T cell–derived interleukin (IL)-21 promotes brain injury following stroke in mice

T lymphocytes are key contributors to the acute phase of cerebral ischemia reperfusion injury, but the relevant T cell–derived mediators of tissue injury remain unknown. Using a mouse model of transient focal brain ischemia, we report that IL-21 is highly up-regulated in the injured mouse brain after cerebral ischemia. IL-21–deficient mice have smaller infarcts, improved neurological function, and reduced lymphocyte accumulation in the brain within 24 h of reperfusion. Intracellular cytokine staining and adoptive transfer experiments revealed that brain-infiltrating CD4⁺ T cells are the predominant IL-21 source. Mice treated with decoy IL-21 receptor Fc fusion protein are protected from reperfusion injury. In postmortem human brain tissue, IL-21 localized to perivascular CD4⁺ T cells in the area surrounding acute stroke lesions, suggesting that IL-21–mediated brain injury may be relevant to human stroke.Stroke is one of the leading causes of death and disability worldwide. Clinical and preclinical experimental studies highlight the importance of inflammation in both acute and delayed neuronal tissue damage after ischemic stroke; however, the mechanisms and cells involved in this neuroinflammation are not fully understood. There is currently no available treatment targeting the acute immune response that develops in the brain after transient focal ischemia. Therefore, we sought to identify novel T cell–derived cytokines that contribute to acute cerebral reperfusion using the mouse model of transient middle cerebral artery occlusion (tMCAO).During the reperfusion of infarcted brain tissue, leukocytes accumulate in the injured brain where, in addition to clearing cell debris, they promote secondary tissue injury (Yilmaz and Granger, 2010). Within the acute phase of ischemic reperfusion (I/R) injury there are multiple waves of cell infiltration of macrophages, neutrophils, and lymphocytes (Gelderblom et al., 2009). Brain-infiltrating T cells have also been widely reported in stroke and animal models of stroke and are thought to have acute detrimental and delayed protective effects (Magnus et al., 2012). Conventionally, the protective role of T cells has been attributed to the accumulation of regulatory T cells within the CNS in later stages of reperfusion injury. These T cells produce a variety of cytokines including TGFβ and IL-10, which are both antiinflammatory and neuroprotective. (Liesz et al., 2009; Stubbe et al., 2013). In addition to having an established role in delayed neuroprotection, Kleinschnitz et al. (2013) have recently shown that CD4⁺ CD25⁺ regulatory T cells also promote acute ischemic injury through interaction with the cerebral vasculature. The acute detrimental effects can be further divided into early (24 h) and late (72 h) phases, with IL-17 production by nonconventional γδ T cells (less common T cell subset associated with mucosal tissues) possibly accounting for the latter by promoting neutrophil accumulation (Gelderblom et al., 2012).The mechanisms of the early detrimental effects of T cells after cerebral ischemia are least understood. Several laboratories have reported reduced neurological deficit and infarct volumes at 24–48 h reperfusion in T cell–deficient mice after tMCAO (Yilmaz and Granger, 2010). After tMCAO, recombination activating gene 1–deficient (RAG1 KO) mice, which lack T and B lymphocytes, have significantly smaller brain injury compared with controls; whereas, adoptive transfer of WT CD4⁺ helper T cells or CD8⁺ cytotoxic T cells increases stroke infarct volumes within 24 h after ischemia in these mice (Kleinschnitz et al., 2010). Additionally, TCR-transgenic mice and mice lacking co-stimulatory TCR signaling molecules were fully susceptible to acute I/R injury, indicating that T cell involvement at early time points is antigen-independent (Kleinschnitz et al., 2010). These data demonstrate that conventional CD4⁺ or CD8⁺ αβ T cells exacerbate acute injury after cerebral ischemia independently of TCR ligation, and this effect seems to be concomitant with an early increase in T cell infiltration into the postischemic brain, which many have reported to be between 3 and 48 h (Yilmaz et al., 2006; Gelderblom et al., 2009).Recent findings suggest that, in the postischemic brain, within hours of reperfusion T cells accumulate in postcapillary segments of periinfarct inflamed cerebral microvasculature characterized by high endothelial expression of chemokines and adhesion molecules. These postcapillary venules have been postulated to allow accumulating immune cells to activate each other and promote platelet adhesion in a process termed thrombo-inflammation (Nieswandt et al., 2011). Much research has been devoted to identifying T cell factors that promote thrombo-inflammation (Barone et al., 1997; Hedtjärn et al., 2002; Yilmaz et al., 2006; Shichita et al., 2009; Gelderblom et al., 2012); however, to our knowledge no study has yet identified the T cell–derived factors responsible for the early increase in infarct volumes at 24 h reperfusion. Here, we present data that identify IL-21 as a key CD4⁺ T cell–derived inflammatory factor that contributes to increased early ischemic tissue injury.     

Gangliosides modulate proliferation,migration, and invasiveness of human brain tumor cells in vitro

Gliomas, the most common form of intrinsic brain tumor, are characterized by diffuse local invasion of the normal brain structures, irrespective of their histological grade of malignancy; a feature that is a major obstacle to successful therapy. They generally infiltrate the central nervous system (CNS) as individual tumor cells several centimeters beyond the macroscopic tumor margin and consequently often recur, after subtotal surgical resection. Factors involved in the control of both their proliferation and invasiveness are poorly documented. In this work, the role of gangliosides on proliferation of both human fetal human brain cells and five cell lines derived from human gliomas with different grades of malignancy was investigated. In addition, 8 μm-porosity polycarbonate filters were used to study cell motility. In addition, these filters were coated with the reconstituted extracellular matrix (ECM) composite, Matrigel, to assess invasiveness. The results presented show that gangliosides generally exert a proliferation inhibitory effect on fetal brain cells and glioma cell lines in vitro and play an important role in promoting glioma cell motility and invasiveness. The molecular mechanisms involved in the action of gangliosides may prove useful in identifying new targets for an anti-invasion therapy.     

Prognostic value of postoperative proteinuria in cardiac surgery: a pilot study

BACKGROUND: Proteinuria is a non-specific marker of inflammation that may reflect the glomerular component of systemic capillary leak. The objective of this pilot study was to determine if postoperative proteinuria is associated with adverse outcomes following cardiac surgery with cardiopulmonary bypass. METHODS: Eligible patients were individuals undergoing cardiac surgery with cardiopulmonary bypass who did not have severe pre-existing renal dysfunction. Urine was collected after induction of anesthesia (baseline) and two to four hours after arrival to the intensive care unit (ICU). Proteinuria was measured as random protein creatinine ratio in g.mol(-1). Adverse events were defined a priori as prolonged ICU stay (> or = 90th percentile) and organ dysfunction. The relationship between proteinuria and adverse events was assessed by bivariate (Chi-square or Fisher's exact tests) and multivariable (multiple logistic regression) analyses. RESULTS: The study included 197 (of 243 eligible) patients. Postoperative proteinuria (protein creatinine ratio > or = 30 g.mol(-1)) was associated with prolonged (> or = four days) ICU stay [odds ratio (OR) 7.0; 95% confidence interval (CI) 2.8-17.1] and organ dysfunction (OR 3.9; CI 1.9-8.1). After adjustment for confounders, proteinuria was associated with a 3.2-fold increase in the odds of both prolonged ICU stay (CI 1.1-9.7) and organ dysfunction (CI 1.4-7.0). CONCLUSIONS: Proteinuria two to four hours after cardiac surgery with cardiopulmonary bypass may be a useful marker for systemic capillary leak and adverse postoperative events. Large prospective studies are needed to confirm these findings.     

Internal mammary artery collateral to the external iliac artery: an angiographic consideration prior to coronary bypass surgery

The role of routine selective angiography of the internal mammary artery prior to myocardial revascularization is controversial. We report a patient with coronary artery disease and peripheral vascular disease in whom the left internal mammary artery supplied blood flow to the left external iliac artery via a collateral network. Thus, selective angiography of the internal mammary artery did play a major role in the proper management of this patient who required coronary bypass surgery. A major potential postoperative complication of left lower extremity ischemia may have been prevented. © 1994 Wiley-Liss,Inc..     

Declining incidence of esophageal cancer in the Turkmen Plain, eastern part of the Caspian Littoral of Iran: a retrospective cancer surveillance

BACKGROUND: Previous studies have shown that upper gastrointestinal cancers are the most common cancers in Caspian Littoral, and rate of esophageal cancer (EC) in Iranian Turkmens residing in the Eastern part of littoral are among the highest in the world. Our aim was to reassess the rate 30 years later and following socioeconomic changes in the region. METHODS: A comprehensive retrospective search was undertaken to find all new cancer cases during the 1996-2000 period. Diagnosis of cancer was based on histopathological reports in 68.2%, clinical and/or radiological evidence in 29.7% and death certificate only (DCO) in 2.1% of the cases. RESULTS: A total of 5143 new cancer cases were registered of whom 3063 (59.6%) were males. The median (IQR) age was 60 (44-69) years. Age-standardized rates (ASR) for all cancers in males and females were 134.7 and 104.5 per 100,000, respectively. Based on ASR, the top five common cancers in males (excluding skin cancer) were cancers of esophagus (43.4), stomach (27.8), colorectal (10.7), bladder (7.8) and oral cavity (6.3), while in females cancer of esophagus (36.3) was followed by cancers of breast (15.7), stomach (8.3) colorectal (6.6) and cervix (3.6). CONCLUSION: We conclude that EC incidence rate has decreased to less than half the rate reported 30 years ago, while the incidence rates of colorectal and breast cancers have increased significantly.     

Four novel C20orf54 mutations identified in Brown-Vialetto-Van Laere syndrome patients

Brown-Vialetto-Van Laere syndrome (BVVLS) is a very rare neurodegenerative disorder characterized by pontobulbar palsy and sensorineural hearing loss. Its mode of inheritance in affected families has usually been autosomal recessive, although autosomal dominant inheritance and incomplete penetrance have also been reported. Recently, C20orf54 was identified as a causative gene for BVVLS. Twelve different mutations have so far been identified in 10 patients affected with BVVLS or the related disorder Fazio Londe syndrome. Here, results of screening of C20orf54 in three unrelated BVVLS patients are reported. Four novel mutations that affect amino acid changes, p.Asn21Ser, p.Pro220His, p.Ala312Val and p.Gly375Asp, were identified in the patients. The causative nucleotide variations were not observed in 200 control individuals. One of the patients harbored compound heterozygous mutations, but only one mutated allele was observed in each of the two remaining patients.     

The new wave: time to bring EEG to the emergency department

Emergency electroencephalography (EEG) is indicated in the diagnosis and management of non-convulsive status epilepticus (NCSE) underlying an alteration in the level of consciousness. NCSE is a frequent, treatable, and under-diagnosed entity that can result in neurological injury. This justifies the need for EEG availability in the emergency department (ED). There is now emerging evidence for the potential benefits of EEG monitoring in various acute conditions commonly encountered in the ED, including convulsive status after treatment, breakthrough seizures in chronic epilepsy patients who are otherwise controlled, acute head trauma, and pseudo seizures. However, attempts to allow for routine EEG monitoring in the ED face numerous obstacles. The main hurdles to an optimized use of EEG in the ED are lack of space, the high cost of EEG machines, difficulty of finding time, as well as the expertise needed to apply electrodes, use the machines, and interpret the recordings. We reviewed the necessity for EEGs in the ED, and to meet the need, we envision a product that is comprised of an inexpensive single-use kit used to wirelessly collect and send EEG data to a local and/or remote neurologist and obtain an interpretation for managing an ED patient.     

Kidney function tests in children with beta-thalassemia minor in Zahedan, southeast of Iran

There is little information regarding kidney function in patients with beta-thalassemia minor. In this study we investigated kidney function tests in 50 children with beta-thalassemia minor (22 boys and 28 girls). Twenty-four-hour urine samples were collected and analyzed for sodium, potassium, calcium, magnesium, creatinine, phosphate, uric acid, protein, and beta2-microglobulin. Blood samples were obtained for hematologic and biochemical analyses including complete blood count, serum ferritin, sodium, potassium, calcium, phosphate, magnesium, creatinine, and uric acid. This group of children with beta-thalassemia showed some evidence of tubulopathy such as proteinuria (32%), beta2-microglobulin excretion (36%), calciuria (4%), phosphaturia (4%), and uricosuria (20%). Our findings support the existence of renal tubular dysfunction in beta-thalassemia minor. However, further studies in large series are needed to shed light on the possible relation of these two distinct diseases.