Impact of hyperglycemia on neurological deficits and extracellular glucose levels in aneurysmal subarachnoid hemorrhage patients

OBJECTIVE: Hyperglycemia after aneurysmal subarachnoid hemorrhage (SAH) is associated with serious complications. Blood glucose may indicate a target for therapy to prevent delayed ischemic neurological deficits (DIND) and improve outcome. The objective of this study was to investigate energy metabolism in the extracellular/cerebrospinal fluid and blood in relation to outcome. METHODS: Prospective non-randomized study was carried out in the intensive care unit (ICU) of university hospital (n = 170 aneurysmal SAH patients, age: 51.0 +/- 12.6 years old). Following approval by the ethics committee, a microdialysis catheter was inserted into the vascular territory of the aneurysm after clipping. Patients were studied for 165 +/- 84 hours and classified according to the presence of neurological symptoms as asymptomatic (n = 66) and symptomatic (n = 104): acute focal neurological deficits (AFND, n = 61) and delayed ischemic neurological deficits (DIND, n = 43). The microdialysates were analysed hourly for energy metabolites. Daily morning blood glucose and cerebrospinal fluid (CSF) levels (glucose and lactate) were determined. Six-month Glasgow outcome scale (GOS) was assessed. RESULTS: Hyperglycemia on admission and high blood glucose levels on the following days were significantly related to the presence of symptoms, most pronounced in patients with poor outcome (p<0.05). In symptomatic patients (high blood glucose), the lowest extracellular fluid (ECF) glucose concentrations were found, most pronounced in the AFND group (1.0 +/- 1.2 mmol/l). The anaerobic metabolites lactate, lactate/pyruvate ratio (LPR) and lactate/glucose ratio (LGR) were higher in symptomatic patients (p<0.001) indicating cerebral metabolic distress. CSF concentrations of glucose and lactate were of no specific value. CONCLUSION: This study confirms the relevance of hyperglycemia to neurological outcome in SAH patients. Cerebral glucose was significantly lower in AFND patients despite hyperglycemic blood levels. More detailed works are necessary to select risk patients for optimized targeted therapy to avoid insulin-induced cerebral metabolic crisis.     

Incidence of social anxiety disorder and the consistent risk for secondary depression in the first three decades of life

CONTEXT: Epidemiological findings demonstrating an increased risk for individuals with social anxiety disorder (SAD) to develop depression have been challenged by discrepant findings from prospective longitudinal examinations in childhood and early adolescence. OBJECTIVES: To examine patterns of SAD incidence, the consistency of associations of SAD with subsequent depression, and distal and proximal predictors for subsequent depression. DESIGN: Face-to-face, 10-year prospective longitudinal and family study of up to 4 waves. The DSM-IV Munich-Composite International Diagnostic Interview was administered by clinically trained interviewers. SETTING: Community sample in Munich. PARTICIPANTS: Three thousand twenty-one individuals aged 14 to 24 years at baseline and 21 to 34 years at follow-up. MAIN OUTCOME MEASURES: Cumulative incidence of SAD and depression (major depressive episode or dysthymia). RESULTS: Cumulative incidence for SAD was 11.0%; for depression, 27.0%. Standardized person-years of incidence for SAD were highest for those aged 10 to 19 years (0.72%) and were low before (0.20%) and after (0.19%) that age range. Depression incidence was different, characterized by delayed and continued high rates. Social anxiety disorder was consistently associated with subsequent depression, independent of age at onset for SAD (relative risk range, 1.49-1.85, controlling for age and sex). Crude Cox regressions showed significant distal (eg, parental anxiety or depression, behavioral inhibition) and proximal SAD characteristics (eg, severity measures, persistence) as predictors. Most associations were attenuated in multiple models, leaving behavioral inhibition (hazard ratio, 1.30 [95% confidence interval, 1.04-1.62; P = .02]) and, less consistently, panic (hazard ratio, 1.85 [95% confidence interval, 1.08-3.18; P = .03]) as the remaining significant predictors. CONCLUSIONS: Social anxiety disorder is an early, adolescent-onset disorder related to a substantially and consistently increased risk for subsequent depression. The demonstration of proximal and particularly distal predictors for increased depression risks requires further exploration to identify their moderator or mediator role. Along with previous evidence that comorbid SAD is associated with a more malignant course and character of depression, these results call for targeted prevention with the aim of reducing the burden of SAD and its consequences.     

Sarcoidosis--immunopathogenetic concepts

Sarcoidosis is a chronic granulomatous disorder characterized by an accumulation of activated lymphocytes, predominantly T helper cells, expressing the Th1 phenotype and macrophages at sites of disease activity. Although the cause of sarcoidosis has not been elucidated, several lines of evidence suggest that granuloma formation results from exposure to one or more antigens, eliciting a T lymphocyte response. The induction and evolution of granuloma formation results from a complex interplay between diverse cell types, cytokines, and chemokines. Genetic polymorphisms may influence the clinical expression of the granuloma formation and disease outcome. This article discusses in depth the key cellular elements and signals that generate and orchestrate the sarcoid granulomatous response. The precise factors inciting the sarcoid granulomatous response have not yet been identified, but chronic exposure to microbial agents, their products, or inorganic substances may be important in the pathogenesis.     

Alteration in the gene expression pattern of primary monocytes after adhesion to endothelial cells

Monocytes originate from precursors made in the bone and remain in the circulation for nearly 24 h. Much effort has been done to identify the molecules regulating transendothelial migration of monocytes during inflammatory conditions. In contrast, considerably less is known about the process of constitutive monocyte emigration although nearly 340 million monocytes leave the circulation each day in healthy individuals. Previous studies indicated that chemokines were up-regulated in monocytes cocultured with endothelial cells that induce the retraction of the latter cell type, thereby increasing vascular permeability. Thus, we hypothesized that the utilities required for efficient constitutive monocyte extravasation are generated by monocytes themselves because of adhesion to na?ve endothelial cells. To test this hypothesis, cDNA microarray analysis was performed to determine the changes in the gene expression pattern of primary monocytes that have been attached to endothelial cells compared with monocytes that were held in suspension, and we were able to identify three major groups of genes. The first group includes genes such as matrix metalloproteinase 1, monocyte chemoattractant protein 1, and tissue transglutaminase 2, which are likely required for monocyte extravasation. The second group consists of genes that are expressed in phagocytes such as caveolin-1 and CD74. Finally, the third group comprises genes that are expressed in cells of endothelial tissue and cartilage including E-selectin, fibronectin-1, matrix Gla protein, and aggrecanase-2. In summary, we conclude that adhesion of peripheral blood monocytes to na?ve endothelial cells has two effects: mandatory extravasation-specific genes are regulated, and the differentiation program of monocytes is initiated.     

CXCR5- and CCR7-dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with unknown etiology and only partially defined pathogenesis. The aim of this study was to establish a murine model of chronic arthritis in which the development of tertiary lymphoid tissue, a hallmark of human RA, is locally induced, and to characterize the roles of the homeostatic chemokine receptors CXCR5 and CCR7 in this process. METHODS: We developed a modified model of chronic antigen-induced arthritis (AIA) in mice with a strong bias toward inflammation. Disease pathology was assessed up to 9 months in wild-type, CXCR5-deficient, and CCR7-deficient mice by determination of knee joint swelling and cellular and humoral immune responses, as well as by histologic analysis of arthritic knee joints. RESULTS: In this novel model of AIA, mice developed organized ectopic lymphoid follicles with topologically segregated B cell and T cell areas, high endothelial venules, and germinal center formation within the chronically inflamed synovial tissue. Analysis of the initiation and progression of AIA in wild-type, CXCR5-/-, and CCR7-/- mice revealed a reduction of acute inflammatory parameters in both knockout strains as well as significantly reduced joint destruction in CXCR5-/- mice. Most importantly, the development and organization of tertiary lymphoid tissue were significantly impaired in CXCR5-deficient and CCR7-deficient mice. CONCLUSION: Our results suggest that an inflammatory microenvironment efficiently triggers lymphoid neogenesis in autoimmune diseases such as RA. Moreover, the generation of autoreactive tertiary lymphoid tissues, which is entirely dependent on homeostatic chemokines, may in turn maintain local aberrant chronic immune responses.     

Activity-dependent regulation of neuronal apoptosis in neonatal mouse cerebral cortex

A massive neuronal loss during early postnatal development has been well documented in the murine cerebral cortex, but the factors that drive cells into apoptosis are largely unknown. The role of neuronal activity in developmental apoptosis was studied in organotypic neocortical slice cultures of newborn mice. Multielectrode array and whole-cell patch-clamp recordings revealed spontaneous network activity characterized by synchronized burst discharges, which could be blocked by tetrodotoxin and ionotropic glutamate receptor antagonists. The identical neuropharmacological manipulations also caused a significant increase in the number of apoptotic neurons as early as 6 h after the start of drug treatment. Moreover, inhibition of the NMDA receptor subunit NR2A or NR2B induced a differential short-term versus delayed increase in the apoptosis rate, respectively. Activation of L-type, voltage-dependent calcium channels was neuroprotective and could prevent activity-dependent apoptosis during NMDA receptor blockade. Furthermore, this effect involved phosphorylation of cAMP response element-binding protein and activation of the tropomyosin-related kinase (Trk) receptors. Inhibition of electrical synapses and blockade of ionotropic gamma-aminobutyric acid receptors induced specific changes in spontaneous electrical activity patterns, which caused an increase in caspase-3-dependent cell death. Our results demonstrate that synchronized spontaneous network bursts activating ionotropic glutamate receptors promote neuronal survival in the neonatal mouse cerebral cortex.