Perturbations in the apoptotic pathway and mitochondrial network dynamics in peripheral blood mononuclear cells from bipolar disorder patients.

Bipolar disorder (BD) is a severe psychiatric disorder characterized by phasic changes of mood and can be associated with progressive structural brain change and cognitive decline. The numbers and sizes of glia and neurons are reduced in several brain areas, suggesting the involvement of apoptosis in the pathophysiology of BD. Because the changes in mitochondrial dynamics are closely related with the early process of apoptosis and the specific processes of apoptosis and mitochondrial dynamics in BD have not been fully elucidated, we measured the apoptotic pathway and the expression of mitochondrial fission/fusion proteins from BD patients and healthy controls. We recruited 16 patients with BD type I and sixteen well-matched healthy controls and investigated protein levels of several pro-apoptotic and anti-apoptotic factors, as well as the expression of mitochondrial fission/fusion proteins in peripheral blood mononuclear cells (PBMCs). Our results showed that the levels of the anti-apoptotic proteins Bcl-xL, survivin and Bcl-xL/Bak dimer were significantly decreased, while active caspase-3 protein levels were significantly increased in PBMCs from BD patients. Moreover, we observed the downregulation of the mitochondrial fusion-related proteins Mfn2 and Opa1 and the upregulation of the fission protein Fis1 in PBMCs from BD patients, both in terms of gene expression and protein levels. We also showed a significantly decrease in the citrate synthase activity. Finally, we found a positive correlation between Mfn2 and Opa1 with mitochondrial content markers, as well as a negative correlation between mitochondrial fission/fusion proteins and apoptotic markers. Overall, data reported here are consistent with the working hypothesis that apoptosis may contribute to cellular dysfunction, brain volume loss and progressive cognitive in BD. Moreover, we show an important relationship between mitochondrial dynamics and the cell death pathway activation in BD patients, supporting the link between mitochondrial dysfunction and the pathophysiology of BD.

Integrated transcriptome and methylome analysis in youth at high risk for bipolar disorder: a preliminary analysis.

First-degree relatives of patients with bipolar disorder (BD), particularly their offspring, have a higher risk of developing BD and other mental illnesses than the general population. However, the biological mechanisms underlying this increased risk are still unknown, particularly because most of the studies so far have been conducted in chronically ill adults and not in unaffected youth at high risk. In this preliminary study we analyzed genome-wide expression and methylation levels in peripheral blood mononuclear cells from children and adolescents from three matched groups: BD patients, unaffected offspring of bipolar parents (high risk) and controls (low risk). By integrating gene expression and DNA methylation and comparing the lists of differentially expressed genes and differentially methylated probes between groups, we were able to identify 43 risk genes that discriminate patients and high-risk youth from controls. Pathway analysis showed an enrichment of the glucocorticoid receptor (GR) pathway with the genes MED1, HSPA1L, GTF2A1 and TAF15, which might underlie the previously reported role of stress response in the risk for BD in vulnerable populations. Cell-based assays indicate a GR hyporesponsiveness in cells from adult BD patients compared to controls and suggest that these GR-related genes can be modulated by DNA methylation, which poses the theoretical possibility of manipulating their expression as a means to counteract the familial risk presented by those subjects. Although preliminary, our results suggest the utility of peripheral measures in the identification of biomarkers of risk in high-risk populations and further emphasize the potential role of stress and DNA methylation in the risk for BD in youth.

Newer insights into the role of miRNA a tiny genetic tool in psychiatric disorders: focus on post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a mental disorder occurring in about 2-9% of individuals after their exposure to life-threatening events, such as severe accidents, sexual abuse, combat or a natural catastrophe. Because PTSD patients are exposed to trauma, it is likely that epigenetic modifications have an important role in disease development and prognosis. For the past two decades, abnormal expression of the epigenetic regulators microRNAs (miRs) and miR-mediated gene regulation have been given importance in a variety of human diseases, such as cancer, heart disease and viral infection. Emerging evidence supports a role for miR dysregulation in psychiatric and neurological disorders, including schizophrenia, bipolar disorder, anxiety, major depressive disorder, autism spectrum disorder and Tourette's syndrome. Recently mounting of evidence supports the role of miR both in preclinical and clinical settings of psychiatric disorders. Abnormalities in miR expression can fine-tune the expression of multiple genes within a biological network, suggesting that miR dysregulation may underlie many of the molecular changes observed in PTSD pathogenesis. This provides strong evidence that miR not only has a critical role in PTSD pathogenesis, but can also open up new avenues for the development of diagnostic tools and therapeutic targets for the PTSD phenotype. In this review, we revisit some of the recent evidence associated with miR and PTSD in preclinical and clinical settings. We also discuss the possible clinical applications and future use of miRs in PTSD therapy.

Childhood trauma, family history, and their association with mood disorders in early adulthood.

OBJECTIVE: To assess the prevalence of childhood trauma and types of trauma on mood disorders among young adults in a population-based sample. We further gathered data on family history of mood disorders to test the hypothesis that childhood trauma is a mediating factor for the association between family history of mood disorder and mood disorder in adulthood. METHOD: This is a cross-sectional study, including young adults with bipolar disorder, major depressive disorder, and matched controls without any mood disorder. Childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). The Hicks and Tingley implementation was employed to assess whether trauma is a mediator of the effect of family history on diagnosis of any mood disorder. RESULTS: All types of trauma were associated with both major depression and bipolar disorder, with the exception of sexual abuse, which was only associated with bipolar disorder. Moreover, family history of psychiatric illness was also associated with mood disorder in adulthood and with childhood trauma. Using the presence of any mood disorder as the outcome, a third of the effect of having any family history of mood disorder was mediated via childhood trauma. CONCLUSION: This investigation provides further support, in a population-based sample of young adults, of the association between childhood trauma and mood disorders, with sexual abuse being specifically linked with bipolar disorder. The hypothesis that childhood trauma would function as a partial mediator of the association between family history of mood disorder and mood disorder in adulthood was also confirmed.

The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders.

Psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia, affect a significant percentage of the world population. These disorders are associated with educational difficulties, decreased productivity and reduced quality of life, but their underlying pathophysiological mechanisms are not fully elucidated. Recently, studies have suggested that psychiatric disorders could be considered as inflammatory disorders, even though the exact mechanisms underlying this association are not known. An increase in inflammatory response and oxidative stress may lead to inflammation, which in turn can stimulate microglia in the brain. Microglial activation is roused by the M1 phenotype, which is associated with an increase in interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). On the contrary, M2 phenotype is associated with a release of anti-inflammatory cytokines. Thus, it is possible that the inflammatory response from microglial activation can contribute to brain pathology, as well as influence treatment responses. This review will highlight the role of inflammation in the pathophysiology of psychiatric disorders, such as MDD, BD, schizophrenia, and autism. More specifically, the role of microglial activation and associated molecular cascades will also be discussed as a means by which these neuroinflammatory mechanisms take place, when appropriate.

Increased serum levels of eotaxin/CCL11 in late-stage patients with bipolar disorder: An accelerated aging biomarker?

BACKGROUND: Bipolar disorder (BD) is commonly comorbid with many medical disorders including atopy, and appears characterized by progressive social, neurobiological, and functional impairment associated with increasing number of episodes and illness duration. Early and late stages of BD may present different biological features and may therefore require different treatment strategies. Consequently, the aim of this study was to evaluate serum levels of eotaxin/CCL11, eotaxin-2/CCL24, IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, IFNγ, BDNF, TBARS, carbonyl, and GPx in a sample of euthymic patients with BD at early and late stages compared to controls. METHODS: Early-stage BD patients, 12 late-stage patients, and 25 controls matched for sex and age were selected. 10mL of peripheral blood was drawn from all subjects by venipuncture. Serum levels of BDNF, TBARS, carbonyl content, glutathione-peroxidase activity (GPx), cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α and IFNγ), and chemokines (eotaxin/CCL11 and eotaxin-2/CCL24) were measured. RESULTS: There were no demographic differences between patients and controls. No significant differences were found for any of the biomarkers, except chemokine eotaxin/CCL11, whose serum levels were higher in late-stage patients with BD when compared to controls (p=0.022; Mann-Whitney U test). LIMITATIONS: Small number of subjects and use of medication may have influenced in our results. CONCLUSION: The present study suggests a link between biomarkers of atopy and eosinophil function and bipolar disorder. These findings are also in line with progressive biological changes partially mediated by inflammatory imbalance, a process referred to as neuroprogression.

Damage-associated molecular patterns and immune activation in bipolar disorder.

OBJECTIVE: Immune activation in bipolar disorder (BD) has been frequently reported. Damage-associated molecular patterns (DAMPs) are key players in the immune activation reaction. The aim of this study was to assess DAMP levels in drug-free patients with BD during acute episodes. METHOD: Serum levels of a predetermined set of DAMPs were assessed in drug-free patients with BD (n = 20) during an acute mood episode. We also included two control groups: healthy subjects, used as a negative control (n = 20); and patients with sepsis, used as a positive control for severe immune activation (n = 20). RESULTS: Multivariate analysis using generalized linear mixed model indicated that all DAMPs differed as a function of group membership after controlling for age and addressing multiplicity (P < 0.0006 for all comparisons). Follow-up analyses showed higher levels in BD subjects of circulating cell-free (ccf) nuclear (n)DNA (P = 0.02), HSP70 (P = 0.03) and HSP90α (P = 0.02) as compared to healthy subjects. Also, patients with BD showed lower levels of ccf nDNA (P = 0.04), HSP60 (P = 0.03), HSP70 (P = 0.01), and HSP90α (P = 0.002) as compared to patients with sepsis and higher levels of ccf mitochondrial DNA (P < 0.0001). CONCLUSION: The present findings may be linked to the inflammatory activity previously described among patients with BD and may help in the development of more targeted and personalized treatments for patients under acute episodes of BD.

Brain-derived neurotrophic factor and inflammatory markers in school-aged children with early trauma.

OBJECTIVE: The impact of childhood trauma (CT) on brain-derived neurotrophic factor (BDNF) and cytokines levels remains unclear. We investigated the association between CT and changes in BDNF and cytokines plasma levels in children. METHOD: We recruited 36 children with trauma (CT+) and 26 children without trauma (CT-). The presence of CT was based on a clinical interview and by Criteria A of DSM-IV criteria for PTSD. Blood samples were drawn from all children to assess BDNF and cytokines. ancova was performed with psychiatric symptoms and BMI as covariates to evaluate group differences in plasma levels. RESULTS: CT+ showed increased levels of BDNF and TNF-α after excluding children with history of inflammatory disease (P<0.05) when compared with those CT-. IL-12p70, IL-6, IL-8, IL-10, and IL-1ß levels were not statistically different between groups. CONCLUSION: CT+ showed increased BDNF and proinflammatory cytokines levels. The increase in BDNF levels may be an attempt to neutralize the negative effects of CT, while an increase in TNF-a levels be associated with a proinflammatory state after CT. How these changes associated with trauma relate to other biological changes and illness trajectory later in life remain to be further studied.

Val66Met polymorphism and serum brain-derived neurotrophic factor in bipolar disorder: an open-label trial.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is consistently associated with acute mood episodes in bipolar disorder, but there is a lack of longitudinal data to support this hypothesis. In this 16-week open-label clinical trial, we tested the predictive role of BDNF Val66Met polymorphism on serum BDNF levels and the relationship of serum BDNF and clinical response in people with bipolar disorder during an acute illness episode. METHOD: Sixty-four people with bipolar disorder who were medication-free at baseline and in an acute mood episode were recruited. They were matched with 64 healthy controls. Clinical evaluation, serum BDNF, and BDNF Val66Met polymorphism were determined at baseline, and change in serum BDNF was assessed in patients at weeks 2, 4, 8 and 16. RESULTS: There were no differences between patients and controls in serum BDNF or in frequencies of the BDNF Val66Met polymorphism genotype at baseline. The multivariable model showed that Met carriers had a significantly different change in BDNF levels compared with Val homozygotes. Not achieving a complete remission was also associated with lower prospectively assessed BDNF levels. CONCLUSION: This study provides the first longitudinal evidence that both the BDNF Val66Met polymorphism and remission status predict change in circulating BDNF levels.

Symptomatic cysts of the cavum septi pellucidi and cavum vergae: the role of endoscopic neurosurgery in the treatment of four consecutive cases.

Cavum septi pellucidi and cavum vergae are generally asymptomatic fluid collections between the leaves of the septum pellucidum and are present in approximately 15 % of adult brains. These cavities rarely enlarge and become symptomatic causing significant neurological dysfunction as a result of obstruction of the interventricular foramina, distortion of the vascular structures of the deep venous system or compression of the hypothalamoseptal triangle. The authors present a series of four patients with symptoms related directly to pressure effects from the cyst wall to the neighbouring deep brain structures. There were two females and two males with a mean age of 47.5 years. All four patients underwent endoscopic cyst fenestration with a rigid endoscope. In 2 patients frameless neuronavigation was accomplished with the optical tracking system (Radionics, Burlington, USA). All symptoms related to pressure effect resolved after surgery. Endoscopic pellucidotomy of symptomatic cysts of the septum pellucidum produces immediate relief of the mass effect of the cyst and resolution of associated symptoms. Additionally, frameless neuronavigation is a useful tool in planning and realizing the approach and improving intraoperative orientation.

Treated wood in livestock facilities: relationships among residues of pentachlorophenol, dioxins, and furans in wood and beef.

Wood and other environmental samples were collected from sites that produced beef with higher than average residues of dibenzo-p-dioxin (PCDD) and dibenzofuran (PCDF). Analyses of these samples for PCDD/Fs and pentachlorophenol (PCP) indicated that the high beef residues were associated with PCP-treated wood in the animal facilities. Concentrations of PCDD/Fs in wood as toxic equivalents ranged from 10 to 320,000 pg/g. These concentrations were closely related to the concentrations of PCP, indicating that analysis for PCP provides an economical method to identify wood with high concentrations of PCDD/Fs. Further evidence for the PCP-treated wood as the source of the beef residues is provided by the similarity of the congener profiles in beef from the sites and those profiles predicted from the profiles in wood.

A New Synthetic Route to Unsymmetrical 1,2-Bis(phosphanyl)ethanes and 1,2-Arsanyl(phosphanyl)ethanes with and without a Stereogenic Center.

A one-pot reaction affords unsymmetrical 1,2-bis(phosphanyl)ethanes 2 and 1,2-arsanyl(phosphanyl)ethanes 3 from the cyclic sulfate 1 in high yield. Similarly, chiral 1,2-bis(phosphanyl)ethanes and 1,3-bis(phosphanyl)propanes could be obtained in enantiomerically pure form. R, R'=alkyl, phenyl.

Intracranial endoscopy.

Since 1910, when Lespinasse [73] in Chicago was the first surgeon to use an endoscopic device for the treatment of a neurologic disease, various methods of endoscopy have evolved into accepted diagnostic and therapeutic adjuncts of modern neurosurgery. Nevertheless, until recently technical shortcomings of the available endoscopes have prevented the widespread use of neuroendoscopy. However, now, at the end of the 20th century, endoscopes can be regarded as some of the most important instruments for the development of microneurosurgery into the 3rd millennium. The aim of this review of intracranial endoscopy in neurosurgery, which admittedly might not be completely objective in the authors' personal assessment of various endoscopic techniques, is first to depict the historical evolution of neuroendoscopy, second to describe the technical equipment used in intracranial endoscopic neurosurgery, third to characterize the most frequent endoscopic methods in brain surgery, and fourth to indicate how neuroendoscopy might develop in the near future. It will be shown that this ongoing evolutionary process in neuroendoscopy was only possible with the mutual influence of improved diagnostic techniques, increased microanatomical knowledge, refined neurosurgical instrumentation--especially the introduction of the surgical microscope, and endoscopic diagnostic and therapeutic strategies.

Endoscopic third ventriculostomy: outcome analysis of 100 consecutive procedures.

OBJECTIVE: Endoscopic third ventriculostomy (ETV) has been shown to be a sufficient alternative in the surgical treatment of occlusive hydrocephalus. To elucidate the ongoing discussion of timing, indication, and surgical technique, a retrospective analysis of 100 consecutive ETVs was conducted. METHODS: One hundred ETVs were performed in 95 patients (43 female and 52 male patients). Their age ranged from 3 weeks to 77 years (mean age, 36 yr). Hydrocephalus was caused by aqueductal stenosis in 40 patients, space-occupying lesions in 42, and intraventricular or subarachnoid hemorrhage in 8. One patient had postinflammatory hydrocephalus, and four patients had occlusive hydrocephalus of unknown origin. In 33 cases, surgery was performed using stereotactic guidance. RESULTS: ETV was accomplished in 98 of 100 cases. The overall success rate was 76%. Patients with benign space-occupying lesions and nontumorous aqueductal stenosis had the highest success rates, which were 95 and 83%, respectively. Complications were arterial bleeding in one case, venous bleeding in three cases, intracerebral bleeding in one case, and infection in one case. There were no permanent morbidities or mortalities. CONCLUSION: ETV is most effective in treating uncomplicated occlusive hydrocephalus caused by aqueductal stenosis and space-occupying lesions. ETV is still effective in two-thirds of the patients with previous infections or intraventricular bleeding. Patients who have previously undergone shunting and who have occlusive hydrocephalus should undergo ETV at the time of shunt failure, with immediate ligation or removal of the shunt device. In selected cases of distorted anatomy or impaired visual conditions, stereotactic guidance is helpful.

Isolation of Abiotrophia adiacens from a brain abscess which developed in a patient after neurosurgery.

We report the case of a patient who developed a large brain abscess after neurosurgery. Cerebrospinal fluid from the abscess drainage yielded Abiotrophia adiacens-specific PCR products and microorganisms that were identified by conventional microbiological methods and by 16S ribosomal DNA analysis as Abiotrophia adiacens, which was formerly classified as a member of nutritionally variant streptococci.

From sugar beet molasses to Lyphan. Integrated quality management from the raw material to the drug.

L-tryptophan is produced at the AMINO GmbH (Frellstedt, FRG) via biocatalytical condensation of the amino acid L-serine with indole. As a biocatalyst, tryptophan synthetase is used which is produced in high activities by a natural mutant Escherichia coli strain. The enzyme mechanism and specificity and the individual process-parameters for the biotransformation procedure are explained as well as the purification process of educts and products. This includes a detailed description of the quality control of educts, intermediates and final product. The active ingredient L-tryptophan is subsequently used by AMINO's subsidiary company esparma GmbH to produce and distribute the pharmaceutical Lyphan. The quality management system and the production procedure for Lyphan are described and discussed.

Cerebral blood flow velocities after subarachnoid haemorrhage in relation to the amount of blood clots in the initial computed tomography.

In 72 patients with acute subarachnoid haemorrhage (SAH) the relationship between the amount of subarachnoid blood clots detected by initial cranial computed tomography (CCT) up to 48 hours after bleeding and the later development of vasospasm, established by blood flow velocity measurement with transcranial Doppler ultrasound (TCD) was investigated. The serial Doppler examinations started within the first 72 hours after SAH and were carried out every second day up to three weeks. Each Doppler recording was accompanied by a neurological examination. Patients classified as Hunt and Hess grade V were excluded from the study. All patients with remarkable brain oedema in CCT or with intracranial pressure above 25 mmHg were also excluded. Because of the well known age-dependence of vasospasm after SAH, two age groups were formed. A statistically significant correlation (p > 0.05) between blood flow velocities and blood load after SAH was not found. The mean age of the investigated 72 individuals was 48.9 years (14 up to 76 years). 47 patients were younger than 56 years. Linear regression analysis indicated a correlation with a quite low significance level (r = 0.350, p < 0.025) between TCD blood flow velocities and blood load in CCT in these younger subjects. No significant correlation (p > 0.05) between these two variables could be established in the 25 patients older than 55 years. In a second step an intra-individual comparison of side-to-side differences in TCD and CCT was made. There were no significant differences in blood flow velocities between subjects with or without side-to-side differences in cisternal blood load. It is concluded that the amount of blood visible on initial CCT after SAH is not a powerful predictor of cerebral blood flow velocities measured by TCD.

The supraorbital keyhole approach to supratentorial aneurysms: concept and technique.

BACKGROUND: Anterior surgical approaches to the base of the brain have always required relatively large craniotomies, most larger than the lesion itself. Especially in aneurysm surgery, the size of the lesion is not always proportionate to the extent of brain exposure. The improvement of surgical techniques and diagnostic imaging, as well as the introduction of neuroendoscopy and new surgical instruments, enable us now to treat various intracranial lesions through small keyholes. In particular, cerebral aneurysms, because of their anatomic characteristics, are apt to be treated by the keyhole approach. The supraorbital keyhole approach has the broadest field of indications, although its technical aspects have not yet been evaluated. METHODS: The concept and technique of the supraorbital keyhole approach are presented in detail. We conducted a retrospective study in which we evaluated the technical aspects of the supraorbital keyhole approach considering the indications, limitations, and complications of this approach as well as new instrumentation in surgery of supratentorial aneurysms. RESULTS: The use of 139 supraorbital keyhole approaches for 197 aneurysms is described. Multiple aneurysms have been treated by one approach in 38 patients. Clipping of the aneurysm was performed in 94% and wrapping in 6% of patients. Eighteen aneurysms were contralateral to the approach. In four patients, intraoperative accidental aneurysm rupture occurred. There were no approach-related complications. CONCLUSIONS: The supraorbital keyhole approach offers equal surgical possibilities with less intraoperative accidental rupture and less approach-related morbidity as conventional approaches in the treatment of supratentorial aneurysms.

Endoscope-assisted brain surgery: part 1--evolution, basic concept, and current technique.

RATIONALE: The evolution of neurosurgical techniques indicates the effort to reduce surgery-related traumatization of patients. The reduction of traumatization contributes to better postoperative outcomes. The improvement of diagnostic imaging techniques facilitates not only the precise localization of lesions but also the accurate determination of topographical relations of specific lesions to individual anatomic variations of intracranial structures. This precision of diagnostic imaging should be used to perform individual surgical procedures through so-called keyhole approaches. Keyhole craniotomies are afflicted with a reduction of light intensity in the depth of the operating field, and they provide rather narrow viewing angles. Thus, objects located directly opposite the approach entrance are more visible than those in the shadow of the microscope beam. These two deficiencies of keyhole craniotomies can be compensated for by the intraoperative use of rigid rod lens endoscopes, the shaft of which remains easily controllable through the surgical microscope. CONCEPT: Endoscope-assisted microsurgery, like all routine microsurgical procedures, is performed with both hands; the endoscope is fixed in its desired position via a mechanical arm to the headholder. Because of their superior optical quality and maneuverability, only rigid lens scopes are used for endoscope-assisted brain microsurgery. There are five ways of observing the endoscopic and microscopic images at the same time: 1) observation of the microscopic image through the oculars of the microscope and observation of the endoscopic image on a video screen placed in front of the surgeon, 2) observation of the microscopic image through the oculars of the microscope and display of the endoscopic image on a head-mounted LCD screen, 3) projection of both microscopic and endoscopic images on one screen in a picture-in-picture mode, 4) projection of both microscopic and endoscopic images into specially designed microscope oculars, and 5) transmission of both microscopic and endoscopic images into a head-mounted LCD screen. DISCUSSION: With the knowledge of almost all individual anatomic and pathoanatomic details of a specific patient, it is possible to target the individual lesion through a keyhole approach using the particular anatomic windows. As the light intensity and the depiction of important anatomic details are improved by the intraoperative use of lens scopes, endoscope-assisted microsurgery during keyhole approaches may provide maximum efficiency to remove the lesion, maximum safety for the patient, and minimum invasiveness.