Neuropsychiatric phenotypes of anti-NMDAR encephalitis: a prospective study.

BACKGROUND: Patients with anti-N-methyl-d-aspartate (NMDA) receptor encephalitis (ANMDARE) show a wide range of behavioral abnormalities and are often mistaken for primary psychiatric presentations. We aimed to determine the behavioral hallmarks of ANMDARE with the use of systematic neuropsychiatric and cognitive assessments. METHODS: A prospective study was conducted, with 160 patients admitted to the National Institute of Neurology and Neurosurgery of Mexico, who fulfilled criteria for possible autoimmune encephalitis and/or red flags along a time window of seven years. Cerebrospinal fluid (CSF) antibodies against the NR1 subunit of the NMDAR were processed with rat brain immunohistochemistry and cell-based assays with NMDA expressing cells. Systematic cognitive, neuropsychiatric, and functional assessments were conducted before knowing NMDAR antibodies results. A multivariate analysis was used to compare patients with and without definite ANMDARE according to antibodies in CSF. RESULTS: After obtaining the CSF antibodies results in 160 consecutive cases, 100 patients were positive and classified as having definite ANMDARE. The most frequent neuropsychiatric patterns were psychosis (81%), delirium (75%), catatonia (69%), anxiety-depression (65%), and mania (27%). Cognition was significantly impaired. A total of 34% of the patients had a predominantly neuropsychiatric presentation without seizures. After multivariate analysis, the clinical hallmarks of ANMDARE consisted of a catatonia-delirium comorbidity, tonic-clonic seizures, and orolingual dyskinesia. CONCLUSIONS: Our study supports the notion of a neurobehavioral phenotype of ANMDARE characterized by a fluctuating course with psychotic and affective symptoms, catatonic signs, and global cognitive dysfunction, often accompanied by seizures and dyskinesia. The catatonia-delirium comorbidity could be a distinctive neurobehavioral phenotype of ANMDARE.

Corrigendum to 'Role of electroencephalogram oscillations and the spectrogram in monitoring anaesthesia' [BJA Education 20 (2020) 166-172].

[This corrects the article DOI: 10.1016/j.bjae.2020.01.004.].

Isolation rearing significantly perturbs brain metabolism in the thalamus and hippocampus.

Psychosocial neglect during childhood severely impairs both behavioral and physical health. The isolation rearing model in rodents has been employed by our group and others to study this clinical problem at a basic level. We previously showed that immediate early gene (IEG) expression in the hippocampus and medial prefrontal cortex (mPFC) is decreased in isolation-reared (IR) compared to group-reared (GR) rats. In the current study, we sought to evaluate: (1) whether these changes in IEG expression would be detected by the measurement of brain glucose metabolism using positron emission tomography (PET) with fluorodeoxyglucose (FDG) and (2) whether PET FDG could illuminate other brain regions with different glucose metabolism in IR compared to GR rats. We found that there were significant differences in FDG uptake in the hippocampus that were consistent with our findings for IEG expression (decreased mean FDG uptake in IR rats). In contrast, in the mPFC, the FDG uptake between IR and GR rats did not differ. Finally, we found decreased mean FDG uptake in the thalamus of the IR rats, a region we had not previously examined. The results suggest that PET FDG has the potential to be utilized as a biomarker of molecular changes in the hippocampus. Further, the differences found in thalamic brain FDG uptake suggest that further investigation of this region at the molecular and cellular levels may provide an important insight into the neurobiological basis of the adverse clinical outcomes found in children exposed to psychosocial deprivation.

Rapid screening for major depression in post-myocardial infarction patients: an investigation using Beck Depression Inventory II items.

OBJECTIVE: To determine the ability of three questions from the Beck Depression Inventory II (BDI-II) to detect major depressive disorder (MDD) in a cohort of patients hospitalised for acute myocardial infarction (MI). DESIGN: Prospective observational study. SETTING: Coronary care unit and cardiac step-down unit of an urban academic medical centre. PATIENTS: 131 post-MI patients within 72 h of symptom onset. INTERVENTIONS: Patients were administered the BDI-II and participated in a structured diagnostic interview for MDD. Three individual BDI-II items (regarding sadness, loss of interest and loss of pleasure) were examined individually and in two-question combinations to determine their ability to screen for MDD. MAIN OUTCOME MEASURES: Sensitivity, specificity, negative and positive predictive values and proportion of patients with MDD correctly identified. RESULTS: The individual items and two-question combinations had good sensitivity (76-94%), specificity (70-88%) and negative predictive values (97-99%). Item 1 (sadness) performed the best of the individual items (48% with a positive response to the item had MDD; 3% with a negative response had MDD; over 80% of patients with MDD were correctly identified). A combination of questions about sadness and loss of interest performed best among the two-question combinations (37% with positive response had MDD v 1% with a negative response; 94% of patients with MDD were identified). CONCLUSIONS: One to two questions regarding sadness and loss of interest serve as simple and effective screening tools for post-MI depression.

Dracunculus medinensis and Schistosoma mansoni contain opiate alkaloids.

The results of analysis, by high-performance liquid chromatography coupled with electrochemical detection and by nano-electrospray-ionization, double quadrupole/orthogonal-acceleration, time-of-flight mass spectrometry, indicate that adult Dracunculus medinensis and Schistosoma mansoni both contain the opiate alkaloid morphine and that D. medinesis also contains the active metabolite of morphine, morphine 6-glucuronide. From these and previous observations, it would appear that many helminths are probably using opiate alkaloids as potent immunosuppressive and antinociceptive signal molecules, to down-regulate immunosurveillance responsiveness and pain signalling in their hosts.

The relationship of psychiatric illnesses and seizures.

The relationship between epilepsy and behavioral disturbances has been a subject of controversy since the 19th century. Affective changes may occur prior, during, or after the ictal discharge. Depression is the most prevalent comorbidity. Anxiety, panic attacks, and pseudoseizures may resemble complex partial seizures, and their diagnosis and treatment may be confusing, even to experienced clinicians. Epilepsy-related psychosis is less common, manifesting occasionally with symptoms that are indistinguishable from schizophrenia. There is no clear evidence of a distinct "epileptoid" personality, and interictal violence is extremely rare. Pharmacologic treatment with anticonvulsants remains the cornerstone of treatment. In case of psychiatric comorbidities or refractory seizures, the diagnosis should be re-examined.

The placebo effect and relaxation response: neural processes and their coupling to constitutive nitric oxide.

The placebo effect appears to be a real phenomenon as is the scientifically demonstrated and examined relaxation response. Given this, we attempt to understand how these phenomena work in light of our current understanding of central and peripheral nervous system mechanisms. Central to our hypothesis is the significance of norepinephrine, nitric oxide and opioid signaling both in the central and peripheral nervous system. In this regard, we find that nitric oxide controls norepinephrine processes on many levels, including synthesis, release and actions. In closing, we conclude that enough scientific information exists to support these phenomena as actual physical processes that can be harnessed to provide better patient care.

Psychiatric symptoms and medical utilization in primary care patients.

In two studies, the authors evaluated the impact of psychiatric disorders on medical care utilization in a primary care setting. In the first study, 526 consecutive patients in a teaching hospital primary care practice completed the 18-item RAND Mental Health Inventory to identify clinically significant depression and/or anxiety and a questionnaire about the use of psychiatric treatment and psychoactive medications. The medical utilization of those patients defined as depressed and/ or anxious was compared with those defined as not depressed and/or anxious. Patients identified as depressed and/or anxious reported significantly increased medical utilization, but this was not confirmed by the hospital's computerized record system. In the second study, the authors analyzed medical care utilization for the years before and after the first outpatient psychiatry appointment of a sample of 91 patients referred from the same primary care practice to the hospital's outpatient psychiatry clinic over a 1-year period. In both studies there was not a statistically significant difference in medical utilization among those patients receiving psychiatric treatment. The findings demonstrate the difficulties in examining cost offset in a primary care population and raise questions about it as a realistic outcome measure of the effect of psychiatric treatment.

The presence of antibacterial and opioid peptides in human plasma during coronary artery bypass surgery.

Antibacterial peptides, found in both invertebrates and vertebrates, represent a potential innate defense mechanism against microbial infections. However, it is unknown whether this process occurs in humans during surgery. We looked for evidence of release of antibacterial peptides during coronary artery bypass grafting (CABG). We used immunological techniques and antibacterial assays combined with high-performance gel-permeation chromatography, reverse-phase HPLC, N-terminal sequencing and comparison with synthetic standards to characterize the peptide B/enkelytin. We show the presence of anionic antibacterial peptide, the peptide B/enkelytin which correspond to the C-terminal part of proenkephalin A, from the plasma of patients undergoing CABG. Our studies show that peptide B/enkelytin is initially present at low levels in plasma and is then released in increased amounts just after skin incision. Antibacterial assays confirmed that the peptides specifically target gram-positive bacteria. We also demonstrate that peptide B/enkelytin is metabolized in vivo to the opioid peptides methionine-enkephalin-Arg-Phe and methionine-enkephalin, peptides that we show have granulocyte chemotactic activity. These findings suggest that in humans, surgical incision leads to the release of antibacterial peptides. Furthermore, these antibacterial peptides can be metabolized into compounds that have immune-activating properties.

Endogenous morphine.

It is now well accepted that endogenous morphine is present in animals, both in invertebrates and vertebrates. It is a key signaling molecule that plays an important role in downregulating physiological responses, such as those in the immune system, including immune elements in the CNS. It has been demonstrated that a specific mu-opiate-receptor subtype, mu3, mediates these downregulatory effects through release of NO. This article examines morphine as an endogenous signaling molecule, in terms of its role in neural and immune regulation.

Functional brain mapping of the relaxation response and meditation.

Meditation is a conscious mental process that induces a set of integrated physiologic changes termed the relaxation response. Functional magnetic resonance imaging (fMRI) was used to identify and characterize the brain regions that are active during a simple form of meditation. Significant (p<10(-7)) signal increases were observed in the group-averaged data in the dorsolateral prefrontal and parietal cortices, hippocampus/parahippocampus, temporal lobe, pregenual anterior cingulate cortex, striatum, and pre- and post-central gyri during meditation. Global fMRI signal decreases were also noted, although these were probably secondary to cardiorespiratory changes that often accompany meditation. The results indicate that the practice of meditation activates neural structures involved in attention and control of the autonomic nervous system.

Cell-surface estrogen receptors mediate calcium-dependent nitric oxide release in human endothelia.

BACKGROUND: Although estrogen replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, the mechanism for this benefit remains unclear. Because nitric oxide (NO) is considered an important endothelium-derived relaxing factor and may function to protect blood vessels against atherosclerotic development, we investigated the acute effects of physiological levels of estrogen on NO release from human internal thoracic artery endothelia and human arterial endothelia in culture. METHODS AND RESULTS: We tested the hypothesis that estrogen acutely stimulates constitutive NO synthase activity in human endothelial cells by acting on a cell-surface receptor. NO release was measured in real time with an amperometric probe. 17beta-Estradiol exposure to internal thoracic artery endothelia and human arterial endothelia in culture stimulated NO release within seconds in a concentration-dependent manner. 17beta-Estradiol conjugated to bovine serum albumin also stimulated NO release, suggesting action through a cell-surface receptor. Tamoxifen, an estrogen receptor inhibitor, antagonized this action. We further showed with the use of dual emission microfluorometry that 17beta-estradiol-stimulated release of endothelial NO was dependent on the initial stimulation of intracellular calcium transients. CONCLUSIONS: Physiological doses of estrogen immediately stimulate NO release from human endothelial cells through activation of a cell-surface estrogen receptor that is coupled to increases in intracellular calcium.

Relation between myocardial infarction, depression, hostility, and death.

OBJECTIVE: To examine the independent impact of major depression and hostility on mortality rate at 6 months and 12 months after discharge from the hospital in patients with a myocardial infarction. METHOD: Three hundred thirty-one patients were prospectively evaluated for depression with a modified version of the National Institute of Mental Health Diagnostic Interview Schedule for major depressive episode. The Cook Medley Hostility Scale data were analyzed by chi(2) procedures for nominal and categoric data, and Student t test was used for continuous data types. RESULTS: Depression was a significant predictor of death at 12 months (P =. 04) but not at 6 months (P =.08). Hostility was not found to be a predictor of death at 6 months or 12 months. CONCLUSIONS: Major depression in patients hospitalized after myocardial infarction is a significant univariable predictor of death at 12 months, although it was not a statistically significant predictor after adjusting for other variables. Hostility is not a predictor of death. Prospective studies are needed to determine the impact of aggressive treatment of depression on post-myocardial infarction survival.

Estradiol coupling to endothelial nitric oxide stimulates gonadotropin-releasing hormone release from rat median eminence via a membrane receptor.

The median eminence (ME), which is the common termination field for adenohypophysiotropic systems, has been shown to produce nitric oxide (NO), a signaling molecule involved in neuroendocrine secretion. Using an ex vivo technique, 17beta-estradiol exposure to ME fragments, including vascular tissues, stimulated NO release within seconds in a concentration-dependent manner, whereas 17alpha-estradiol or testosterone had no effect. 17Beta-estradiol conjugated to BSA (E2-BSA) also stimulated NO release, suggesting mediation by a membrane surface receptor. Tamoxifen, an estrogen receptor inhibitor, antagonized the action of both 17beta-estradiol and E2-BSA. Furthermore, estradiol-stimulated NO stimulates GnRH release. This was demonstrated by hemoglobin (a NO scavenger), N(omega)-nitro-L-arginine methyl ester, and L-N5-(1-iminoethyl)ornithine (nitric oxide synthase inhibitors) inhibition of estradiol stimulated NO and GnRH release. In this regard, L-N5-(1-iminoethyl)ornithine, specific for endotheliol constitutive nitric oxide synthase, was significantly more potent, suggesting that the estradiol-stimulated NO release arose from vascular endothelial cells. Additionally, the NO-stimulated GnRH release occurs via guanylyl cyclase activation in GnRH nerve terminals, as ODQ, a potent and selective inhibitor of NO-sensitive guanylyl cyclase, abolished the estradiol-stimulated GnRH release. The results suggest that at physiological concentrations, 17beta-estradiol may have immediate actions on ME endothelial cells via nongenomic signaling pathways leading to NO-stimulated GnRH release.

Aspirin inhibits granulocyte and monocyte adherence to saphenous vein endothelia in a process not mediated by nitric oxide.

We examined the effects of aspirin on human immunocyte adherence to human saphenous vein preparations in vitro. Monocytes and granulocytes were analyzed by phase-contrast microscopy in conjunction with a time-lapse video recording system for cell counting in the medium. Saphenous vein samples taken from five volunteer subjects during their elective coronary artery bypass grafting procedures were used for an in vitro experiment in which each subject's immune cells were added to his/her respective endothelial tissues. In addition, aspirin or morphine was added to the preparations. After 30 min the endothelium and the medium were examined for cell numbers using feature color detection software. The endothelium exposed to a 10 min preincubation with 10 mmol/l aspirin was found to have significantly fewer monocytes and granulocytes attached. The saphenous vein preparations were examined for nitric oxide (NO) release using an NO-selective amperometric microprobe. Aspirin at its immunocyte inhibitory concentrations did not induce NO release from the endothelium, whereas morphine, which is known to stimulate NO production by endothelium, did so. These findings demonstrate that the administration of aspirin in high doses can diminish human granulocyte and monocyte adherence to saphenous vein endothelium in vitro through an NO-independent mechanism.

Cell behavior and signal molecule involvement in a case study of malignant histiocytosis: a negative model of morphine as an immunoregulator.

In a patient diagnosed with histiocytic medullary reticulosis (HM), we examined immunocytes for their responsiveness towards known signaling molecules. Both the granulocytes and monocytes were found to exhibit a high level of spontaneous activation (96% compared to normal cells 7%; P < 0.001). These cells could not be downregulated when exposed to morphine. Following patient treatment with doxorubicin and cyclophosphamide, the immunocytes still exhibited a high spontaneous activation. They responded to morphine exposure in vitro with a cell rounding and becoming immobile for only 20 min whereas normal cells would remain round and immobile for up to 1-2 h. An examination of the plasma from the HM patient revealed that monocyte colony stimulating factor (MCSF) levels were elevated (6.4 and 5.78 compared to a control range of 1-1.75 ng/ml). In the HM patient, the immunocytes did not express the opiate selective and opioid peptide insensitive receptor, mu3, supporting the lack of opiate action. Given this finding, we incubated normal monocytes with MCSF and found that it significantly reduced the mu3 Bmax. Given the role of intracellular calcium in the activation process of immunocytes, we examined the action of various calcium channel blockers for their ability to inhibit the activated HM monocytes. The agents (nimodipine, cardiazem, and verapamil; 10[-9] M) were able to inhibit the HM-associated chemokinesis. Taken together, the data indicate that in the HM patient the immunocytes appear to be overactivated because stimulatory molecules are high and have the ability to downregulate the normal "braking" process. Additionally, the data indicate that MCSF deregulation may be involved as an initiating factor for this disorder.