Sleep and pain: recent insights, mechanisms, and future directions in the investigation of this relationship.

Sleep disturbances and chronic pain are considered public health concerns. They are frequently associated, and the direction of its relationship and possible mechanisms underlying it are frequently debated. The exploration of the sleep-pain association is of great clinical interest to explore in order to steer potential therapeutic avenues, accommodate the patient's experience, and adapt the common practice of health professionals. In this review, the direction between sleep-pain in adult and pediatric populations will be discussed. Moreover, the possible mechanisms contributing to this relationship as endogenous pain modulation, inflammation, affect, mood and other states, the role of different endogenous substances (dopamine, orexin, melatonin, vitamin D) as well as other lesser known such as cyclic alternating pattern among others, will be explored. Finally, directions for future studies on this area will be discussed, opening up to the addition of tools such as brain imaging (e.g., fMRI), electrophysiology and non-invasive brain stimulation techniques. Such resources paired with artificial intelligence are key to personalized medicine management for patients facing pain and sleep interacting conditions.

Neuroimmunological antibody-mediated encephalitis and implications for diagnosis and therapy in neuropsychiatry.

The past decade has seen a surge of reports and investigations into cases of autoimmune-mediated encephalitis. The increasing recognition of these disorders is especially of relevance to the fields of neurology and psychiatry. Autoimmune encephalitis involves antibodies against synaptic receptors, neuronal cell surface proteins and intracellular targets. These disorders feature prominent symptoms of cognitive impairment and behavioural changes, often associated with the presence of seizures. Early in the clinical course, autoimmune encephalitis may manifest as psychiatric symptoms of psychosis and involve psychiatry as an initial point of contact. Although commonly associated with malignancy, these disorders can present in the absence of an inciting neoplasm. The identification of autoimmune encephalitis is of clinical importance as a large proportion of individuals experience a response to immunotherapy. This review focuses on the current state of knowledge on n-methyl-d-aspartate (NMDA) receptor-associated encephalitis and limbic encephalitis, the latter predominantly involving antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, the γ-aminobutyric acid (GABA)B receptor and leucine-rich glioma-inactivated 1 (LGI1) protein. In addition, we briefly describe anti-dopamine D2 receptor encephalitis. A summary of the literature will focus on common clinical presentations and course, diagnostic approaches and response to treatment. Since a substantial proportion of patients with autoimmune encephalitis exhibit symptoms of psychosis, the relevance of this disorder to theories of psychosis and schizophrenia will also be discussed.

Alexithymia and its relationships with inflammatory response mediated by IL-1 family members.

The major aim of this study is to provide a review of the research studies regarding the clinical link between alexithymia and interleukins (IL). We performed a search for the relevant literature by using search terms as "alexithymia" combined with "interleukin or IL". A total of 9 original research studies were identified and included. Alexithymia was found to be prevalent in inflammatory response and associated with inflammatory cytokines. Our review emphasized for the first time the relationships of alexithymia with inflammatory response mediated by IL-1 family members. Therefore, the screening of alexithymic traits and the administration of appropriate psychological and psychotherapeutical interventions should be integral parts of disease management programs. Supplying such interventions will probably help with prevention of the development of the disease and/or its exacerbation by improving the quality of life of alexithymic individuals.

Are the emergence of affective disturbances in neuropathic pain states contingent on supraspinal neuroinflammation?

Neuro-immune interactions contribute to the pathogenesis of neuropathic pain due to peripheral nerve injury. A large body of preclinical evidence supports the idea that the immune system acts to modulate the sensory symptoms of neuropathy at both peripheral and central nervous system sites. The potential involvement of neuro-immune interactions in the highly debilitating affective disturbances of neuropathic pain, such as depression, anhedonia, impaired cognition and reduced motivation has received little attention. This is surprising given the widely accepted view that sickness behaviour, depression, cognitive impairment and other neuropsychiatric conditions can arise from inflammatory mechanisms. Moreover, there is a set of well-described immune-to-brain transmission mechanisms that explain how peripheral inflammation can lead to supraspinal neuroinflammation. In the last 5years increasing evidence has emerged that peripheral nerve injury induces supraspinal changes in cytokine or chemokine expression and alters glial cell activity. In this systematic review, based on strong preclinical evidence, we advance the argument that the emergence of affective disturbances in neuropathic pain states are contingent on pro-inflammatory mediators in the interconnected hippocampal-medial prefrontal circuitry that subserve affective behaviours. We explore how dysregulation of inflammatory mediators in these networks may result in affective disturbances through a wide variety of neuromodulatory mechanisms. There are also promising results from clinical trials showing that anti-inflammatory agents have efficacy in the treatment of a variety of neuropsychiatric conditions including depression and appear suited to sub-groups of patients with elevated pro-inflammatory profiles. Thus, although further research is required, aggressively targeting supraspinal pro-inflammatory mediators at critical time-points in appropriate clinical populations is likely to be a novel avenue to treat debilitating affective disturbances in neuropathic conditions.

Alexithymia and its relationships with acute phase proteins and cytokine release: an updated review.

The alexithymia construct is multidimensional and comprises several features: (a) difficulty in identifying and describing feelings, (b) difficulty in distinguishing feelings from the bodily sensations, (c) diminution of fantasy, and (d) concrete and poorly introspective thinking. Altered immune responses have been seen in some psychiatric disorders and several data suggest that analogous changes could also be observable in alexithymia. Hence, the aim of this review is to investigate the relationships between alexithymia and acute phase proteins and cytokines in psychiatric, psychosomatic and medical diseases. Several studies have reported an association between alexithymia and higher circulating levels of acute phase proteins, especially C-Reactive Protein. Moreover, in alexithymic subjects the pro-inflammatory and anti-inflammatory cytokine balance may be tuned toward a pro-inflammatory imbalance with a concomitant altered cell-mediated immunity. These findings may be consistent with the "“stress-alexithymia hypothesis"”. Therefore, the screening of alexithymic traits and the administration of appropriate psychological and psychotherapeutical interventions should be integral parts of disease management programs. Supplying such interventions will probably help with prevention of the development of the disease and/or its exacerbation by improving the quality of life of alexithymic individuals.

Alexithymia is linked to neurocognitive, psychological, neuroendocrine, and immune dysfunction in persons living with HIV.

The neuropathological changes resulting from Human Immunodeficiency Virus (HIV) infection may manifest in alexithymia (AL), a multidimensional trait characterized by impairments in the cognitive assimilation of feelings and emotions. A sample of 93 HIV survivors scoring high, i.e., ⩾74 on the 26-item Toronto Alexithymia Scale (TAS-26), were compared to 79 low AL (TAS-26⩽54) survivors on measures of neurocognitive, psychological, neuroendocrine and immune function. Neurocognitive function was evinced by a standardized test of psychomotor speed, cognitive flexibility and task switching ability, HIV Dementia and general cognitive status. Patients were also screened for levels of depression, anxiety and psychological stress. A 24-h urinary norepinephrine (NE) and cortisol (CORT) collection was taken; blood was drawn for T lymphocyte subset counts (CD4+CD3+) and HIV-1 viral load. Alexithymic patients exhibited higher levels of executive dysfunction, psychological distress, norepinephrine-to-cortisol (NE/CORT) ratio and viral load. Linear regression models accounting for sociodemographic and disease-related variables revealed two AL subscales, difficulties identifying and describing feelings, predicted and explained a significant proportion of variance in the outcome measures. Specifically, poorer executive task-switching/cognitive flexibility was associated with greater difficulty describing feelings; dysregulated autonomic response (high NE/CORT ratio) and depressive symptoms were predicted by difficulty identifying feelings; higher levels of anxiety and psychological stress were both predicted by greater difficulty describing and identifying feelings. Overall, the psychoneuroimmunological profile of alexithymia in HIV positive persons at mid-stage of infection suggests a greater vulnerability for disease progression.

Attachment style and immunity: a 1-year longitudinal study.

Previous cross-sectional studies suggested an association between attachment-related avoidance and altered immune function. We aimed at testing this hypothesis with longitudinal data. A random sample of 65 female nurses provided a blood sample and completed measures of perceived stress, social support, alexithymia, and attachment style. Immune assays included lymphocyte proliferative response (LPR) to Phytohemagglutinin and NK cell cytotoxicity (NKCC). State measures (perceived stress and support) and immune measures were collected again after 4, 8, and 12 months. Linear mixed effects models were used to examine the relationship between attachment and immunity. While low to moderate levels of attachment-related avoidance were not associated with NKCC, there was a significant negative association (beta -.35; p=.005) between high levels of avoidance and NKCC. No association was observed between NKCC and attachment-related anxiety, and between LPR and both attachment dimensions. While our findings should be interpreted with caution due to study limitations such as the relatively small sample size and the inclusion of only female participants, they corroborate the notion that attachment is linked to physiology and health.

Efeitos da acupuntura sobre os pacientes com asma leve e moderada persistentes: um estudo randomizado, controlado e cruzado / Effects of acupuncture on patients with mild to moderate persistent asthma: a randomized, controlled, crossover

Introdução: Este estudo foi realizado com o intuito de avaliar efeitos da acupuntura sobre os pacientes com asma leve e moderada persistentes com o uso de beta-2 agonista ou corticoide inalatório. Métodos e casuística: Trata-se de um estudo prospectivo, duplo-cego, randomizado e cruzado com dois braços. Os 74 pacientes com diagnóstico de asma leve/moderada, de acordo com a classificação de GINA 2002/2003, foram divididos em dois grupos, sendo 31 do Grupo I, e 43 do Grupo II inicialmente. Foram realizadas consultas médicas e exames que incluíram espirometria, citologia de escarro induzido, NO expirado, preenchimento de escala de sintoma, questionários de qualidade de vida de asma e de SF 36, e realização de peak-flow, dependendo da Fase do protocolo. A Fase I constituiu-se dos exames pré-intervenção. Na Fase II, foram realizadas 10 sessões de Acupuntura Real no Grupo I e 10 sessões de Acupuntura Sham no Grupo II, na Fase III, houve 4 semana de washout, na Fase IV, houve a troca de técnicas de acupuntura, sendo uma sessão por semana e, na Fase V, realização dos exames. Resultados: Não há diferença nos critérios de avaliação no pré-tratamento entre dois grupos, com exceção de maior celularidade inflamatória no Grupo II. No entanto, houve uma redução significativa de eosinófilos (p = 0,035) e neutrófilos (p = 0,047), e aumento de macrófagos (p = 0,001), melhora da medida de volume do peak-flow (p = 0,01) na fase IV do Grupo II. No Grupo I, na avaliação de escala de sintomas diária, havia menor uso de medicação de resgate (p = 0,043) na Fase II, e, depois de receber a Acupuntura Sham na Fase IV, havia menos tosse (p = 0,007), menos chiado (p = 0,037), menos dispneia (p < 0,001) e menor uso de medicação de resgate (p < 0,001). No Grupo II, após receber o tratamento com a Acupuntura Sham na Fase II, houve diminuição de tosse (p = 0,037), de chiado (p = 0,013) e de dispneia (p = 0,014), e, na...

Introduction: This survey has been conducted in order to evaluate the effects of acupuncture in patients with persistent mild and moderate asthma (according to GINA criteria 2003), using beta agonist and/or inhaled glucocorticoid. Methods and patients: This is a prospective, double blinded, randomized and cross-over study with two branches: 74 patients diagnosed with mild and moderate asthma were divided into two groups: Group I with 31, initiating with real acupuncture and Group II, starting with sham acupuncture. Medical interview and laboratory tests including spirometry, induced sputum citology, exhaled NO measurement, quality of life questionnaire (SF-36 and QQL), besides, daily symptom scores and measurement of peak-flow were performed, in the beginning of the study, and in the end of each phase of treatment. Phase I: laboratory tests and other qualitative measurements. There were 10 real acupuncture weekly sessions to Group I and 10 sham acupuncture sessions to Group II in Phase II. On the other hand, in the Phase IV, there was an exchange between Group I and Group II, which was receiving real acupuncture started to receive sham, and vice-versa, the number of sessions remained the same (10 weekly sessions). Phase III, during the interval between Phase II and Phase IV, there was an interval of 4 weeks of washout. Phase V: laboratory tests and other qualitative measurements. Results: There was no difference beween both the groups in all criteria of evaluation pré treatment, with only na exception: in the Group II there was large inflammatory cell counts. However, there was a significant reduction in eosinophils (p = 0.035) and neutrophils (p = 0.047), and increase of macrophages (p = 0.001), improved peak-flow measurement in the morning (p = 0.01) in Group II (started with sham) in Phase IV. In Daily Symptons Score, there was a significant reduction in use of rescue medication (p = 0.043) in Group I (real acupuncture) in Phase II and after received...

Cognitive and emotional abnormalities in systemic lupus erythematosus: evidence for amygdala dysfunction.

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disorder characterized by the production of autoantibodies. Approximately 30-50 % of patients produce autoantibodies directed against N-Methyl-D-aspartic acid receptors (NMDARs). Once they have gained access to brain tissue, these autoantibodies bind to the NR2A subunit of the NMDARs and synergize with glutamate to cause excitatory, non-inflammatory cell death or alter neuron function. Both humans with SLE and animal models of SLE have shown structural and functional damage to the amygdala. The amygdala is a brain region important for processing the emotional relevance of stimuli in the environment. It also serves to modulate perception, attention, and memory to facilitate the processing and learning of relevant stimuli. Research has linked amygdala damage to deficits in emotional memory and emotional behavior. Individuals with SLE often exhibit emotional dysregulation, such as lability and depression; however, the behavioral impact of possible amygdala dysfunction has yet to be studied in this population. The purpose of this review is to 1) examine possible associations between SLE, anti-NMDAR antibodies, amygdala damage, and emotional processing deficits and 2) to identify the clinical, social, and treatment implications for individuals with SLE who suffer from deficits in emotional processing.

Alexithymia and tissue inflammation.

BACKGROUND: Altered immune responses are seen in depression, and recent data suggest that similar changes could also be observable in alexithymia. We examined whether the inflammatory markers high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6 are independently related to alexithymia or its factors in a population-based sample. METHODS: This study formed a clinical part of the Kuopio Depression (KUDEP) general population study focusing on the mental health of a general population of adults aged 25-64 years (n = 308). Alexithymia was measured using the Toronto Alexithymia Scale (TAS-20), and depressive symptoms were assessed using the Beck Depression Inventory (BDI-21). RESULTS: The levels of IL-6 (in picograms per milliliter) and hs-CRP (in milligrams per liter) were significantly higher in alexithymic than in nonalexithymic subjects (IL-6 effect size, ES: 0.50; hs-CRP ES: 0.27). The BDI scores, hs-CRP and IL-6 explained 33.5% of the variation in TAS scores in the whole study population. According to logistic regression analysis, hs-CRP but not IL-6 increased the likelihood of belonging to the alexithymic group. This observation remained unaltered after additional adjustments for chronic inflammation-related disorders, the use of inflammation-modulating medications and depressive symptoms. CONCLUSIONS: Our findings suggest that the association between hs-CRP and alexithymia resembles that observed in depressed patients. It is, however, independent of depressive symptoms. These findings widen our view on the stress-alexithymia concept.

Detection of plasma autoantibodies to brain tissue in young children with and without autism spectrum disorders.

Autism spectrum disorders (ASDs) are characterized by impaired language and social skills, often with restricted interests and stereotyped behaviors. A previous investigation of blood plasma from children with ASDs (mean age=5½ years) demonstrated that 21% of samples contained autoantibodies that reacted intensely with GABAergic Golgi neurons of the cerebellum while no samples from non-sibling, typically developing children showed similar staining (Wills et al., 2009). In order to characterize the clinical features of children positive for these autoantibodies, we analyzed plasma samples from children enrolled in the Autism Phenome Project, a multidisciplinary project aimed at identifying subtypes of ASD. Plasma from male and female children (mean age=3.2 years) was analyzed immunohistochemically for the presence of autoantibodies using histological sections of macaque monkey brain. Immunoreactivity to cerebellar Golgi neurons and other presumed interneurons was observed for some samples but there was no difference in the rate of occurrence of these autoantibodies between children with ASD and their typically developing peers. Staining of neurons, punctate profiles in the molecular layer of the dentate gyrus, and neuronal nuclei were also observed. Taken together, 42% of controls and subjects with ASD demonstrated immunoreactivity to some neural element. Interestingly, children whose plasma reacted to brain tissue had scores on the Child Behavior Checklist (CBCL) that indicated increased behavioral and emotional problems. Children whose plasma was immunoreactive with neuronal cell bodies scored higher on multiple CBCL scales. These studies indicate that additional research into the genesis and prevalence of brain-directed autoantibodies is warranted.

[Psychological aspects of systemic approach to diagnostics of mental and immunological disorders in diffuse-nodular form of Hashimoto's thyroiditis].

Authors have studied 162 patients with the diffuse-nodular form of chronic autoimmune thyroiditis (AIT). Alexithymic personality type was found to be prevalent in patients in the euthyroid phase (51.9%). In autoimmune thyroiditis, alexithymia and certain cytokine parameters were correlated with psychopathological symptoms as asthenia, anxiety and depression which might be caused by their participation in the pathogenesis of non-psychotic mental disorders during the euthyroid phase. The linkage of alexithymia with certain emotional-personal parameters allows to regard it as one of the components of the integral personality characteristics. These findings show that alexithymia is not only an indirect risk factor of the autoimmune thyroiditis development but also a predictor of the disease course.

The relationship between alexithymia and circulating cytokine levels in subjects undergoing upper endoscopy.

OBJECTIVE: Despite emerging evidence suggesting a link between alexithymia and immune function, previous studies yielded contrasting results. The proposed link between alexithymia and immune function remains controversial as does the role, in this relationship, of anxiety, depression and subjective stress. The aim of the study is to investigate the possible association between alexithymia and circulating levels of cytokines in subjects awaiting an upper endoscopy, a stressful procedure, controlling for anxiety levels, depression and subjective stress. METHODS: Participants were recruited from among consecutive patients referred for routine diagnostic upper endoscopy. All participants completed the Toronto Alexithymia Scale (TAS-20), the Hospital Anxiety and Depression Scale, and the Stress-related Vulnerability Scale. Serum levels of IL-1ß, IL-4, IL-6, IL-10, TNF-α and IFN-γ were measured by ELISA. RESULTS: Of the 90 subjects initially approached, 68 completed the study. The TAS-20 identified 22 alexithymic and 36 non-alexithymic patients. ELISA detected significantly lower IL-4 and IL-6 concentrations in alexithymic than in non-alexithymic patients. According to multiple linear regression analysis, alexithymia predicted low IL-4 and IL-6 levels in the sample overall, independently of stress, anxiety, depression and other possible confounders. No between-group differences were found in serum levels of IFN-γ, IL-1ß, and TNF-α. CONCLUSION: These findings argue against an isolated shift towards pro-inflammatory or anti-inflammatory mediators and suggest that circulating cytokine profiles differ in alexithymic and non-alexithymic subjects.

Non-paraneoplastic limbic encephalitis associated with antibodies to potassium channels leading to bilateral hippocampal sclerosis in a pre-pubertal girl.

Limbic encephalitis (LE) is increasingly recognized as a precipitating factor of adult onset temporal lobe epilepsy frequently associated with bilateral hippocampal damage. So far, clinical data in children are rare and only comprise paraneoplastic forms of LE. We describe a 13-year-old pre-pubertal girl in whom non-paraneoplastic LE was diagnosed according to diagnostic criteria proposed by Bien and Elger (2007). The girl presented with a subacute syndrome comprising memory impairment, affective disturbances, and refractory temporal lobe seizures. Serial MRI scans demonstrated an initial temporo-medial swelling with T2/FLAIR signal increase progressing to bilateral hippocampal atrophy within seven months. Two years after onset of symptoms, antibodies to potassium channels were found to be slightly elevated. Immunosuppressive therapy with steroid-pulses was followed by a transient reduction of seizure frequency, even though this was started more than two years after onset of first symptoms. However, extended immunotherapy was refused by the patient's parents, so no full assessment of the treatment response was possible. In conclusion, this case shows that non-paraneoplastic LE leading to mesial temporal lobe epilepsy is not restricted to adult patients. The proposed diagnostic criteria therefore should be adapted for paediatric patients. Patients may profit from immunosuppressive therapy even when it is started at a late stage with already overt hippocampal sclerosis.

Decreased immune response in alexithymic women: a cross-sectional study.

It has been reported in a few studies that alexithymia is associated with impaired immune response but results are still contradictory. The present study investigates whether alexithymia is associated with lower cell-mediated (Th-1) immune response. Fifty-one healthy 18-27-year-old women were selected from healthy subjects on the basis of high or low cut-off scores on the 20-item Toronto Alexithymia Scale (TAS-20). They were evaluated using standardized psychiatric rating scales notably the Hospital Anxiety Depressive Scale (HAD) and the Mini Neuropsychiatric Interview (MINI). None of the subjects were suffering from psychiatric disorders. Twenty-seven were classified as alexithymics and 24 as non-alexithymics according to the TAS-20. Blood was drawn for lymphocyte subset counts (CD4, CD8), in vitro production of interleukin 1 (IL-1beta), IL-2, IL-4, and IL-10 by phytohaemagglutinin stimulated peripheral lymphocytes, and cortisol. Women with alexithymia exhibited decreased interleukin 1beta, IL-2 and IL-4 production with reduced ratios of Th1/Th2 (IL-2/IL-10) and of CD4/CD8, as well as reduced CD4 percentages. IL-2 and IL-4 production remained significantly diminished in the alexithymic group, even after adjusting for between-group differences in anxiety and depression levels on the HAD. This study further demonstrates that alexithymic women have altered immune function, with a predominance of depressed cell-mediated immunity and a skewed Th1/Th2 ratio towards Th2 response.

Stimulant use is associated with immune activation and depleted tryptophan among HIV-positive persons on anti-retroviral therapy.

Cocaine, crack, and methamphetamine are stimulants that promote autonomic nervous system activation. Although these stimulants may have immunomodulatory effects, relatively few studies have examined this possibility. The present cross-sectional investigation utilized baseline data from 127 HIV-positive individuals on anti-retroviral therapy (ART) that were enrolled in a randomized controlled trial. The goal of this study was to examine whether stimulant use is independently associated with immune activation and indices of tryptophan degradation. Forty-four participants reported using stimulants 2-3 times a month or more (i.e., monthly stimulant use) and a sub-set of these (n=27) reported using stimulants once a week or more (i.e., weekly stimulant use) during the past three months. These stimulant-using groups were compared to a group of participants who reported no stimulant use (n=83) during the past three months. Results indicated that individuals who reported either monthly or weekly stimulant use displayed elevated neopterin, a measure of immune activation. Those who reported weekly stimulant use also displayed a markedly elevated HIV viral load and lower tryptophan levels. Even after controlling for self-reported ART non-adherence, weekly stimulant use was independently associated with higher neopterin, elevated HIV viral load, and lower tryptophan. To our knowledge, this is the first study to observe that stimulant use may independently promote immune activation and tryptophan degradation among HIV-positive persons on ART. Further research is needed to replicate these findings and examine the plausible bio-behavioral pathways that may account for the effects of stimulant use on HIV disease markers and depleted tryptophan.

Association between burnout and circulating levels of pro- and anti-inflammatory cytokines in schoolteachers.

OBJECTIVE: The burnout syndrome has been associated with an increased risk of cardiovascular disease. The physiological mechanisms potentially involved in this link are underexplored. Knowing that a chronic low-grade systemic inflammatory state contributes to atherosclerosis, we investigated circulating cytokine levels in relation to burnout symptoms. METHODS: We studied 167 schoolteachers (median, 48 years; range, 23-63 years; 67% women) who completed the Maslach Burnout Inventory with its three subscales emotional exhaustion (EE), lack of accomplishment (LA), and depersonalization (DP). Levels of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha and of the anti-inflammatory cytokines interleukin (IL)-4 and IL-10 were determined in fasting morning plasma samples. The TNF-alpha/IL-4 ratio and the TNF-alpha/IL-10 ratio were computed as two indices of increased inflammatory activity. Analyses were adjusted for demographic factors, medication, lifestyle factors (including sleep quality), metabolic factors, and symptoms of depression and anxiety. RESULTS: Higher levels of total burnout symptoms aggregating the EE, LA, and DP subscales independently predicted higher TNF-alpha levels (DeltaR(2)=.024, P=.046), lower IL-4 levels (DeltaR(2)=.021, P=.061), and a higher TNF-alpha/IL-4 ratio (DeltaR(2)=.040, P=.008). Higher levels of LA predicted decreased IL-4 levels (DeltaR(2)=.041, P=.008) and a higher TNF-alpha/IL-4 ratio (DeltaR(2)=.041, P=.007). The categorical dimensions of the various burnout scales (e.g., burnout yes vs. no) showed no independent relationship with any cytokine measure. CONCLUSION: Burnout was associated with increased systemic inflammation along a continuum of symptom severity rather than categorically. Given that low-grade systemic inflammation promotes atherosclerosis, our findings may provide one explanation for the increased cardiovascular risk previously observed in burned-out individuals.

Type C coping, alexithymia, and heart rate reactivity are associated independently and differentially with specific immune mechanisms linked to HIV progression.

The maladaptive Type C coping style has been linked to disease progression in HIV and other immunologically mediated disorders. We hypothesized that strong Type C coping, higher levels of alexithymia, and greater cardiovascular (particularly heart rate) responses to, and prolonged recovery from stress would be associated with poorer functioning of immune parameters previously linked to HIV pathogenesis and progression: (1) antigen-stimulated production of the beta (beta)-chemokines MIP-1 alpha and MIP-1 beta, which bind to the HIV co-receptor CCR5 and block HIV entry into CD4(+) lymphocytes; and (2) antigen-stimulated production of the proinflammatory cytokine interleukin-6 (IL-6), which synergizes immune activation associated with HIV replication. We examined relations among psychological, cardiovascular, and immune variables in a baseline sample of 200 HIV-infected, predominantly African American outpatients attending an HIV primary care clinic in inner-city Baltimore. In regression analyses adjusted for CD4(+) count and age, strong Type C coping was associated with significantly higher IL-6 production, as predicted. The theoretically related construct of alexithymia was correlated with significantly lower stimulated production of HIV-inhibiting MIP-1 alpha. Independent of alexithymia, greater heart rate reactivity, and poorer heart rate recovery in response to experimental stressors were also significantly associated with lower production of MIP-1 alpha, adjusted for cardiovascular medications, methadone use, CD4(+) count, and age. These findings support our primary set of hypotheses that maladaptive Type C coping, alexithymia, and heart rate reactivity/recovery are associated with disturbances in two key immune parameters implicated in HIV pathogenesis. Our secondary hypothesis, that dysregulated heart rate reactivity may mediate the connections between Type C coping and/or alexithymia and IL-6/ MIP-1 alpha was not confirmed. The finding that Type C coping, alexithymia, and heart rate reactivity/recovery are associated independently and differentially with specific aspects of relevant immune functioning may reflect distinct biobehavioral pathways that contribute to HIV progression.

Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal.

OBJECTIVE: To report the definitive diagnosis of anti-NMDA receptor (NMDAR) encephalitis in four Japanese women previously diagnosed with "juvenile acute nonherpetic encephalitis" of unclear etiology, and to describe their long-term follow-up in the absence of tumor resection. METHODS: We extensively reviewed the case histories with current clinical and laboratory evaluations that include testing for antibodies to NR1/NR2 heteromers of the NMDAR in serum/CSF available from the time of symptom onset (4 to 7 years ago) and the present. RESULTS: All patients sequentially developed prodromal symptoms, psychosis, hypoventilation, severe orofacial dyskinesias, and bizarre immunotherapy-resistant involuntary movements that lasted 1 to 12 months. Two patients required mechanical ventilation for 6 and 9 months. Initial tests were normal or unrevealing, including the presence of nonspecific CSF pleocytosis, and normal or mild changes in brain MRI. Eventually, all patients had dramatic recovery of cognitive functions, although one had bilateral leg amputation due to systemic complications. Antibodies to NR1/NR2 heteromers were found in archived serum or CSF but not in long-term follow-up samples. An ovarian teratoma was subsequently demonstrated in three patients (all confirmed pathologically). CONCLUSION: 1) These findings indicate that "juvenile acute nonherpetic encephalitis" or a subset of this disorder is mediated by an antibody-associated immune response against NR1/NR2 heteromers of the NMDA receptor (NMDAR). 2) Our patients' clinical features emphasize that anti-NMDAR encephalitis is severe but potentially reversible and may precede by years the detection of an ovarian teratoma. 3) Although recovery may occur without tumor removal, the severity and extended duration of symptoms support tumor removal.

Juvenile onset central nervous system folate deficiency and rheumatoid arthritis.

Isolated cerebral folate deficiency was detected in a 13-year-old girl with cognitive and motor difficulties and juvenile rheumatoid arthritis. Her serum contains autoantibodies that block membrane-bound folate receptors that are on the choroid plexus and diminish the uptake of folate into the spinal fluid. Whereas her serum folate exceeded 21 ng/mL, her spinal fluid contained 3.2 ng/mL of 5-methyltetrahydrofolate as a consequence of the autoantibodies diminishing the uptake of this folate.