentiates morphine-induced impairment of memory consolidation in mice: involvement of dopaminergic mechanisms.

The purpose of the present research was to study the interaction between the non-competitive NMDA receptor antagonist MK-801 and morphine in memory consolidation. The involvement of dopamine (DA) mechanisms in this interaction was also studied. Four sets of experiments were carried out with CD1 mice in a one-trial inhibitory avoidance task with post-training injections of drugs. In a first series of experiments post-training administration of morphine or of the non-competitive NMDA receptor antagonist MK-801 impaired memory consolidation. In the second set of experiments the memory consolidation impairment exerted by MK-801 was potentiated by the administration of the D1 dopamine (DA) receptor antagonist SCH 23390 and by that of the D2 DA receptor antagonist (-)-sulpiride. In the third set of experiments, administration of a dose of MK-801 ineffective by itself potentiated the memory impairment exerted by morphine. In the fourth series of experiments, similar ineffective doses of the D1 DA receptor agonist SKF 38393 or of the D2 DA receptor agonist LY 171555 antagonized the impairment of memory consolidation produced by MK-801 and morphine in combination, suggesting the involvement of dopaminergic mechanisms.

Impaired learning in mice with abnormal short-lived plasticity.

BACKGROUND: Many studies suggest that long term potentiation (LTP) has a role in learning and memory. In contrast, little is known about the function of short-lived plasticity (SLP). Modeling results suggested that SLP could be responsible for temporary memory storage, as in working memory, or that it may be involved in processing information regarding the timing of events. These models predict that abnormalities in SLP should lead to learning deficits. We tested this prediction in four lines of mutant mice with abnormal SLP, but apparently normal LTP-mice heterozygous for a alpha-calcium calmodulin kinase II mutation (alpha CaMKII +/-) have lower paired-pulse facilitation (PPF) and increased post-tetanic potentiation (PTP); mice lacking synapsin II (SyII-/-), and mice defective in both synapsin I and synapsin II (SyI/II-/-), show normal PPF but lower PTP; in contrast, mice just lacking synapsin I (SyI-/-) have increased PPF, but normal PTP. RESULTS: Our behavioral results demonstrate that alpha CaMKII +/-, SyII-/- and SyI/II-/- mutant mice, which have decreased PPF or PTP, have profound impairments in learning tasks. In contrast, behavioral analysis did not reveal learning deficits in SyI-/- mice, which have increased PPF. CONCLUSIONS: Our results are consistent with models that propose a role for SLP in learning, as mice with decreased PPF or PTP, in the absence of known LTP deficits, also show profound learning impairments. Importantly, analysis of the SyI-/- mutants demonstrated that an increase in PPF does not disrupt learning.

Amygdala lesions block the effect of cocaine on memory in mice.

Post-training cocaine intraperitoneal administration enhanced memory consolidation in unoperated and sham-lesioned mice tested in a one-trial inhibitory avoidance task. Bilateral electrolytical amygdala lesions blocked this effect. The results are interpreted in terms of involvement of neurotransmitter, and in particular dopaminergic, systems in the effects of cocaine on memory.

Caffeine and cocaine interaction on memory consolidation in mice.

The main aim of this study was to investigate the interaction between the effects of caffeine and cocaine on memory consolidation in mice. For this purpose, CD1 mice were used; they were injected intraperitoneally and tested in a one-trial inhibitory avoidance task. The apparatus consisted of two compartments, one lighted and the other in darkness. On the training day, the animal had to go from the lighted to the dark compartment, where it received an electric shock. On the test day, carried out in our experiments 24 hours later, the time the animal waited to enter the dark compartment is the measure of its retention (for further details, see Methods). Three sets of experiments were carried out. In a first set, immediately posttraining, caffeine (0.25, 0.5 and 1 mg/kg) or cocaine (1, 2.5 and 5 mg/kg) administrations enhanced the memory consolidation of mice. In a second set, the D2 dopamine receptor antagonist, (-)-sulpiride, antagonized the enhancing effect of caffeine on memory. In a third set, a clear interaction between caffeine and cocaine was evident. The results are interpreted in terms of interaction of the drugs used with the dopaminergic system.

Interaction between the NMDA competitive antagonist CPP and the dopaminergic system in one-trial inhibitory avoidance in C57BL/6 mice.

Post-training administration of the N-methyl-D-aspartate (NMDA) receptors antagonist CPP, at doses of 0.5 and 1.0 mg/kg, impaired, in dose-dependent fashion, retention of the inhibitory avoidance response in C57BL/6J (C57) mice. Post-training subeffective doses of selective D1 and D2 dopamine receptor agonists, were able to antagonize the action of CPP, while subeffective doses of SCH 23390 and (-) sulpiride, respectively, D1- and D2-selective antagonists, enhanced the effects of the NMDA antagonist. Furthermore, subchronic blockade of dopamine receptor through a 10-day daily treatment with 4 mg/kg of haloperidol induced an adaptation of both the dopaminergic and the glutamatergic system. The possible upregulation of D2 receptors, in response to repeated injection with haloperidol is shown in the one-trial inhibitory avoidance by an increased response to the D2 agonist. In addition, our data show a potentiation of CPP effects after the same treatment. These results suggest a complex interaction between dopamine and glutamate in modulating one-trial inhibitory avoidance behavior in mice.