Involvement of Pre-limbic Cortex-Nucleus accumbens projections in Context-Induced alcohol seeking.

Alcohol use disorder (AUD) remains a critical public health issue worldwide, characterized by high relapse rates often triggered by contextual cues. This research investigates the neural mechanisms behind context-induced reinstatement of alcohol-seeking behavior, focusing on the nucleus accumbens and its interactions with the prelimbic cortex, employing Male Long-Evans rats in an ABA renewal model. In our experimental setup, rats were trained to self-administer 10 % ethanol in Context A, followed by extinction of lever pressing in the presence of discrete cues in Context B. The context-induced reinstatement of ethanol-seeking was then assessed by re-exposing rats to Context A or B under extinction conditions, aiming to simulate the environmental cues' influence on relapse behaviors. Three experiments were conducted: Experiment 1 utilized Fos-immunohistochemistry to examine neuronal activation in the nucleus accumbens; Experiment 2 applied the baclofen + muscimol inactivation technique to probe the functional importance of the nucleus accumbens core; Experiment 3 used Fos-immunofluorescence along with Retrobeads injection to investigate activation of neurons projecting from the prelimbic cortex to the nucleus accumbens core. Our findings revealed significant increases in Fos-immunoreactive nuclei within the nucleus accumbens core and shell during the reinstatement phase in Context A, underscoring the environment's potent effect on ethanol-seeking behavior. Additionally, inactivation of the nucleus accumbens core markedly reduced reinstatement, and there was a notable activation of neurons from the prelimbic cortex to the nucleus accumbens core in the ethanol-associated context. These results highlight the critical role of the nucleus accumbens core and its corticostriatal projections in the neural circuitry underlying context-driven ethanol seeking.

Kikuchi-Fujimoto Disease: A Case of SARS-CoV-2 Infection Triggering the Rare Disease.

Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a rare, benign, and self-limited disease caused by subacute necrotizing regional lymphadenopathy. The etiology is unknown, although virus and autoimmune mechanisms have been proposed. Patients develop enlarged lymph nodes, fever, and, less frequently, extranodal signs. No specific laboratory test contributes to the diagnosis, and lymph node biopsy is the gold standard to define the diagnosis. The treatment is generally with supportive therapy and usually is spontaneously resolved within six months.  In this article, the authors present the case of a 41-year-old female with mild SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection 10 weeks before she was admitted to the emergency department (ED) due to cervical lymphadenopathies and fever lasting over three weeks. Physical examination revealed multiple lymphadenopathies on the submandibular and jugular regions, cutaneous rash, and hepatosplenomegaly. Blood tests showed elevated acute phase proteins, thrombocytopenia, and increased transaminases and lactate dehydrogenase (LDH). Computed tomography (CT) of the neck showed multiple adenopathies at levels I, II, III, and IV according to the Classification for Lymph Nodes from the American Head and Neck Society and American Academy of Otolaryngology on the right side. Excision biopsy was performed and histopathological examination confirmed KFD. A comprehensive analysis performed was unrevealing of an infectious or autoimmune cause and was assumed to be most likely triggered by SARS-CoV-2 infection given the timeframe correlation. KFD diagnosis is challenging and there are few reported cases of association with SARS-CoV-2 in the literature. Although further investigation is still needed to better understand the relation between them, it is important that physicians take SARS-CoV-2 infection and vaccination into consideration in KFD's differential diagnosis.

Drug-Induced Liver Injury Due To Losartan.

Drug-induced liver injury (DILI) is a challenging diagnosis since a wide variety of medicines can cause adverse reactions. Losartan is an angiotensin II receptor antagonist (ARA-II) approved for the treatment of arterial hypertension. The most common adverse effects are fatigue, anaemia, weakness and cough. An increase in transaminases has been reported with less frequency (<2% of cases). Although the mechanism is not fully understood, DILI onset is usually within 1-8 weeks of therapy, and hepatic enzymology usually normalizes 2-4 months after drug suspension. The authors present the case of a 66-year-old male patient with a medical history of arterial hypertension and a prior hospitalization (4 years previously) for drug-induced hepatitis, which, at the time, was attributed to a dietary supplement. Four years later, because of new onset of hypertension, losartan was reintroduced. After 3 weeks, the patient was admitted to the emergency department with complaints of acute abdominal pain associated with asthenia, nausea and increased abdominal volume that had first developed 8 days previously. After exclusion of other causes, DILI associated with losartan was assumed. This is a very rare adverse effect since only seven cases have been described in the literature. LEARNING POINTS: Toxic hepatitis due to losartan is very rare, despite widespread use of the drug.A high index of suspicion for drug-induced liver injury (DILI) should be maintained while other diagnoses are carefully excluded.Monitoring the use of the offending drug is crucial, since DILI recurrence is associated with worse prognosis.

Q Fever: An Emerging Reality in Portugal.

Q fever is a zoonosis caused by Coxiella burnetii with worldwide distribution at the increasing expression in Europe and endemic in Portugal. It is transmitted by inhalation of aerosols containing spores, main reservoir being cattle, goats and sheep as by ingesting cottage cheese or unpasteurized milk. The majority of patients are asymptomatic; however, they may present with fever, atypical pneumonia, acute hepatitis, cutaneous manifestations and rarely with cardiac or neurological involvement. Although most cases are self-limited, focal persistent or chronic Q fever can manifest years after the onset, wherefore follow-up is essential. The clinical heterogeneity may be so variable that the disease is often diagnosed only if it has been systematically considered. It should be especially taken into account in the presence of risk factors as valvular or joint prostheses, immunocompromised patients, pregnant women and epidemiological setting. The authors present a rare case of Coxiella burnetii pneumonia with cutaneous and hepatic manifestations without any risk factor. This case aims to emphasize the importance of Q fever in the differential diagnosis of fever or atypical pneumonia, even in the absence of known risk factors. The diagnosis is often challenging for clinicians and it is necessary to maintain a high index of suspicion. In Europe and specifically in Portugal is mandatory to report the cases to establish the real impact of this disease.

Maternal Separation Stress Affects Voluntary Ethanol Intake in a Sex Dependent Manner.

Maternal separation (MS) stress is a predictive animal model for evaluating the effects of early stress exposure on alcohol use disorders (AUD). The extended amygdala (AMY) is a complex circuit involved in both stress- and ethanol-related responses. We hypothesized that MS stress may increase ethanol consumption in adulthood, as well as augment neuronal activity in extended AMY, in a sex-dependent manner. We aimed to investigate the influence of MS stress on the ethanol consumption of male and female mice, and the involvement of extended amygdala sub-nuclei in this process. The C57BL/6J pups were subjected to 180min of MS, from postnatal day (PND) 1 to 14. The control group was left undisturbed. On PND 45, mice (n=28) in cages were exposed to a bottle containing 20% ethanol (w/v) for 4h during the dark period of the light-dark cycle, for 3weeks. Afterward, mice underwent ethanol self-administration training in operant chambers under fixed ratio (FR) schedule. Then, subjects were tested under 2h sessions of a progressive-ratio (PR) schedule of reinforcement (the last ratio achieved was considered the breaking point), and at the end, a 4h session of FR schedule (binge-intake). An immunohistochemistry assay for Fos protein was performed in Nucleus Accumbens (NAcc), Bed Nucleus of Stria Terminalis (BNST), and AMY. Our results showed that in the third week of training, the female MS group consumed more ethanol than the respective control group. The MS group presented increased breakpoint parameters. Female control group and male MS group were more resistant to bitter quinine taste. Increased Fos-immunoreactive neurons (Fos-IR) were observed in the central nucleus of AMY, but not in NAcc nor BNST in male maternal-separated mice. Maternal separation stress may influence ethanol intake in adulthood, and it is dependent on the sex and reinforcement protocol.

Chronic ethanol vapor exposure potentiates cardiovascular responses to acute stress in male but not in female rats.

BACKGROUND: Ethanol use is related to a wide variety of negative health outcomes, including cardiovascular diseases. Stress is also involved in numerous pathologies, such as cardiovascular diseases and psychiatric disorders. Sexual dimorphism is an important factor affecting cardiovascular response and has been proposed as a potential risk factor for sex-specific health problems in humans. Here, we evaluated the effect of prolonged ethanol vapor inhalation on arterial pressure, heart rate, and tail skin temperature responses to acute restraint stress, investigating differences between male and female rats. METHODS: We exposed male and female Long-Evans rats to ethanol vapor for 14 h, followed by ethanol withdrawal for 10 h, for 30 consecutive days, or to room air (control groups). The animals underwent surgical implantation of a cannula into the femoral artery for assessment of arterial pressure and heart rate values. The tail skin temperature was measured as an indirect measurement of sympathetic vasomotor response. RESULTS: Chronic ethanol vapor inhalation reduced basal heart rate in both female and male rats. Sex-related difference was observed in the decrease of tail cutaneous temperature evoked by stress, but not in the pressor and tachycardiac responses. Furthermore, prolonged ethanol inhalation enhanced the blood pressure and heart rate increase caused by acute restraint stress in male, but not in female rats. However, no effect of chronic ethanol vapor was observed in the tail cutaneous temperature response to restraint in either sex. CONCLUSION: Chronic ethanol vapor exposure increased the cardiovascular reactivity to stress in male, but not in female rats.

Ethanol-induced locomotor sensitization: Neuronal activation in the nucleus accumbens and medial prefrontal cortex.

Ethanol consumption may promote neuroplasticity and alterations in synapses, resulting in modifications in neuronal activity. Here, we treated male Swiss mice with ethanol (2.2 g/kg) or saline once per day for 21 consecutive days. Nine days after the last ethanol administration, they received a challenge injection of ethanol or saline, and we assessed locomotor activity. After the behavioral analysis, we evaluated neuronal activation in the medial Prefrontal Cortex (Cingulate, Prelimbic, and Infralimbic) and the Nucleus Accumbens (Shell and Core) using Fos/DAB immunohistochemistry. In another group of animals, we performed the quantitative analysis of the ARC and PSD-95 protein levels by Western blotting in the medial prefrontal cortex and nucleus accumbens brain areas. Repeated ethanol administration produced locomotor sensitization, accompanied by an increase in the nucleus accumbens shell's activation but not core. Furthermore, the ethanol pretreatment reduced ARC expression in the nucleus accumbens and medial prefrontal cortex. Our results suggest the participation of the nucleus accumbens shell in ethanol behavioral sensitization and add new pieces of evidence that neuroplasticity in synapses may contribute to the mechanism underlying this behavior.

Effects of biperiden (cholinergic muscarinic m1/m4 receptor antagonist) on ethanol conditioned place preference in mice.

BACKGROUND: Previous studies suggest that muscarinic cholinergic receptors might act upon the dopamine release in the mesolimbic system and alter drug-reinforcing values related to drug craving. AIMS: We examined the effects of systemic biperiden administration, a muscarinic cholinergic (M1/M4) receptor antagonist, on ethanol (dose of 2 g/Kg) conditioned place preference (CPP), neuronal activation, dopamine and its metabolites levels in the nucleus accumbens. METHODS: Thirty minutes before the ethanol-induced CPP test, mice received saline or biperiden at doses of 1.0, 5.0, or 10.0 mg/kg. The time spent in each compartment was recorded for 15 min. After the CPP protocol, animals were euthanized, and we investigated the activation of the nucleus accumbens by immunohistochemistry for Fos. We also quantified dopamine, homovanillic acid (HVA), and dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens by high-performance liquid chromatography (HPLC). Additionally, the rotarod was employed to evaluate the effects of biperiden on motor coordination. RESULTS: Biperiden at different doses (1.0, 5.0, and 10.0 mg/kg) blocked the expression of ethanol-induced CPP. These biperiden doses increased the number of Fos-positive cells and the dopamine turnover in the nucleus accumbens. None of the doses affected the motor coordination evaluated by the rotarod. CONCLUSIONS: Our results show that biperiden can modulate the effect of alcohol reward, and its mechanism of action may involve a change in dopamine and cholinergic mesolimbic neurotransmission.

Dorsal hippocampus plays a causal role in context-induced reinstatement of alcohol-seeking in rats.

Drug addiction is a chronic mental disorder characterized by frequent relapses. Contextual cues associated with drug use to play a critical causal role in drug-seeking behavior. The hippocampus has been implicated in encoding drug associative memories. Here we examine whether the dorsal hippocampus mediates context-induced reinstatement of alcohol-seeking. Male Long-Evans rats were trained to self-administer alcohol in Context A. Alcohol self-administration was extinguished in a distinct context (Context B). On the test day, animals were re-exposed to the alcohol Context A or the extinction Context B. Next, to assess a causal role for the dorsal hippocampus in context-induced alcohol-seeking, on the test day, we injected cobalt chloride (CoCl2; a nonselective synapse inhibitor) or vehicle into the dorsal hippocampus, and 15 min later, rats were tested by re-exposing them to the drug-associated context. The re-exposure to the alcohol-associated Context A reinstated alcohol seeking and increased Fos-positive cells in the dorsal hippocampus neurons (CA1, CA3, and Dentate Gyrus). Pharmacological inactivation with cobalt chloride of the dorsal hippocampus attenuated the reinstatement of alcohol-seeking. Our data suggest that the dorsal hippocampus may be involved in context-induced alcohol-seeking behavior.

Prolonged Exposure to Alcohol Vapor Causes Change in Cardiovascular Function in Female but not in Male Rats.

BACKGROUND: Alcohol abuse is a health concern worldwide. Studies have associated alcohol abuse with cardiovascular impairments. In this study, we investigated differences in the effects of chronic alcohol vapor exposure on cardiovascular function between male and female rats by using the alcohol vapor chamber method to induce alcohol addiction-like behaviors in rats. METHODS: We exposed male and female Long-Evans rats to alcohol vapor for 14 hours, followed by ethanol withdrawal for 10 hours, for 30 consecutive days or room air (control groups). The animals underwent preparation for the surgical implantation of cannulas into femoral vessels, for allowing the assessment of the basal arterial pressure and heart rate values, baroreflex function, and autonomic activity. RESULTS: Female control rats showed higher basal heart rate compared to male control rats. Chronic alcohol vapor inhalation reduced basal heart rate in females, but not in males; this effect was followed by an increase in the parasympathetic tone of the heart. Further, female rats subjected to alcohol vapor showed an increase in the baroreflex activity. CONCLUSIONS: These findings suggest that females are more sensitive to chronic alcohol vapor exposure than males because they had a reduction in basal heart rate and changes in the baroreflex activity.

Impedance cardiography in the evaluation of patients with arterial hypertension / Impedância cardiografica na avaliação de pacientes com hipertensão arterial

Arterial hypertension is responsible for high morbidity and mortality. Despite increasing awareness of the consequences of uncontrolled hypertension and the publication of several recommendations and guidelines, blood pressure control rates are suboptimal, and approximately half of the patients do not reach the targets. Defined as an increase in blood pressure, hypertension is characterized by hemodynamic abnormalities in cardiac output, systemic vascular resistance, or arterial compliance. Therefore, the approach to arterial hypertension can be improved by the knowledge of the hemodynamics underlying the blood pressure increase. Impedance Cardiography has emerged as a new strategy to customize therapy and monitor patients aiming to improve blood pressure control according to the hemodynamic profile, rather than a blind intensive care approach. This is a review of impedance cardiography evidence, its benefits, actual and future applications in the approach and management of arterial hypertension

Functional inactivation of the orbitofrontal cortex disrupts context-induced reinstatement of alcohol seeking in rats.

BACKGROUND: The high rate of relapse to drug use remains a central challenge to treating drug addiction. In human and rat models of addiction, environmental stimuli in contexts associated with previous drug use can provoke a relapse of drug seeking. Pre-clinical studies have used the ABA renewal procedure to study context-induced reinstatement of drug seeking. In the current study, we studied the role of the orbitofrontal cortex (OFC) in context-induced reinstatement to alcohol. METHODS: We trained male and female rats to self-administer alcohol in context A, extinguished drug-reinforced responding in a distinct context B, and assessed context-induced reinstatement in context A or B (control group). Next, we determined the effect of context-induced renewal of alcohol-seeking behavior on the expression of Fos (a neuronal activity marker) in the OFC. Finally, we determined the effect of reversible inactivation by GABAa and GABAb receptor agonists (i.e., muscimol and baclofen, respectively) in the OFC. RESULTS AND CONCLUSIONS: There were no differences between male and female rats in context-induced reinstatement of alcohol-seeking behavior. Re-exposure to Context A, but not Context B, reinstated alcohol-seeking behavior and increased expression of the neural activity marker Fos in the OFC. Reversible inactivation of the OFC with muscimol and baclofen attenuated context-induced reinstatement. Our data indicated that the OFC mediates context-induced reinstatement of alcohol-seeking behavior.

Good agreement between echocardiography and impedance cardiography in the assessment of left ventricular performance in hypertensive patients.

BACKGROUND: Impedance cardiography (ICG) is a noninvasive hemodynamic monitoring tool which can define hypertensive patients' hemodynamic profiles and help to tailor antihypertensive therapy. This study assesses the concordance between ICG-derived indexes used to evaluate left ventricular performance and transthoracic echocardiography (TTE) in hypertensive patients. METHODS: In this IMPEDDANS post-hoc analysis, the ICG-derived indexes are compared with TTE by Bland-Altman method. Statistical significance of the relationship between the values obtained was assessed by generalized linear mixed-effects models. RESULTS: In supine position, Bland-Altman analysis showed good concordance for cardiac output (CO) (mean difference of 0.006 mL/min [-0.120; 0.133]), cardiac index (CI) (mean difference of 0.016 mL/min/m2 [-0.471; 0.504]), pre-ejection period (PEP) (mean difference of -0.216 ms [-4.510; 4.077]), left ventricular ejection time (LVET) (mean difference of -0.140 ms [-6.573; 6.293]), and systolic time ratio (STR) (mean difference of -0.00004 [-0.008; 0.008]). In orthostatic position, good concordance was found for CO (mean difference 0.028 mL/min [-2.036; 1.980]), CI (mean difference -0.012 mL/min/m2 [-1.063; 1.039]), and STR (mean difference -0.101 [0.296; 0.094]). No significant difference between methods was identified by the linear mixed-effects models. CONCLUSION: The ICG-derived indexes CO, CI, PEP, LVET, and STR in supine position have good agreement with TTE. Therefore, ICG can be used to accurately evaluate left ventricular performance.

Inactivation of the Prelimbic Cortex Impairs the Context-Induced Reinstatement of Ethanol Seeking.

Evidence indicates that drug relapse in humans is often provoked by exposure to the self-administered drug-associated context. An animal model called "ABA renewal procedure" has been used to study the context-induced relapse to drug seeking. Here, we reported a new and feasible training procedure for the ABA renewal method to explore the role of the prelimbic cortex in context-induced relapse to ethanol seeking. By using a saccharin fading technique, we trained rats to self-administer ethanol (10%). The drug delivery was paired with a discrete tone-light cue. Lever pressing was subsequently extinguished in a non-drug-associated context in the presence of the discrete cue. Rats were subsequently tested for reinstatement in contexts A or B, under extinction conditions. Ethanol-associated context induced the reinstatement of ethanol seeking and increased the expression of Fos in the prelimbic cortex. The rate of neural activation in the prelimbic cortex was 3.4% in the extinction context B and 7.7% in the drug-associated context A, as evidenced by double-labeling of Fos and the neuron-specific protein NeuN. The reversible inactivation of the neural activity in the prelimbic cortex with gamma-Aminobutyric acid (GABA) receptor agonists (muscimol + baclofen) attenuated the context-induced reinstatement of ethanol self-administration. These results demonstrated that the neuronal activation of the prelimbic cortex is involved in the context-induced reinstatement of ethanol seeking.

Systolic time ratio measured by impedance cardiography accurately screens left ventricular diastolic dysfunction in patients with arterial hypertension.

BACKGROUND: The use of impedance cardiography (ICG) may play a role in the assessment of cardiac effects of hypertension (HT), especially its hemodynamic features. Hypertensive heart disease involves structural changes and alterations in left ventricular geometry that end up causing systolic and/or diastolic dysfunction. The IMPEDDANS study aims to assess the usefulness of ICG for the screening of left ventricular diastolic dysfunction (LVDD) in patients with HT. METHODS: Patients with HT were assessed by echocardiography and ICG. Receiver-operating characteristic curve and the area under the curve were used to assess the discriminative ability of the parameters obtained by ICG to identify LVDD, as diagnosed by echocardiography. RESULTS: ICG derived pre-ejection period (PEP), left ventricle ejection time (LVET), systolic time ratio (STR) and D wave were associated (p < 0.001) with LVDD diagnosis, with good discriminative ability: PEP (AUC 0.81; 95% CI 0.74-0.89), LVET (AUC 0.82; 95% CI 0.75-0.88), STR (AUC 0.97; 95% CI 0.94-1.00) and presence of D wave (AUC = 0.87; 95% CI 0.82-0.93). STR ≥ 0.30 outperformed the other parameters (sensitivity of 98.0%, specificity of 90.2%, positive predictive value of 95.2%, and negative predictive value of 96.1%). CONCLUSION: The ICG derived value of STR allows the accurate screening of LVDD in patients with HT. It might as well be used for follow up assessment. TRIAL REGISTRATION: The study protocol was retrospectively registered as IMPEDDANS on ClinicalTrials.gov (ID: NCT03209141) on July 6, 2017.

Stress-Induced Locomotor Sensitization to Amphetamine in Adult, but not in Adolescent Rats, Is Associated with Increased Expression of ΔFosB in the Nucleus Accumbens.

While clinical and pre-clinical evidence suggests that adolescence is a risk period for the development of addiction, the underlying neural mechanisms are largely unknown. Stress during adolescence has a huge influence on drug addiction. However, little is known about the mechanisms related to the interaction among stress, adolescence and addiction. Studies point to ΔFosB as a possible target for this phenomenon. In the present study, adolescent and adult rats (postnatal day 28 and 60, respectively) were restrained for 2 h once a day for 7 days. Three days after their last exposure to stress, the animals were challenged with saline or amphetamine (1.0 mg/kg i.p.) and amphetamine-induced locomotion was recorded. Immediately after the behavioral tests, rats were decapitated and the nucleus accumbens was dissected to measure ΔFosB protein levels. We found that repeated restraint stress increased amphetamine-induced locomotion in both the adult and adolescent rats. Furthermore, in adult rats, stress-induced locomotor sensitization was associated with increased expression of ΔFosB in the nucleus accumbens. Our data suggest that ΔFosB may be involved in some of the neuronal plasticity changes associated with stress induced-cross sensitization with amphetamine in adult rats.

Distinct Fos-Expressing Neuronal Ensembles in the Ventromedial Prefrontal Cortex Mediate Food Reward and Extinction Memories.

UNLABELLED: In operant learning, initial reward-associated memories are thought to be distinct from subsequent extinction-associated memories. Memories formed during operant learning are thought to be stored in "neuronal ensembles." Thus, we hypothesize that different neuronal ensembles encode reward- and extinction-associated memories. Here, we examined prefrontal cortex neuronal ensembles involved in the recall of reward and extinction memories of food self-administration. We first trained rats to lever press for palatable food pellets for 7 d (1 h/d) and then exposed them to 0, 2, or 7 daily extinction sessions in which lever presses were not reinforced. Twenty-four hours after the last training or extinction session, we exposed the rats to either a short 15 min extinction test session or left them in their homecage (a control condition). We found maximal Fos (a neuronal activity marker) immunoreactivity in the ventral medial prefrontal cortex of rats that previously received 2 extinction sessions, suggesting that neuronal ensembles in this area encode extinction memories. We then used the Daun02 inactivation procedure to selectively disrupt ventral medial prefrontal cortex neuronal ensembles that were activated during the 15 min extinction session following 0 (no extinction) or 2 prior extinction sessions to determine the effects of inactivating the putative food reward and extinction ensembles, respectively, on subsequent nonreinforced food seeking 2 d later. Inactivation of the food reward ensembles decreased food seeking, whereas inactivation of the extinction ensembles increased food seeking. Our results indicate that distinct neuronal ensembles encoding operant reward and extinction memories intermingle within the same cortical area. SIGNIFICANCE STATEMENT: A current popular hypothesis is that neuronal ensembles in different prefrontal cortex areas control reward-associated versus extinction-associated memories: the dorsal medial prefrontal cortex (mPFC) promotes reward seeking, whereas the ventral mPFC inhibits reward seeking. In this paper, we use the Daun02 chemogenetic inactivation procedure to demonstrate that Fos-expressing neuronal ensembles mediating both food reward and extinction memories intermingle within the same ventral mPFC area.

Adolescent vulnerability to cardiovascular consequences of chronic social stress: Immediate and long-term effects of social isolation during adolescence.

It has been demonstrated that disruption of social bonds and perceived isolation (loneliness) are associated with an increased risk of cardiovascular morbidity and mortality. Adolescence is proposed as a period of vulnerability to stress. Nevertheless, the impact of chronic social stress during this ontogenic period in cardiovascular function is poorly understood. Therefore, the purpose of this study was to compare the impact in cardiovascular function of social isolation for 3 weeks in adolescent and adult male rats. Also, the long-term effects of social isolation during adolescence were investigated longitudinally. Social isolation reduced body weight in adolescent, but not in adult animals. Disruption of social bonds during adolescence increased arterial pressure without affecting heart rate and pulse pressure (PP). Nevertheless, social isolation in adulthood reduced systolic arterial pressure and increased diastolic arterial pressure, which in turn decreased PP without affecting mean arterial pressure. Cardiovascular changes in adolescents, but not adults, were followed by facilitation of both baroreflex sensitivity and vascular reactivity to the vasodilator agent acetylcholine. Vascular responsiveness to either the vasodilator agent sodium nitroprusside or the vasoconstrictor agent phenylephrine was not affected by social isolation. Except for the changes in body weight and baroreflex sensitivity, all alterations evoked by social isolation during adolescence were reversed in adulthood after moving animals from isolated to collective housing. These findings suggest a vulnerability of adolescents to the effects of chronic social isolation in cardiovascular function. However, results indicate minimal cardiovascular consequences in adulthood of disruption of social bonds during adolescence.

Hipotermia terapêutica após parada cardíaca: preditores de prognóstico / Therapeutic hypothermia after cardiac arrest: outcome predictors

Resumo Objetivo: A determinação do prognóstico de pacientes em coma após parada cardíaca tem implicações clínicas, éticas e sociais. Exame neurológico, marcadores de imagem e bioquímicos são ferramentas úteis e bem aceitas na previsão da recuperação. Com o advento da hipotermia terapêutica, tais informações devem de ser confirmadas. Neste estudo procurou-se determinar a validade de diferentes marcadores que podem ser utilizados na detecção de pacientes com mau prognóstico durante um protocolo de hipotermia. Métodos: Foram coletados prospectivamente os dados de pacientes adultos, internados após parada cardíaca em nossa unidade de terapia intensiva para realização de protocolo de hipotermia. Nosso intuito foi realizar um estudo descritivo e analítico para analisar a relação entre os dados clínicos, parâmetros neurofisiológicos, de imagem e bioquímicos, e o desfecho após 6 meses, conforme definido pela escala Cerebral Performance Categories (bom, se 1-2, e mau, se 3-5). Foi coletada uma amostra para determinação de neuroenolase após 72 horas. Os exames de imagem e neurofisiológicos foram realizados 24 horas após o período de reaquecimento. Resultados: Foram incluídos 67 pacientes, dos quais 12 tiveram evolução neurológica favorável. Fibrilação ventricular e atividade teta no eletroencefalograma se associaram a bom prognóstico. Pacientes submetidos a resfriamento mais rápido (tempo médio de 163 versus 312 minutos), com lesão cerebral causada por hipóxia/isquemia detectada na ressonância nuclear magnética ou níveis de neuroenolase superiores a 58ng/mL se associaram a desfecho neurológico desfavorável (p < 0,05). Conclusão: A presença de lesão cerebral causada por hipóxia/isquemia e de neuroenolase foram fortes preditores de má evolução neurológica. Apesar da crença de que atingir rapidamente a temperatura alvo da hipotermia melhora o prognóstico neurológico, nosso estudo demonstrou que este fator se associou a um aumento da mortalidade e a uma pior evolução neurológica.

ABSTRACT Objective: The determination of coma patient prognosis after cardiac arrest has clinical, ethical and social implications. Neurological examination, imaging and biochemical markers are helpful tools accepted as reliable in predicting recovery. With the advent of therapeutic hypothermia, these data need to be reconfirmed. In this study, we attempted to determine the validity of different markers, which can be used in the detection of patients with poor prognosis under hypothermia. Methods: Data from adult patients admitted to our intensive care unit for a hypothermia protocol after cardiac arrest were recorded prospectively to generate a descriptive and analytical study analyzing the relationship between clinical, neurophysiological, imaging and biochemical parameters with 6-month outcomes defined according to the Cerebral Performance Categories scale (good 1-2, poor 3-5). Neuron-specific enolase was collected at 72 hours. Imaging and neurophysiologic exams were carried out in the 24 hours after the rewarming period. Results: Sixty-seven patients were included in the study, of which 12 had good neurological outcomes. Ventricular fibrillation and electroencephalographic theta activity were associated with increased likelihood of survival and improved neurological outcomes. Patients who had more rapid cooling (mean time of 163 versus 312 minutes), hypoxic-ischemic brain injury on magnetic resonance imaging or neuron-specific enolase > 58ng/mL had poor neurological outcomes (p < 0.05). Conclusion: Hypoxic-ischemic brain injury on magnetic resonance imaging and neuron-specific enolase were strong predictors of poor neurological outcomes. Although there is the belief that early achievement of target temperature improves neurological prognoses, in our study, there were increased mortality and worse neurological outcomes with earlier target-temperature achievement.