Inhibition of microglial activation with minocycline at the intrathecal level attenuates sympathoexcitatory and proarrhythmogenic changes in rats with chronic temporal lobe epilepsy

The incidence of sudden unexpected death in epilepsy (SUDEP) is highest in people with chronic and drug resistant epilepsy. Chronic spontaneous recurrent seizures cause cardiorespiratory autonomic dysfunctions. Pituitary adenylate cyclase-activating polypeptide (PACAP) is neuroprotective, whereas microglia produce both pro- and anti- inflammatory effects in the CNS. During acute seizures in rats, PACAP and microglia produce sympathoprotective effect at the intermediolateral cell column (IML), whereas their action on the presympathetic rostral ventrolateral medulla (RVLM) neurons mediates proarrhythmogenic changes. We evaluated the effect of PACAP and microglia at the IML on sympathetic nerve activity (SNA), cardiovascular reflex responses, and electrocardiographic changes in the post-status epilepticus (SE) model of acquired epilepsy, and control rats. Chronic spontaneous seizures in rats produced tachycardia with profound proarrhythmogenic effects (prolongation of QT interval). Antagonism of microglia, but not PACAP, significantly reduced the SNA and the corrected QT interval in post-SE rats. PACAP and microglia antagonists did not change baroreflex and peripheral or central chemoreflex responses with varied effect on somatosympathetic responses in post-SE and control rats. We did not notice changes in microglial morphology or changes in a number of M2 phenotype in epileptic nor control rats in the vicinity of RVLM neurons. Our findings establish that microglial activation, and not PACAP, at the IML accounts for higher SNA and proarrhythmogenic changes during chronic epilepsy in rats. This is the first experimental evidence to support a neurotoxic effect of microglia during chronic epilepsy, in contrast to their neuroprotective action during acute seizures

Exploring the latent trait of opioid use disorder criteria among frequent nonmedical prescription opioid users

Background: There is a need to explore the dimensional and categorical phenotypes of criteria of opioid use disorder among frequent nonmedical users of prescription opioids (NMUPO) users. Methods: We used pooled data of 2011–2012 National Survey on Drug Use and Health to examine reliability and phenotypic variability in the diagnosis of OUD secondary to NMUPO in a nationally-representative sample of 18+ years-old frequent past-year NMUPO users (120+ days, n = 806). Through exploratory factor analysis (EFA) and latent class analysis (LCA), we examined 10 past-year OUD criteria. We examined associations between the latent classes and sociodemographic/psychiatric/NMUPO correlates. Results: OUD criteria were unidimensional, and a three-class model was the overall best fitting solution for characterizing individuals into phenotypes along this unidimensional continuum: a “non-symptomatic class” (40.7%), “Tolerance-Time spent class” (29.0%) with high probability of endorsing Tolerance/Time Spent criteria, and a “High-moderate symptomatic class” (30.1%). The last class was significantly associated with being male, having insurance and obtaining prescription opioids (PO) nonmedically via “doctor shopping” as compared to the non-symptomatic class. “Tolerance-Time spent class” was significantly associated with being younger (18–25 years) and obtaining PO nonmedically from family/friends as compared to the non-symptomatic class. Conclusion: This study revealed the different characteristics and routes of access to PO of different classes of frequent NMUPO users. It is possible that these groups may respond to different interventions, however such conclusions would require a clinical study

TREC-Rio trial: a randomised controlled trial for rapid tranquillisation for agitated patients in emergency psychiatric rooms [ISRCTN44153243]

Agitated or violent patients constitute 10% of all emergency psychiatric treatment. Management guidelines, the preferred treatment of clinicians and clinical practice all differ. Systematic reviews show that all relevant studies are small and none are likely to have adequate power to show true differences between treatments. Worldwide, current treatment is not based on evidence from randomised trials. In Brazil, the combination haloperidol-promethazine is frequently used, but no studies involving this mix exist. TREC-Rio (Tranquilização Rápida-Ensaio Clínico [Translation: Rapid Tranquillisation-Clinical Trial]) will compare midazolam with haloperidol-promethazine mix for treatment of agitated patients in emergency psychiatric rooms of Rio de Janeiro, Brazil. TREC-Rio is a randomised, controlled, pragmatic and open study. Primary measure of outcome is tranquillisation at 20 minutes but effects on other measures of morbidity will also be assessed. TREC-Rio will involve the collaboration of as many health care professionals based in four psychiatric emergency rooms of Rio as possible. Because the design of this trial does not substantially complicate clinical management, and in several aspects simplifies it, the study can be large, and treatments used in everyday practice can be evaluated

Monitoring and evaluating capacity building activities in low and middle income countries: challenges and opportunities.

BACKGROUND: Lower and middle income countries (LMICs) are home to >80% of the global population, but mental health researchers and LMIC investigator led publications are concentrated in 10% of LMICs. Increasing research and research outputs, such as in the form of peer reviewed publications, require increased capacity building (CB) opportunities in LMICs. The National Institute of Mental Health (NIMH) initiative, Collaborative Hubs for International Research on Mental Health reaches across five regional 'hubs' established in LMICs, to provide training and support for emerging researchers through hub-specific CB activities. This paper describes the range of CB activities, the process of monitoring, and the early outcomes of CB activities conducted by the five research hubs. METHODS: The indicators used to describe the nature, the monitoring, and the early outcomes of CB activities were developed collectively by the members of an inter-hub CB workgroup representing all five hubs. These indicators included but were not limited to courses, publications, and grants. RESULTS: Results for all indicators demonstrate a wide range of feasible CB activities. The five hubs were successful in providing at least one and the majority several courses; 13 CB recipient-led articles were accepted for publication; and nine grant applications were successful. CONCLUSIONS: The hubs were successful in providing CB recipients with a wide range of CB activities. The challenge remains to ensure ongoing CB of mental health researchers in LMICs, and in particular, to sustain the CB efforts of the five hubs after the termination of NIMH funding

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

The impaired ability of the autonomic nervous system to respond to hypoglycemia is termed "hypoglycemia-associated autonomic failure" (HAAF). This life-threatening phenomenon results from at least two recent episodes of hypoglycemia, but the pathology underpinning HAAF remains largely unknown. Although naloxone appears to improve hypoglycemia counterregulation under controlled conditions, hypoglycemia prevention remains the current mainstay therapy for HAAF. Epinephrine-synthesizing neurons in the rostroventrolateral (C1) and dorsomedial (C3) medulla project to the subset of sympathetic preganglionic neurons that regulate peripheral epinephrine release. Here we determined whether or not C1 and C3 neuronal activation is impaired in HAAF and whether or not 1 wk of hypoglycemia prevention or treatment with naloxone could restore C1 and C3 neuronal activation and improve HAAF. Twenty male Sprague-Dawley rats (250-300 g) were used. Plasma epinephrine levels were significantly increased after a single episode of hypoglycemia (n = 4; 5,438 ± 783 pg/ml vs. control 193 ± 27 pg/ml, P < 0.05). Repeated hypoglycemia significantly reduced the plasma epinephrine response to subsequent hypoglycemia (n = 4; 2,179 ± 220 pg/ml vs. 5,438 ± 783 pg/ml, P < 0.05). Activation of medullary C1 (n = 4; 50 ± 5% vs. control 3 ± 1%, P < 0.05) and C3 (n = 4; 45 ± 5% vs. control 4 ± 1%, P < 0.05) neurons was significantly increased after a single episode of hypoglycemia. Activation of C1 (n = 4; 12 ± 3%, P < 0.05) and C3 (n = 4; 19 ± 5%, P < 0.05) neurons was significantly reduced in the HAAF groups. Hypoglycemia prevention or treatment with naloxone did not restore the plasma epinephrine response or C1 and C3 neuronal activation. Thus repeated hypoglycemia reduced the activation of C1 and C3 neurons mediating adrenal medullary responses to subsequent bouts of hypoglycemia.Zohra M. Kakall, Mary M. Kavurma, E. Myfanwy Cohen, Peter R. Howe, Polina E. Nedoboy, and Paul M. Pilowsk

Disclosure of Maternal HIV Status to Children: To Tell or Not To Tell . . . That Is the Question

HIV-infected mothers face the challenging decision of whether to disclose their serostatus to their children. From the perspective of both mother and child, we explored the process of disclosure, providing descriptive information and examining the relationships among disclosure, demographic variables, and child adjustment. Participants were 23 mothers and one of their noninfected children (9 to 16 years of age). Sixty-one percent of mothers disclosed. Consistent with previous research, disclosure was not related to child functioning. However, children sworn to secrecy demonstrated lower social competence and more externalizing problems. Differential disclosure, which occurred in one-third of the families, was associated with higher levels of depressive and anxiety symptoms. Finally, knowing more than mothers had themselves disclosed was related to child maladjustment across multiple domains. Clinical implications and the need for future research are considered

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

The impaired ability of the autonomic nervous system to respond to hypoglycemia is termed 'hypoglycemia-associated autonomic failure' (HAAF). This life-threatening phenomenon results from at least two recent episodes of hypoglycemia, but the pathology underpinning HAAF remains largely unknown. Although naloxone appears to improve hypoglycemia counterregulation under controlled conditions, hypoglycemia prevention remains the current mainstay therapy for HAAF. Epinephrine-synthesizing neurons in the rostroventrolateral (C1) and dorsomedial (C3) medulla project to the subset of sympathetic preganglionic neurons that regulate peripheral epinephrine release. Here we determined whether or not C1 and C3 neuronal activation is impaired in HAAF and whether or not 1 wk of hypoglycemia prevention or treatment with naloxone could restore C1 and C3 neuronal activation and improve HAAF. Twenty male Sprague-Dawley rats (250–300 g) were used. Plasma epinephrine levels were significantly increased after a single episode of hypoglycemia (n = 4; 5,438 ± 783 pg/ml vs. control 193 ± 27 pg/ml, P < 0.05). Repeated hypoglycemia significantly reduced the plasma epinephrine response to subsequent hypoglycemia (n = 4; 2,179 ± 220 pg/ml vs. 5,438 ± 783 pg/ml, P < 0.05). Activation of medullary C1 (n = 4; 50 ± 5% vs. control 3 ± 1%, P < 0.05) and C3 (n = 4; 45 ± 5% vs. control 4 ± 1%, P < 0.05) neurons was significantly increased after a single episode of hypoglycemia. Activation of C1 (n = 4; 12 ± 3%, P < 0.05) and C3 (n = 4; 19 ± 5%, P < 0.05) neurons was significantly reduced in the HAAF groups. Hypoglycemia prevention or treatment with naloxone did not restore the plasma epinephrine response or C1 and C3 neuronal activation. Thus repeated hypoglycemia reduced the activation of C1 and C3 neurons mediating adrenal medullary responses to subsequent bouts of hypoglycemia

The Effects On Children Of Depressed Mothers' Remission And Relapse Over 9 Months

Background—The high rate of depression among children of depressed mothers is well known. Suggestions that improvement in maternal acute depression has a positive effect on the child have emerged. However, data on the mechanisms of change have been sparse. The aim was to understand how remission and relapse in the mother might explain the changes in the child’s outcome