Investigating the effectiveness of oral ketamine on pain, mood and quality of life in treatment resistant chronic pain.

Introduction: Chronic pain is defined as pain lasting longer than 3 months. This often causes persistent emotional distress and functional disability that is refractory to conventional treatments. Emerging evidence suggests that oral Ketamine therapy may have a specific role in managing treatment-resistant chronic pain. This study aimed to assess the effectiveness of oral ketamine within a tertiary chronic pain management clinic. Methods: This study was a clinic-based retrospective descriptive study of 79 patients with a broad range of chronic pain diagnoses and treated with oral ketamine over a period up to 12 years. Changes in pain, mood and quality of life (QoL) were assessed using a numerical pain severity score, the Brief Pain Inventory (BPI), the Public Health Questionnaire (PHQ-9) and American Chronic Pain Association Quality of Life (QoL) scale. Results: 73 patients were accessible for follow-up (mean daily dose and treatment duration were 193.84 mg and 22.6 months respectively). Pain scores decreased (p < 0.0001) on both numerical scores (41.6% decrease) and BPI scoring (mean decrease 2.61). Mood improved (p < 0.0001) across both PHQ-9 and BPI measurements. Patients also reported less difficulty with daily activities and improved QoL. The most common adverse reaction was drowsiness (21.9%), with 30.1% reporting no adverse reactions from Ketamine. Discussion: This work adds to the growing body of evidence that under the supervision of a pain specialist, oral ketamine therapy may be a safe, tolerable and effective treatment for chronic pain conditions which have not responded to other management options. Further research is required to produce a more accurate understanding of its chronic use. Key message: This real-world study shows that patients being treated with oral ketamine for chronic pain report decreased severity of pain, improved mood and increased quality of life across all conditions.

A Pilot Study of Adolescents with Psychotic Experiences: Potential Cerebellar Circuitry Disruption Early Along the Psychosis Spectrum.

A berrant connectivity in the cerebellum has been found in psychotic conditions such as schizophrenia corresponding with cognitive and motor deficits found in these conditions. Diffusion differences in the superior cerebellar peduncles, the white matter connecting the cerebellar circuitry to the rest of the brain, have also been found in schizophrenia and high-risk states. However, white matter diffusivity in the peduncles in individuals with sub-threshold psychotic experiences (PEs) but not reaching the threshold for a definitive diagnosis remains unstudied. This study investigates the cerebellar peduncles in adolescents with PEs but no formal psychiatric diagnosis.Sixteen adolescents with PEs and 17 age-matched controls recruited from schools underwent High-Angular-Resolution-Diffusion neuroimaging. Following constrained spherical deconvolution whole-brain tractography, the superior, inferior and middle peduncles were isolated and virtually dissected out using ExploreDTI. Differences for macroscopic and microscopic tract metrics were calculated using one-way between-group analyses of covariance controlling for age, sex and estimated Total Intracranial Volume (eTIV). Multiple comparisons were corrected using Bonferroni correction.A decrease in fractional anisotropy was identified in the right (p = 0.045) and left (p = 0.058) superior cerebellar peduncle; however, this did not survive strict Bonferroni multiple comparison correction. There were no differences in volumes or other diffusion metrics in either the middle or inferior peduncles.Our trend level changes in the superior cerebellar peduncle in a non-clinical sample exhibiting psychotic experiences complement similar but more profound changes previously found in ultra-high-risk individuals and those with psychotic disorders. This suggests that superior cerebellar peduncle circuitry perturbations may occur early along in the psychosis spectrum.

Microstructural changes along the cingulum in young adolescents with psychotic experiences: An along-tract analysis.

Psychotic experiences (PEs) such as hallucinations and delusions are common among young people without psychiatric diagnoses and are associated with connectivity and white matter abnormalities, particularly in the limbic system. Using diffusion magnetic resonance imaging (MRI) in adolescents with reported PEs and matched controls, we examined the cingulum white matter tract along its length rather than as the usually reported single indivisible structure. Complex regional differences in diffusion metrics were found along the bundle at key loci following Bonferroni significance adjustment (p < .00013) with moderate to large effect sizes (.11-.76) throughout all significant subsegments. In this prospective community-based cohort of school-age children, these findings suggest that white matter alterations in the limbic system may be more common in the general non-clinical adolescent population than previously thought. Such white matter alternations may only be uncovered using a similar more granular along-tract analysis of white matter tracts.

Childhood Trauma, the HPA Axis and Psychiatric Illnesses: A Targeted Literature Synthesis.

Studies of early life stress (ELS) demonstrate the long-lasting effects of acute and chronic stress on developmental trajectories. Such experiences can become biologically consolidated, creating individual vulnerability to psychological and psychiatric issues later in life. The hippocampus, amygdala, and the medial prefrontal cortex are all important limbic structures involved in the processes that undermine mental health. Hyperarousal of the sympathetic nervous system with sustained allostatic load along the Hypothalamic Pituitary Adrenal (HPA) axis and its connections has been theorized as the basis for adult psychopathology following early childhood trauma. In this review we synthesize current understandings and hypotheses concerning the neurobiological link between childhood trauma, the HPA axis, and adult psychiatric illness. We examine the mechanisms at play in the brain of the developing child and discuss how adverse environmental stimuli may become biologically incorporated into the structure and function of the adult brain via a discussion of the neurosequential model of development, sensitive periods and plasticity. The HPA connections and brain areas implicated in ELS and psychopathology are also explored. In a targeted review of HPA activation in mood and psychotic disorders, cortisol is generally elevated across mood and psychotic disorders. However, in bipolar disorder and psychosis patients with previous early life stress, blunted cortisol responses are found to awakening, psychological stressors and physiological manipulation compared to patients without previous early life stress. These attenuated responses occur in bipolar and psychosis patients on a background of increased cortisol turnover. Although cortisol measures are generally raised in depression, the evidence for a different HPA activation profile in those with early life stress is inconclusive. Further research is needed to explore the stress responses commonalities between bipolar disorder and psychosis in those patients with early life stress.

MRI volumetric changes in hippocampal subfields in psychosis: a protocol for a systematic review and meta-analysis.

BACKGROUND: The hippocampus has for long been known for its ability to form new, declarative memory. However, emerging findings across conditions in the psychosis spectrum also implicate its role in emotional regulation. Systematic reviews have demonstrated consistent volume atrophic changes in the hippocampus. The aim of the systematic review and metanalysis which will follow from this protocol will be to investigate the volume-based neuroimaging findings across each of the subfields of the hippocampus in psychosis independent of diagnosis. METHODS: Volume changes across subfields of the hippocampus in psychotic illnesses will be assessed by systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). MRI neuroimaging studies of patients with a definitive diagnosis of psychosis (including brief pre-diagnostic states) will be included. Studies lacking adequate controls, illicit drug use, medical psychosis, history of other significant psychiatric comorbidities, or emphasis on age groups above 65 or below 16 will be excluded. Subfields investigated will include the CA1, CA2/3, CA4, subiculum, presubiculum, parasubiculum, dentate gyrus, stratum, molecular layer, granular cell layer, entorhinal cortex, and fimbria. Two people will independently screen abstracts from the output of the search to select suitable studies. This will be followed by the two reviewers performing a full-text review of the studies which were selected based on suitable abstracts. One reviewer will independently perform all the data extraction, and another reviewer will then systemically check all the extracted information using the original articles to ensure accuracy. Statistical analysis will be performed using the metafor and meta-packages in R Studio with the application of the random-effects model. DISCUSSION: This study will provide insight into the volumetric changes in psychosis of the subfields of the hippocampus, independent of diagnosis. This may shed light on the intricate neural pathology which encompasses psychosis and will open avenues for further exploration of the structures identified as potential drivers of volume change. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020199558.

Amygdala substructure volumes in Major Depressive Disorder.

The role of the amygdala in the experience of emotional states and stress is well established. Connections from the amygdala to the hypothalamus activate the hypothalamic-pituitaryadrenal (HPA) axis and the cortisol response. Previous studies have failed to find consistent whole amygdala volume changes in Major Depressive Disorder (MDD), but differences may exist at the smaller substructural level of the amygdala nuclei. High-resolution T1 and T2-weighted-fluid-attenuated inversion recovery MRIs were compared between 80 patients with MDD and 83 healthy controls (HC) using the automated amygdala substructure module in FreeSurfer 6.0. Volumetric assessments were performed for individual nuclei and three anatomico-functional composite groups of nuclei. Salivary cortisol awakening response (CAR), as a measure of HPA responsivity, was measured in a subset of patients. The right medial nucleus volume was larger in MDD compared to HC (p = 0.002). Increased right-left volume ratios were found in MDD for the whole amygdala (p = 0.004), the laterobasal composite (p = 0.009) and in the central (p = 0.003) and medial (p = 0.014) nuclei. The CAR was not significantly different between MDD and HC. Within the MDD group the left corticoamygdaloid transition area was inversely correlated with the CAR, as measured by area under the curve (AUCg) (p ≤ 0.0001). In conclusion, our study found larger right medial nuclei volumes in MDD compared to HC and relatively increased right compared to left whole and substructure volume ratios in MDD. The results suggest that amygdala substructure volumes may be involved in the pathophysiology of depression.

Blame it on the pump.

Although intrathecal pumps may lead to spinal symptoms that are likely related to the pump itself, the case presented herein underscores the importance of casting a broad differential diagnosis at the time of initial presentation.

Hippocampal and Amygdalar Volume Changes in Major Depressive Disorder: A Targeted Review and Focus on Stress.

Medial temporal lobe structures have long been implicated in the pathogenesis of major depressive disorder. Although findings of smaller hippocampal and amygdalar volumes are common, inconsistencies remain in the literature. In this targeted review, we examine recent and significant neuroimaging papers examining the volumes of these structures in major depressive disorder. A targeted PubMed/Google Scholar search was undertaken focusing on volumetric neuroimaging studies of the hippocampus and amygdala in major depressive disorder. Where possible, mean volumes and accompanying standard deviations were extracted allowing computation of Cohen's ds effect sizes. Although not a meta-analysis, this allows a broad comparison of volume changes across studies. Thirty-nine studies in total were assessed. Hippocampal substructures and amygdale substructures were investigated in 11 and 2 studies, respectively. The hippocampus was more consistently smaller than the amygdala across studies, which is reflected in the larger cumulative difference in volume found with the Cohen's ds calculations. The left and right hippocampi were, respectively, 92% and 91.3% of the volume found in controls, and the left and right amygdalae were, respectively, 94.8% and 92.6% of the volume of controls across all included studies. The role of stress in temporal lobe structure volume reduction in major depressive disorder is discussed.

Untangling the dorsal diencephalic conduction system: a review of structure and function of the stria medullaris, habenula and fasciculus retroflexus.

The often-overlooked dorsal diencephalic conduction system (DDCS) is a highly conserved pathway linking the basal forebrain and the monoaminergic brainstem. It consists of three key structures; the stria medullaris, the habenula and the fasciculus retroflexus. The first component of the DDCS, the stria medullaris, is a discrete bilateral tract composed of fibers from the basal forebrain that terminate in the triangular eminence of the stalk of the pineal gland, known as the habenula. The habenula acts as a relay hub where incoming signals from the stria medullaris are processed and subsequently relayed to the midbrain and hindbrain monoaminergic nuclei through the fasciculus retroflexus. As a result of its wide-ranging connections, the DDCS has recently been implicated in a wide range of behaviors related to reward processing, aversion and motivation. As such, an understanding of the structure and connections of the DDCS may help illuminate the pathophysiology of neuropsychiatric disorders such as depression, addiction and pain. This is the first review of all three components of the DDCS, the stria medullaris, the habenula and the fasciculus retroflexus, with particular focus on their anatomy, function and development.

Magnetic resonance diffusion weighted imaging using constrained spherical deconvolution-based tractography of the extracranial course of the facial nerve.

OBJECTIVE: To evaluate the accuracy of magnetic resonance diffusion weighted imaging (DWI) featuring constrained spherical deconvolution-based tractography in tracking the extracranial course of the facial nerve to provide a reliable facial nerve map to facilitate well-tolerated and effective tumor resection. STUDY DESIGN: Magnetic resonance DWI was conducted on 2 parotid-healthy cadaveric patients with various protocols to identify the best representation of the extracranial facial nerve tract. This was subsequently correlated to dissection of the facial nerves to ascertain anatomic validation. These protocols were applied to 2 live, parotid-healthy patients to assess feasibility of in vivo facial nerve tract identification. RESULTS: Correlations between imaged tracts and the anatomic course of the extracranial facial nerve were identified to an accuracy of 1 mm. The main trunk and bifurcation tracts were identified on imaging. Fractional anisometry values in cadaveric and live patients were within the range expected for the facial nerve within the parotid gland. CONCLUSIONS: Our results indicated the potential for accurate 3-dimensional visualization of the extracranial course of the facial nerve, which could have diagnostic implications in differentiating benign from malignant tumors and, crucially, neural involvement. Preoperative planning applications of DWI could help in planning surgical approaches and providing focused counseling.

Magnetic resonance spectroscopy across chronic pain disorders: a systematic review protocol synthesising anatomical and metabolite findings in chronic pain patients.

BACKGROUND: Chronic pain is pain greater than 3 months duration that may result from disease, trauma, surgery, or unknown origin. The overlap between the psychological, behavioural, and management aspects of pain suggest that limbic brain neurochemistry plays a role in chronic pain pathology. Proton magnetic resonance spectroscopy (1H-MRS) can evaluate in vivo brain metabolites including creatine, N-acetylaspartate, myo-inositol, choline, glutamate, glutamine, and gamma-aminobutyric acid in chronic pain; however, a comprehensive systemic review of metabolite expression patterns across all brain areas has yet to be performed. METHODS AND ANALYSIS: Online databases including PubMed/MEDLINE, Google Scholar, EMBASE, the Cochrane Library, OVID, and PsycINFO will be searched for articles relating to 1H-MRS and chronic pain. Study inclusion criteria will include ages of between 18 and 65 years with a definite diagnosis of chronic pain, no comorbidities, clearly stated brain volumes of interest, and imaging protocols, with comparisons to healthy controls. Two reviewers will extract data relating to volumes of interest, metabolites, study participant demographics, diagnostic method and pain scores, treatments and duration of treatment, scanner information, 1H-MRS acquisition protocols, and spectral processing software. Where possible, volumes of interest will be reassigned as regions of interest consistent with known regional anatomical and functional properties to increase the power and relevance of the analysis. Statistical analyses will then be conducted using STATA. A central common pathway may exist for chronic pain due to the behavioural manifestations and management similarities between its different types. The goal of this systemic review is to generate a comprehensive neurochemical theory of chronic pain in different brain compartments. SYSTEMATIC REVIEW REGISTRATION: This study is registered with PROSPERO CRD42018112640.

Papez's Forgotten Tract: 80 Years of Unreconciled Findings Concerning the Thalamocingulate Tract.

The thalamocingulate tract is a key component of the Papez circuit that connects the anterior thalamic nucleus (ATN) to the cingulum bundle. While the other white matter connections, consisting of the fornix, cingulum bundle and mammillothalamic tract, were well defined in Papez's original 1937 paper, the anatomy of the thalamocingulate pathway was mentioned only in passing. Subsequent research has been unable to clarify the precise anatomical trajectory of this tract. In particular, the site of thalamocingulate tract interactions with the cingulum bundle have been inconsistently reported. This review aims to synthesize research on this least studied component of the Papez circuit. A systemic approach to reviewing historical anatomical dissection and neuronal tracing studies as well as contemporary diffusion magnetic resonance imaging studies of the thalamocingulate tract was undertaken across species. We found that although inconsistent, prior research broadly encompasses two differing descriptions of how the ATN interfaces with the cingulum after passing laterally through the anterior limb of the internal capsule. The first group of studies show that the pathway turns medially and rostrally and passes to the anterior cingulate region (Brodmann areas 24, 33, and 32) only. A second group suggests that the thalamocingulate tract interfaces with both the anterior and posterior cingulate (Brodmann areas 23 and 31) and retrosplenial region (Brodmann area 29). We discuss potential reasons for these discrepancies such as altering methodologies and species differences. We also discuss how these inconsistencies may be resolved in further research with refinements of terminology for the cingulate cortex and the thalamocingulate tract. Understanding the precise anatomical course of the last remaining unresolved final white matter tract in the Papez circuit may facilitate accurate investigation of the role of the complete Papez circuit in emotion and memory.

The Hippocampus in Depression: More Than the Sum of Its Parts? Advanced Hippocampal Substructure Segmentation in Depression.

BACKGROUND: Hippocampal volume reduction is the most replicated finding in neuroimaging studies of major depressive disorder (MDD). Varying hippocampal volume definition is a well-established problem in this field. Given that hippocampal function can be mapped onto anatomically defined substructures and that detailed examination of substructure volumes is now possible, we examined different hippocampal composite measures in MDD to look for hippocampal markers of MDD. METHODS: Magnetic resonance imaging brain scans were compared between 80 patients with a range of MDD duration and 83 healthy control subjects. High-resolution T1-weighted and T2-weighted-fluid-attenuated inversion recovery magnetic resonance images were examined using the automated hippocampal substructure module in FreeSurfer 6.0. Between-group volumetric assessments were performed at substructure and composite substructures levels. RESULTS: Patients with MDD showed a bilateral pattern of volume reduction in principal hippocampal substructures: the cornu ammonis (CA1-CA4), dentate gyrus, and subiculum. Changes were more pronounced on the left of these structures and in recurrent depression. CA2 to CA4 were the only substructures reduced in first-presentation depression. Overall changes were most marked in the left CA1, and CA1 volume was a predictor of illness duration. CONCLUSIONS: Hippocampal involvement in MDD is confined to principal substructures only. Differences between patients with MDD and healthy control subjects increased with progressively restricted hippocampal definitions, with the left CA1 emerging as a potential marker of MDD. Changes were more extensive in patients with recurrent, as opposed to first-presentation, MDD, suggesting a hippocampal disease process. These findings identify core hippocampal regions in the pathology of MDD, suggesting a potential marker of disease progression in MDD.

A comprehensive regional neurochemical theory in depression: a protocol for the systematic review and meta-analysis of 1H-MRS studies in major depressive disorder.

BACKGROUND: Magnetic resonance spectroscopy (MRS) is a non-invasive analytical technique that investigates the presence and concentrations of brain metabolites. In the context of major depressive disorder (MDD), MRS has revealed regional biochemical changes in GABA, glutamate, and choline across different brain compartments. Technical and methodological advances in MRS data acquisition, in particular proton-based 1H-MRS, have resulted in a significant increase in the incidence of reports utilizing the technique for psychiatric disorder research and diagnosis. The most recent comprehensive meta-analysis reviewing MRS in MDD stems from 2006. Using contemporary systemic reviews and meta-analysis, the aim is to first test a neurochemical circuit-based theory of depression and then to determine if clinical scores relate to metabolite concentrations before and during treatment. METHODS: Region-specific metabolite changes in MDD will be assessed by systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Inclusion criteria will include participant age (18 to 65), English language studies, known regions of interest, and detailed documentation of 1H-MRS procedures. Reported brain regions will be standardized according neuroanatomical expertise allowing increased power of the meta-analysis. Regions of interest will initially include the hippocampus, thalamus, prefrontal cortex, anterior and posterior cingulate gyri, parietal lobe, and basal ganglia. Exclusion criteria will include comorbid psychiatric illness and drug use. Two independent reviewers will undertake all data extraction, while a third reviewer will check for reviewer discrepancies. Statistical analysis will be performed using STATA supplemented by Metan software and SPSS. DISCUSSION: This data will shed new light on the biochemical basis of depression in different brain regions, thereby highlighting the potential of MRS in identifying biomarkers and generating models of MDD and treatment response. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018091494.

Guía práctica de tratamiento urgente de la microangiopatía trombótica / Practice guidelines for the emergency treatment of thrombotic microangiopathy

Antecedentes y objetivo: El término microangiopatía trombótica (MAT) incluye un grupo heterogéneo de enfermedades potencialmente mortales o invalidantes, rápidamente evolutivas, caracterizadas por anemia hemolítica microangiopática y trombocitopenia. La actuación en las primeras horas es crucial para mejorar el pronóstico de los pacientes. El objetivo de esta revisión es proporcionar recomendaciones orientadas a optimizar el tratamiento inicial de la MAT y agilizar el diagnóstico etiológico. Pacientes y métodos: Se diseña una guía práctica en la cual se diferencian cuatro apartados en el abordaje inicial de las MAT: sospecha diagnóstica, confirmación sindrómica, tratamiento urgente y estudios complementarios. Resultados: La detección de anemia hemolítica microangiopática (caracterizada por aumento de reticulocitos, LDH y bilirrubina indirecta, Coombs directo negativo y esquistocitos en el frotis de sangre periférica) y trombocitopenia no justificable por otras causas secundarias confirma el diagnóstico sindrómico de anemia hemolítica microangiopática y trombocitopenia (AHMAT). Estos pacientes requieren ingreso en la unidad de cuidados intensivos para iniciar lo antes posible el recambio plasmático, preferiblemente en las primeras 4-8h. Antes de realizar el recambio plasmático deben extraerse las muestras para el estudio de ADAMTS13 y de complemento. Finalmente, es importante solicitar las pruebas complementarias necesarias para obtener un correcto diagnóstico etiológico. Conclusiones: La puesta en práctica de las recomendaciones consensuadas en esta guía permitirá mejorar los resultados terapéuticos al facilitar la cooperación de los distintos especialistas implicados en la atención de las MAT

Background and aim: The term thrombotic microangiopathy (TMA) involves a heterogeneous group of diseases that can be overwhelming or invalidating, with an acute development, characterised by microangiopathic haemolytic anaemia and thrombocytopaenia. Its management during its initial hours is essential to improving the prognostic of these patients. The aim of this review is to give recommendations about the optimisation of TMA initial treatment and to accelerate the aetiological diagnosis. Patients and methods: We provide a practice guideline based on four steps for the initial management of TMA: diagnosis of suspicion, syndromic confirmation, emergent treatment and complementary tests. Results: The detection of microangiopathic haemolytic anaemia (characterised by elevated reticulocytes, LDH and indirect bilirubin, negative direct Coombs test and schistocytes in peripheral blood), and thrombocytopaenia not explained by other secondary aetiologies confirm the syndromic diagnosis of microangiopathic haemolytic anaemia and thrombocytopaenia (MAHAT). These patients require admission to an Intensive Care Unit to initiate plasma exchange therapy as soon as possible, ideally within the first 4-8hours. Prior to this, samples for ADAMTS13 and complement study should be obtained. Finally, it is important to request the complementary tests necessary to have a correct aetiological diagnosis. Conclusions: Adherence to the agreed recommendations in this guideline will improve therapeutic results by facilitating cooperation between different specialists involved in TMA management

Awakening Neuropsychiatric Research Into the Stria Medullaris: Development of a Diffusion-Weighted Imaging Tractography Protocol of This Key Limbic Structure.

The Stria medullaris (SM) Thalami is a discrete white matter tract that directly connects frontolimbic areas to the habenula, allowing the forebrain to influence midbrain monoaminergic output. Habenular dysfunction has been shown in various neuropsychiatric conditions. However, there exists a paucity of research into the habenula's principal afferent tract, the SM. Diffusion-weighted tractography may provide insights into the properties of the SM in vivo, opening up investigation of this tract in conditions of monoamine dysregulation such as depression, schizophrenia, addiction and pain. We present a reliable method for reconstructing the SM using diffusion-weighted imaging, and examine the effects of age and gender on tract diffusion metrics. We also investigate reproducibility of the method through inter-rater comparisons. In consultation with neuroanatomists, a Boolean logic gate protocol was developed for use in ExploreDTI to extract the SM from constrained spherical deconvolution based whole brain tractography. Particular emphasis was placed on the reproducibility of the tract, attention to crossing white matter tract proximity and anatomical consistency of anterior and posterior boundaries. The anterior commissure, pineal gland and mid point of the thalamus were defined as anatomical fixed points used for reconstruction. Fifty subjects were scanned using High Angular Resolution Diffusion Imaging (HARDI; 61 directions, b-value 1500 mm3). Following constrained spherical deconvolution whole brain tractography, two independent raters isolated the SM. Each output was checked, examined and cleaned for extraneous streamlines inconsistent with known anatomy of the tract by the rater and a neuroanatomist. A second neuroanatomist assessed tracts for face validity. The SM was reconstructed with excellent inter-rater reliability for dimensions and diffusion metrics. Gender had no effect on the dimensions or diffusion metrics, however radial diffusivity (RD) showed a positive correlation with age. Reliable identification and quantification of diffusion metrics of the SM invites further exploration of this key habenula linked structure in neuropsychiatric disorders such as depression, anxiety, chronic pain and addiction. The accurate anatomical localization of the SM may also aid preoperative stereotactic localization of the tract for deep brain stimulation (DBS) treatment.

Practice guidelines for the emergency treatment of thrombotic microangiopathy. / Guía práctica de tratamiento urgente de la microangiopatía trombótica.

BACKGROUND AND AIM: The term thrombotic microangiopathy (TMA) involves a heterogeneous group of diseases that can be overwhelming or invalidating, with an acute development, characterised by microangiopathic haemolytic anaemia and thrombocytopaenia. Its management during its initial hours is essential to improving the prognostic of these patients. The aim of this review is to give recommendations about the optimisation of TMA initial treatment and to accelerate the aetiological diagnosis. PATIENTS AND METHODS: We provide a practice guideline based on four steps for the initial management of TMA: diagnosis of suspicion, syndromic confirmation, emergent treatment and complementary tests. RESULTS: The detection of microangiopathic haemolytic anaemia (characterised by elevated reticulocytes, LDH and indirect bilirubin, negative direct Coombs test and schistocytes in peripheral blood), and thrombocytopaenia not explained by other secondary aetiologies confirm the syndromic diagnosis of microangiopathic haemolytic anaemia and thrombocytopaenia (MAHAT). These patients require admission to an Intensive Care Unit to initiate plasma exchange therapy as soon as possible, ideally within the first 4-8hours. Prior to this, samples for ADAMTS13 and complement study should be obtained. Finally, it is important to request the complementary tests necessary to have a correct aetiological diagnosis. CONCLUSIONS: Adherence to the agreed recommendations in this guideline will improve therapeutic results by facilitating cooperation between different specialists involved in TMA management.

Efectos adversos de la acumulación renal de hemoproteínas. Nuevas herramientas terapéuticas / Adverse effects of the renal accumulation of haem proteins. Novel therapeutic approaches

La hemoglobina y la mioglobina son hemoproteínas que juegan un papel fundamental en el organismo ya que participan en el transporte de oxígeno. Sin embargo, debido a su estructura química, estas moléculas pueden ejercer efectos deletéreos cuando se liberan al torrente sanguíneo de forma masiva, como sucede en determinadas condiciones patológicas asociadas a rabdomiólisis o hemólisis intravascular. Una vez en el plasma, estas hemoproteínas se pueden filtrar y acumular en el riñón, donde resultan citotóxicas, principalmente para el epitelio tubular, e inducen fracaso renal agudo y enfermedad renal crónica. En la presente revisión analizaremos los distintos contextos patológicos que provocan la acumulación renal de estas hemoproteínas, su relación con la pérdida de función renal a corto y largo plazo, los mecanismos fisiopatólogicos responsables de sus efectos adversos y los sistemas de defensa que contrarrestan tales acciones. Por último, describiremos los distintos tratamientos utilizados actualmente y mostraremos nuevas opciones terapéuticas basadas en la identificación de nuevas dianas celulares y moleculares, prestando especial atención a los diversos ensayos clínicos que se encuentran en marcha en la actualidad (AU)

Haemoglobin and myoglobin are haem proteins that play a key role as they help transport oxygen around the body. However, because of their chemical structure, these molecules can exert harmful effects when they are released massively into the bloodstream, as reported in certain pathological conditions associated with rhabdomyolysis or intravascular haemolysis. Once in the plasma, these haem proteins can be filtered and can accumulate in the kidney, where they become cytotoxic, particularly for the tubular epithelium, inducing acute kidney failure and chronic kidney disease. In this review, we will analyse the different pathological contexts that lead to the renal accumulation of these haem proteins, their relation to both acute and chronic loss of renal function, the pathophysiological mechanisms that cause adverse effects and the defence systems that counteract such actions. Finally, we will describe the different treatments currently used and present new therapeutic options based on the identification of new cellular and molecular targets, with particular emphasis on the numerous clinical trials that are currently ongoing (AU)

Adverse effects of the renal accumulation of haem proteins. Novel therapeutic approaches. / Efectos adversos de la acumulación renal de hemoproteínas. Nuevas herramientas terapéuticas.

Haemoglobin and myoglobin are haem proteins that play a key role as they help transport oxygen around the body. However, because of their chemical structure, these molecules can exert harmful effects when they are released massively into the bloodstream, as reported in certain pathological conditions associated with rhabdomyolysis or intravascular haemolysis. Once in the plasma, these haem proteins can be filtered and can accumulate in the kidney, where they become cytotoxic, particularly for the tubular epithelium, inducing acute kidney failure and chronic kidney disease. In this review, we will analyse the different pathological contexts that lead to the renal accumulation of these haem proteins, their relation to both acute and chronic loss of renal function, the pathophysiological mechanisms that cause adverse effects and the defence systems that counteract such actions. Finally, we will describe the different treatments currently used and present new therapeutic options based on the identification of new cellular and molecular targets, with particular emphasis on the numerous clinical trials that are currently ongoing.

Podocytes are new cellular targets of haemoglobin-mediated renal damage.

Recurrent and massive intravascular haemolysis induces proteinuria, glomerulosclerosis, and progressive impairment of renal function, suggesting podocyte injury. However, the effects of haemoglobin (Hb) on podocytes remain unexplored. Our results show that cultured human podocytes or podocytes isolated from murine glomeruli bound and endocytosed Hb through the megalin-cubilin receptor system, thus resulting in increased intracellular Hb catabolism, oxidative stress, activation of the intrinsic apoptosis pathway, and altered podocyte morphology, with decreased expression of the slit diaphragm proteins nephrin and synaptopodin. Hb uptake activated nuclear factor erythroid-2-related factor 2 (Nrf2) and induced expression of the Nrf2-related antioxidant proteins haem oxygenase-1 (HO-1) and ferritin. Nrf2 activation and Hb staining was observed in podocytes of mice with intravascular haemolysis. These mice developed proteinuria and showed podocyte injury, characterized by foot process effacement, decreased synaptopodin and nephrin expression, and podocyte apoptosis. These pathological effects were enhanced in Nrf2-deficient mice, whereas Nrf2 activation with sulphoraphane protected podocytes against Hb toxicity both in vivo and in vitro. Supporting the translational significance of our findings, we observed podocyte damage and podocytes stained for Hb, HO-1, ferritin and phosphorylated Nrf2 in renal sections and urinary sediments of patients with massive intravascular haemolysis, such as atypical haemolytic uraemic syndrome and paroxysmal nocturnal haemoglobinuria. In conclusion, podocytes take up Hb both in vitro and during intravascular haemolysis, promoting oxidative stress, podocyte dysfunction, and apoptosis. Nrf2 may be a potential therapeutic target to prevent loss of renal function in patients with intravascular haemolysis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.