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1.
Sci Adv ; 5(5): eaav4111, 2019 05.
Article in English | MEDLINE | ID: mdl-31149632

ABSTRACT

The immune system supports brain plasticity and homeostasis, yet it is prone to changes following psychological stress. Thus, it remains unclear whether and how stress-induced immune alterations contribute to the development of mental pathologies. Here, we show that following severe stress in mice, leukocyte trafficking through the choroid plexus (CP), a compartment that mediates physiological immune-brain communication, is impaired. Blocking glucocorticoid receptor signaling, either systemically or locally through its genetic knockdown at the CP, facilitated the recruitment of Gata3- and Foxp3-expressing T cells to the brain and attenuated post-traumatic behavioral deficits. These findings functionally link post-traumatic stress behavior with elevated stress-related corticosteroid signaling at the brain-immune interface and suggest a novel therapeutic target to attenuate the consequences of severe psychological stress.


Subject(s)
Adrenal Cortex Hormones/metabolism , Brain/immunology , Stress, Psychological/metabolism , Adrenal Cortex Hormones/cerebrospinal fluid , Adrenal Cortex Hormones/immunology , Animals , Behavior, Animal , Brain/metabolism , Choroid Plexus/metabolism , Choroid Plexus/physiopathology , Epithelial Cells/immunology , Epithelial Cells/metabolism , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , GATA3 Transcription Factor/metabolism , Hormone Antagonists/pharmacology , Humans , Mice, Inbred C57BL , Mice, Mutant Strains , Mifepristone/pharmacology , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Signal Transduction , Single-Cell Analysis , Stress, Psychological/immunology , T-Lymphocytes/immunology
2.
Medicine (Baltimore) ; 98(6): e14406, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30732190

ABSTRACT

RATIONALE: We present a case of high spinal anesthesia after inadvertent injection of local anesthetics and corticosteroids into the subarachnoid space during attempted epidural injection. Cerebrospinal fluid (CSF) lavage is a suitable method for treatment. PATIENT CONCERNS: A 45-year-old woman presented with posterior thigh, leg, and ankle pain for >6 months and was treated with epidural injection. Five minutes after the third time of epidural injection, the patient complained loss of sensation and muscle strength in the lower extremities and abdominal area. DIAGNOSES: A high spinal anesthesia was confirmed by the patient loss of sensation and muscle strength in the lower extremities and abdominal area. INTERVENTIONS: CSF lavage was performed for treatment. OUTCOMES: After CSF lavage, the patient gradually returns to normal sensory and motor functions of lower limbs. On the fourth day, the patient sensed her physical function restoring gradually and was discharged uneventfully. At 4-month follow-up, the patient could have normal activities without obvious subsequent complications and any pain. LESSONS: We conclude that CSF lavage could be a helpful maneuver to clear lidocaine and betamethasone and avoid potential nerve damage caused by an unintentional intrathecal injection during an epidural injection for the treatment of chronic low back pain.


Subject(s)
Anesthesia, Epidural/adverse effects , Chronic Pain/drug therapy , Injections, Epidural/adverse effects , Low Back Pain/drug therapy , Therapeutic Irrigation/methods , Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/adverse effects , Adrenal Cortex Hormones/cerebrospinal fluid , Anesthesia, Epidural/methods , Anesthesia, Spinal/methods , Anesthetics, Local/administration & dosage , Anesthetics, Local/adverse effects , Anesthetics, Local/cerebrospinal fluid , Female , Humans , Lidocaine/administration & dosage , Lidocaine/adverse effects , Lidocaine/cerebrospinal fluid , Middle Aged , Subarachnoid Space
3.
Infect Dis (Lond) ; 48(4): 281-286, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26559704

ABSTRACT

Background The aim of this study was to evaluate the clinical outcome of patients with bacterial meningitis following the introduction of dexamethasone treatment in Denmark. Methods Adult patients with bacterial meningitis, admitted from 2003-2010 to two different university hospitals, were included retrospectively. Data at clinical presentation, Glasgow outcome scale (GOS), cerebrospinal fluid and blood biochemistry were collected. Relative risk (RR) with 95% confidence interval (CI) was computed by Cox proportional hazard regression analysis. Results One hundred and forty-seven patients were included in the study. The population had a median age of 62 years and 31% had an immunosuppressive co-morbidity. Eighty-nine patients had an unfavourable outcome (GOS score = 1-4). Adjuvant treatment with corticosteroids (RR = 0.48; 95% CI = 0.30-0.76) was associated with a favourable outcome (GOS score = 5), while altered mental status (RR = 2.36; 95% CI = 1.17-4.78) and age (RR = 1.03; 95% CI = 1.01-1.04) per year increment was associated with an unfavourable outcome. Adjuvant corticosteroid treatment did not affect short- or long-term survival. Short-term mortality was influenced by age (RR = 1.06; 95% CI = 1.04-1.09). Long-term mortality was influenced by age (RR = 1.06; 95% CI = 1.03-1.08) and female sex (RR = 1.81; 95% CI = 1.05-3.14). Conclusion This study indicated that adjuvant corticosteroid treatment in acute bacterial meningitis improves the outcome and can safely be administered in an elderly population with high levels of immunosuppressive co-morbidity.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Meningitis, Bacterial/drug therapy , Adrenal Cortex Hormones/blood , Adrenal Cortex Hormones/cerebrospinal fluid , Adult , Aged , Anti-Bacterial Agents/therapeutic use , Dexamethasone/blood , Dexamethasone/cerebrospinal fluid , Dexamethasone/therapeutic use , Female , Humans , Male , Meningitis, Bacterial/blood , Meningitis, Bacterial/cerebrospinal fluid , Meningitis, Bacterial/microbiology , Middle Aged , Pneumococcal Infections/blood , Pneumococcal Infections/cerebrospinal fluid , Pneumococcal Infections/drug therapy , Randomized Controlled Trials as Topic , Retrospective Studies , Streptococcus pneumoniae/isolation & purification , Treatment Outcome
4.
J Steroid Biochem Mol Biol ; 152: 124-32, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25976421

ABSTRACT

Normal pressure hydrocephalus (NPH) is a treatable neurological disorder affecting elderly people with the prevalence increasing with age. NPH is caused by abnormal cerebrospinal fluid (CSF) reabsorption and manifested as a balance impairment, urinary incontinence and dementia development. These symptoms are potentially reversible if recognized early. Diagnosis of NPH is difficult and can be easily mistaken for other neurodegenerative disorders, which makes NPH one of the major misdiagnosed diseases worldwide. The aim of the study was to find out the appropriate combination of indicators, based on CSF steroids, which would contribute to a clearer NPH diagnosis. The levels of CSF cortisol, cortisone, dehydroepiandrosterone (DHEA), 7α-OH-DHEA, 7ß-OH-DHEA, 7-oxo-DHEA, 16α-OH-DHEA and aldosterone (all LC-MS/MS) were determined in our patients (n=30; NPH, 65-80 years) and controls (n=10; 65-80 years). The model of orthogonal projections to latent structures (OPLS) was constructed to predict NPH. Cortisone, 7α-OH-DHEA, 7ß-OH-DHEA, 7-oxo-DHEA, aldosterone, 7α-OH-DHEA /DHEA, 7-oxo-DHEA/7α-OH-DHEA, 7ß-OH-DHEA/7-oxo-DHEA and 16α-OH-DHEA/DHEA in the CSF were identified as the key predictors and the model discriminated patients from controls with 100% sensitivity and 100% specificity. The suggested model would contribute to early and accurate NPH diagnosis, enabling promptly treatment of the disease.


Subject(s)
Adrenal Cortex Hormones/cerebrospinal fluid , Hydrocephalus, Normal Pressure/cerebrospinal fluid , Hydrocephalus, Normal Pressure/diagnosis , Aged , Aged, 80 and over , Aldosterone/cerebrospinal fluid , Chromatography, Liquid , Cortisone/cerebrospinal fluid , Dehydroepiandrosterone/analogs & derivatives , Dehydroepiandrosterone/cerebrospinal fluid , Female , Humans , Hydrocortisone/cerebrospinal fluid , Male , Mass Spectrometry
5.
J Neurosci ; 35(6): 2612-23, 2015 Feb 11.
Article in English | MEDLINE | ID: mdl-25673853

ABSTRACT

Recent studies have found that those who suffer from posttraumatic stress disorder (PTSD) are more likely to experience dementia as they age, most often Alzheimer's disease (AD). These findings suggest that the symptoms of PTSD might have an exacerbating effect on AD progression. AD and PTSD might also share common susceptibility factors such that those who experience trauma-induced disease were already more likely to succumb to dementia with age. Here, we explored these two hypotheses using a mouse model of PTSD in wild-type and AD model animals. We found that expression of human familial AD mutations in amyloid precursor protein and presenilin 1 leads to sensitivity to trauma-induced PTSD-like changes in behavioral and endocrine stress responses. PTSD-like induction, in turn, chronically elevates levels of CSF ß-amyloid (Aß), exacerbating ongoing AD pathogenesis. We show that PTSD-like induction and Aß elevation are dependent on corticotropin-releasing factor (CRF) receptor 1 signaling and an intact hypothalamic-pituitary-adrenal axis. Furthermore, we show that Aß species can hyperexcite CRF neurons, providing a mechanism by which Aß influences stress-related symptoms and PTSD-like phenotypes. Consistent with Aß causing excitability of the stress circuitry, we attenuate PTSD-like phenotypes in vivo by lowering Aß levels during PTSD-like trauma exposure. Together, these data demonstrate that exposure to PTSD-like trauma can drive AD pathogenesis, which directly perturbs CRF signaling, thereby enhancing chronic PTSD symptoms while increasing risk for AD-related dementia.


Subject(s)
Amyloid beta-Peptides/metabolism , Corticotropin-Releasing Hormone/metabolism , Neurons/metabolism , Stress Disorders, Post-Traumatic/metabolism , Stress, Psychological/metabolism , Adrenal Cortex Hormones/cerebrospinal fluid , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Animals , Behavior, Animal , CHO Cells , Cricetulus , Gene Knock-In Techniques , Mice , Primary Cell Culture , Stress Disorders, Post-Traumatic/psychology , Stress, Psychological/psychology
6.
J Clin Endocrinol Metab ; 95(12): 5348-56, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20826586

ABSTRACT

CONTEXT: The etiology of idiopathic intracranial hypertension (IIH) is unknown. We hypothesized that obesity and elevated intracranial pressure may be linked through increased 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity. OBJECTIVE: The aim was to characterize 11ß-HSD1 in human cerebrospinal fluid (CSF) secretory [choroid plexus (CP)] and drainage [arachnoid granulation tissue (AGT)] structures, and to evaluate 11ß-HSD1 activity after therapeutic weight loss in IIH. DESIGN AND SETTING: We conducted in vitro analysis of CP and AGT and a prospective in vivo cohort study set in two tertiary care centers. PATIENTS OR OTHER PARTICIPANTS: Twenty-five obese adult female patients with active IIH were studied, and 22 completed the study. INTERVENTION: Fasted serum, CSF, and 24-h urine samples were collected at baseline, after 3-month observation, and after a 3-month diet. MAIN OUTCOME MEASURES: Changes in urine, serum, and CSF glucocorticoids (measured by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry) after weight loss were measured. RESULTS: 11ß-HSD1 and key elements of the glucocorticoid signaling pathway were expressed in CP and AGT. After weight loss (14.2±7.8 kg; P<0.001), global 11ß-HSD1 activity decreased (P=0.001) and correlated with reduction in intracranial pressure (r=0.504; P=0.028). CSF and serum glucocorticoids remained stable, although the change in CSF cortisone levels correlated with weight loss (r=-0.512; P=0.018). CONCLUSIONS: Therapeutic weight loss in IIH is associated with a reduction in global 11ß-HSD1 activity. Elevated 11ß-HSD1 may represent a pathogenic mechanism in IIH, potentially via manipulation of CSF dynamics at the CP and AGT. Although further clarification of the functional role of 11ß-HSD1 in IIH is needed, our results suggest that 11ß-HSD1 inhibition may have therapeutic potential in IIH.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Adrenal Cortex Hormones/cerebrospinal fluid , Hydrocortisone/metabolism , Intracranial Hypertension/physiopathology , Intracranial Pressure/physiology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adrenal Cortex Hormones/blood , Adrenal Cortex Hormones/urine , Adult , Biomarkers/cerebrospinal fluid , Biomarkers/metabolism , Choroid Plexus/pathology , Choroid Plexus/physiopathology , Chromatography, Liquid , Epithelial Cells/pathology , Female , Gas Chromatography-Mass Spectrometry , Humans , Hydrocortisone/blood , Hydrocortisone/cerebrospinal fluid , Intracranial Hypertension/complications , Intracranial Hypertension/metabolism , Mass Spectrometry , Obesity/blood , Obesity/cerebrospinal fluid , Obesity/complications , Obesity/urine , Polymerase Chain Reaction , RNA/genetics , RNA/isolation & purification , RNA, Messenger/genetics , Steroids/urine , Weight Loss
7.
Postepy Hig Med Dosw (Online) ; 61: 690-701, 2007 Nov 20.
Article in Polish | MEDLINE | ID: mdl-18033206

ABSTRACT

Stress, defined as coping with environmental challenges, involves the activation of the neuronal and neurohormonal systems. Central monoaminergic (noradrenergic, dopaminergic, serotonergic) neural networks, limbic structures, the sympathoadrenal system, the hypothalamo-pituitary-adrenal axis, and the immune system are considered the most important stress pathways. Their activation determines stress reactivity and pathological consequences on exposure to situations of distress. Both trauma and long-term stress can cause alterations in the activities of neuroanatomical structures and neural networks within the central nervous system. These neurohormonal changes are associated with post-traumatic stress disorder (PTSD), a disturbance thought to be one of the most serious psychiatric illnesses. PTSD may develop in individuals after exposure to a traumatic event (war, violence, accident) and is manifested by various symptoms, such as re-experiencing, flashbacks, intrusive thoughts, impaired memory of the event, sleep disorders, nightmares, panic attacks, and depression. In this review the neurohormonal changes associated with experiencing stress are presented to highlight the molecular and hormonal basis of PTSD.


Subject(s)
Adrenal Cortex Hormones/blood , Hypothalamo-Hypophyseal System/metabolism , Mental Disorders/etiology , Mental Disorders/metabolism , Pituitary-Adrenal System/metabolism , Stress Disorders, Post-Traumatic/complications , Stress Disorders, Post-Traumatic/psychology , Adaptation, Psychological , Adrenal Cortex Hormones/cerebrospinal fluid , Brain/physiopathology , Depression/etiology , Depression/metabolism , Dopamine/metabolism , Epinephrine/metabolism , Fear/psychology , Grief , Humans , Hypothalamo-Hypophyseal System/physiopathology , Life Change Events , Mental Disorders/physiopathology , Norepinephrine/metabolism , Panic Disorder/etiology , Panic Disorder/metabolism , Pituitary-Adrenal System/physiopathology , Stress Disorders, Post-Traumatic/physiopathology , Stress, Physiological
8.
J Neuroendocrinol ; 19(8): 614-20, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17620103

ABSTRACT

The epithelial cells of the choroid plexus (CP) are responsible for cerebrospinal fluid (CSF) secretion into the ventricles of the brain. The balance between CSF production and drainage, in part, facilitates a normal intracranial pressure. The secretion of Na(+) and anions by the CP creates an osmotic gradient driving water into the ventricles. This is opposite to classical Na(+) transporting tissues, such as the kidney, where Na(+) and water reabsorption is mediated by 11beta-hydroxysteroid dehydrogenase type 2 that protects the mineralocorticoid receptor by abrogating active cortisol to inactive cortisone. In the human ocular ciliary epithelium, Na(+) and water secretion is dependent on a novel mediator of ciliary epithelial Na(+) transport, 11beta-HSD type 1 (11beta-HSD1), that generates intraocular cortisol. In a mechanism analogous to that of the embryologically related ocular ciliary epithelium, we propose that autocrine regulation of intracranial cortisol is dependent on 11beta-HSD1 expression in the CP epithelial cells. By conducting immunolocalisation studies on brains from New Zealand White Albino rabbits, we defined the expression of 11beta-HSD1 in the secretory CP epithelial cells. Enzyme assays performed on intact rabbit CP whole tissue explants confirmed predominant 11beta-HSD1 activity, generating cortisol that was inhibited by glycyrrhetinic acid (an 11beta-HSD inhibitor). Using the real time-polymerase chain reaction, rabbit CP tissue was found to express levels of 11beta-HSD1, glucocorticoid receptor alpha and serum and glucocorticoid-regulated kinase 1 mRNA comparable to that expressed in rabbit ocular ciliary body, thereby highlighting the similarity between these two tissues. Furthermore, an enzyme-linked immunosorbent assay of rabbit CSF revealed a median cortisol concentration of 1.7 nmol/l (range 1.4-4.3 nmol/l, n = 9). Our data have identified a functional 11beta-HSD1 within the CP, mediating intracranial cortisol bioavailability. Expression of 11beta-HSD1 may be fundamental in the regulation of CSF secretion and the local generation of cortisol may represent a pathophysiological mechanism underlying cortisol-dependent neuroendocrine diseases.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Adrenal Cortex Hormones/cerebrospinal fluid , Choroid Plexus/enzymology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , Animals , Choroid Plexus/metabolism , Enzyme-Linked Immunosorbent Assay , Female , Hydrocortisone/analysis , Hydrocortisone/cerebrospinal fluid , Immunohistochemistry , Isoenzymes/metabolism , Rabbits , Reverse Transcriptase Polymerase Chain Reaction
9.
Neurotoxicology ; 25(3): 471-80, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15019310

ABSTRACT

BACKGROUND: In children treated for hematological malignancies, a transient elevation of the neurodegenerative marker Tau was found in the cerebrospinal fluid (CSF). In the first part of this study, CSF-Tau, CSF-Phospho-Tau, and CSF-Neuromodulin (CSF-NM) were measured in a heterogeneous group of patients presenting in the pediatric oncology department. In the second part, the neurodegenerative markers were analyzed in a group of children with non-B-cell acute lymphoblastic leukemia (nB-ALL) treated according to EORTC protocols 58881 and 58951. PROCEDURE: CSF was collected from lumbar punctures at diagnosis only in the first group, and at diagnosis and during treatment in the second group. CSF-proteins were measured with ELISA. RESULTS: There was no age variation in any of the markers at diagnosis in the first group of children. After prephase induction therapy with one intrathecal (IT) injection of methotrexate (MTX) and 7 days systemic corticosteroids, an increase in CSF-Tau was observed, and accompanied with increase of both CSF-P-Tau and CSF-NM. While CSF-Tau remained high during induction treatment, CSF-P-Tau, and CSF-NM decreased. CONCLUSION: Neurodegenerative markers do not vary with age. The different protein profiles suggest that the neurotoxicity from the prephase, which results in an increase of CSF-Tau, CSF-P-Tau, and CSF-NM, may have a different mechanism to the neurotoxicity induced later during induction treatment, when only CSF-Tau remains high.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/cerebrospinal fluid , Antineoplastic Combined Chemotherapy Protocols/toxicity , Precursor Cell Lymphoblastic Leukemia-Lymphoma/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Adolescent , Adrenal Cortex Hormones/cerebrospinal fluid , Adrenal Cortex Hormones/toxicity , Age Factors , Biomarkers/cerebrospinal fluid , Chi-Square Distribution , Child , Child, Preschool , Female , Humans , Infant , Linear Models , Male , Methotrexate/cerebrospinal fluid , Methotrexate/toxicity , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Statistics, Nonparametric
10.
J Addict Dis ; 11(4): 9-19, 1992.
Article in English | MEDLINE | ID: mdl-1336674

ABSTRACT

The pathophysiologic effects of cocaine on neuronal, pulmonary, and cardiovascular tissue are related to the drug's interaction with select catecholamine and neuroendocrine systems. Cocaine has been shown to alter circulating levels of the neurotransmitters, dopamine, norepinephrine, epinephrine, as well as the hypothalamic-pituitary-adrenal axis hormones corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cortisol. Furthermore, brain and lung tissue have been identified as primary sites of cocaine sequestration and metabolism. This paper reviews evidence suggesting that steroid-potentiated actions of catecholamines on vascular tissues contributes to the etiology of cocaine-related medical complications, including ischemic stroke, coronary ischemia, and ischemia-based renal failure.


Subject(s)
Brain/drug effects , Catecholamines/pharmacokinetics , Cocaine/adverse effects , Heart/drug effects , Lung/drug effects , Substance-Related Disorders/physiopathology , Adrenal Cortex Hormones/cerebrospinal fluid , Adrenal Cortex Hormones/pharmacokinetics , Adrenocorticotropic Hormone/analysis , Blood-Brain Barrier , Brain/metabolism , Brain/physiopathology , Cocaine/metabolism , Female , Heart/physiopathology , Humans , Lung/metabolism , Lung/physiopathology , Male
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