Cell type and gender-dependent differential regulation of the p202 and Aim2 proteins: implications for the regulation of innate immune responses in SLE

Upon sensing cytosolic double-stranded DNA (dsDNA), the murine Aim2 (encoded by the Aim2 gene) protein forms an inflammasome and promotes the secretion of proinflammatory cytokines, such as IL-1β and IL-18. In contrast, the p202 protein (encoded by the Ifi202 gene) does not form an inflammasome. Previously, we have reported that the interferon (IFN) and female sex hormone-induced increased nuclear levels of p202 protein in immune cells are associated with increased susceptibility to develop a lupus-like disease. However, signaling pathways that regulate the expression of Aim2 protein remain unknown. Here we report that the expression of Aim2 gene is induced in bone marrow-derived macrophages (BMDMs) by IFN-α treatment and the expression is, in part, STAT1-dependent. However, treatment of splenic T or B cells with IFN-α or their stimulation, which induced the expression of Ifi202 gene, did not induce the expression of Aim2 gene. Furthermore, treatment of cells with the male hormone androgen increased levels of Aim2 mRNA and protein. Moreover, treatment of murine macrophage cell lines (RAW264.7 and J774A.1) with IFN-α differentially induced the expression of Aim2 and p202 proteins and regulated their sub-cellular localization. Additionally, activation of Toll-like receptors (TLR3, 4, and 9) in BMDMs and cell lines also differentially regulated the expression of Aim2 and Ifi202 genes. Our observations demonstrate that cell type and gender-dependent factors differentially regulate the expression of the Aim2 and p202 proteins, thus, suggesting opposing roles for these two proteins in innate immune responses in lupus disease.     

Psychological benefits 2 and 4 weeks after a single treatment with near infrared light to the forehead: a pilot study of 10 patients with major depression and anxiety

Background

The paper presents the Motor Function Neurological Assessment (MFNU), as a tool for identifying typical motor function problems in children with Attention Deficit Hyperactivity Disorder (ADHD). The study investigated motor functions in boys diagnosed with Hyperkinetic Disorder (HKD, F.90.0). HKD corresponds to the ADHD-combined (ADHD-C) diagnosis in the DSM-IV. The paper addresses the ability of the instrument to discriminate between non-medicated boys with HKD and a control group consisting of normal non-referred boys without any clinical significant ADHD symptoms.

Methods

25 drug-naïve boys, aged 8–12 years and recently diagnosed as HKD F90.0, were compared with 27 controls, all boys in the same age range, on 17 MFNU subtests, and with a 'Total score' parameter.

Results

On the individual subtests 80–96% (median 88%) of the ADHD group showed 'moderate' to 'severe' problems, compared to 0–44% (median 14.8%) within the control group. The percentage of 'severe problems' ranged from 44–84%, (median 64%) in the ADHD group, and 0–44% (median 0%) in the control group. The highly significant differences found between the groups on all subtests, and on the Total score scores, indicated that the MFNU had a high discriminative power when children with ADHD and normal controls were compared. The Total score parameter seemed to be a meaningful discriminator of a common underlying factor of the 17 subtests used in the study.

Conclusion

The study confirms our clinical findings that the MFNU measures a consistent pattern of motor function problems in children with HKD, and that these problems are rarely represented in individuals without ADHD. Further research is needed to investigate to what extent the MFNU taps motor problems that are truly specific to ADHD, in contrast to motor problems common to children with DCD or other clinical problems.     

Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice

Endothelial dysfunction is a key triggering event in atherosclerosis. Following the entry of lipoproteins into the vessel wall, their rapid modification results in the generation of advanced glycation endproduct epitopes and subsequent infiltration of inflammatory cells. These inflammatory cells release receptor for advanced glycation endproduct (RAGE) ligands, specifically S100/calgranulins and high-mobility group box 1, which sustain vascular injury. Here, we demonstrate critical roles for RAGE and its ligands in vascular inflammation, endothelial dysfunction, and atherosclerotic plaque development in a mouse model of atherosclerosis, apoE-/- mice. Experiments in primary aortic endothelial cells isolated from mice and in cultured human aortic endothelial cells revealed the central role of JNK signaling in transducing the impact of RAGE ligands on inflammation. These data highlight unifying mechanisms whereby endothelial RAGE and its ligands mediate vascular and inflammatory stresses that culminate in atherosclerosis in the vulnerable vessel wall.     

RAGE mediates podocyte injury in adriamycin-induced glomerulosclerosis

In the kidney, the receptor for advanced glycation end products (RAGE) is principally expressed in the podocyte at low levels, but is upregulated in both human and mouse glomerular diseases. Because podocyte injury is central to proteinuric states, such as the nephrotic syndrome, the murine adriamycin nephrosis model was used to explore the role of RAGE in podocyte damage. In this model, administration of the anthracycline antibiotic adriamycin provokes severe podocyte stress and glomerulosclerosis. In contrast to wild-type animals, adriamycin-treated RAGE-null mice were significantly protected from effacement of the podocyte foot processes, albuminuria, and glomerulosclerosis. Administration of adriamycin induced rapid generation of RAGE ligands, and treatment with soluble RAGE protected against podocyte injury and glomerulosclerosis. In vitro, incubation of RAGE-expressing murine podocytes with adriamycin stimulated AGE formation, and treatment with RAGE ligands rapidly activated nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, via p44/p42 MAP kinase signaling, and upregulated pro-fibrotic growth factors. These data suggest that RAGE may contribute to the pathogenesis of podocyte injury in sclerosing glomerulopathies such as focal segmental glomerulosclerosis.     

ELMO1 and Dock180, a bipartite Rac1 guanine nucleotide exchange factor, promote human glioma cell invasion

A distinct feature of malignant gliomas is the intrinsic ability of single tumor cells to disperse throughout the brain, contributing to the failure of existing therapies to alter the progression and recurrence of these deadly brain tumors. Regrettably, the mechanisms underlying the inherent invasiveness of glioma cells are poorly understood. Here, we report for the first time that engulfment and cell motility 1 (ELMO1) and dedicator of cytokinesis 1 (Dock180), a bipartite Rac1 guanine nucleotide exchange factor (GEF), are evidently linked to the invasive phenotype of glioma cells. Immunohistochemical analysis of primary human glioma specimens showed high expression levels of ELMO1 and Dock180 in actively invading tumor cells in the invasive areas, but not in the central regions of these tumors. Elevated expression of ELMO1 and Dock180 was also found in various human glioma cell lines compared with normal human astrocytes. Inhibition of endogenous ELMO1 and Dock180 expression significantly impeded glioma cell invasion in vitro and in brain tissue slices with a concomitant reduction in Rac1 activation. Conversely, exogenous expression of ELMO1 and Dock180 in glioma cells with low level endogenous expression increased their migratory and invasive capacity in vitro and in brain tissue. These data suggest that the bipartite GEF, ELMO1 and Dock180, play an important role in promoting cancer cell invasion and could be potential therapeutic targets for the treatment of diffuse malignant gliomas.     

Early operable breast cancer in elderly women treated with an aromatase inhibitor letrozole as sole therapy

Background:

Primary endocrine therapy (PET) with aromatase inhibitors (AIs) is an option in elderly patients unfit for or unwilling to undergo surgery. We studied the outcome of patients treated with letrozole as PET.

Methods:

Patients with early oestrogen receptor (ER)/progesterone receptor (PR)-positive breast cancer treated with letrozole from February 2001 to September 2009 were reviewed. Inoperable and locally advanced tumours were excluded. Reasons for offering PET, response, survival, cause of death, time to initial and best response, fracture incidence, and late failure rates were studied.

Results:

In all, 104 patients received PET due to frailty (n=48), comorbidity (n=30), old age (n=9), and patient preference (n=17). Median follow-up was 56 months (4–106). Eighty-five cancers responded to letrozole (stable disease (SD, n=19), reduction in size (PR, n=42), and complete response ((CR), n=24)). Median survival was 51 months (4–103), time to initial response (PR/CR) 4.5 months (2–24), and time to best response 8.5 months (3–50). Letrozole was stopped in 25 patients due to progressive disease (n=19), side effects (n=5), and patient choice (n=1). Only 12 of 49 deaths were from breast cancer.

Conclusion:

Letrozole is a reasonable alternative in elderly women with early ER/PR-positive invasive breast cancer who are unfit or unwilling to undergo standard therapy.     

Receptor for Advanced Glycation End Products (RAGE) and Implications for the Pathophysiology of Heart Failure

The receptor for advanced glycation end products (RAGE) is expressed in the heart in cardiomyocytes, vascular cells, fibroblasts, and in infiltrating inflammatory cells. Experiments in murine, rat, and swine models of injury suggest that RAGE and the ligands of RAGE are upregulated in key injuries to the heart, including ischemia/reperfusion injury, diabetes, and inflammation. Pharmacological antagonism of RAGE or genetic deletion of the receptor in mice is strikingly protective in models of these stresses. Data emerging from human studies suggest that measurement of levels of RAGE ligands or soluble RAGEs in plasma or serum may correlate with the degree of heart failure. Taken together, the ligand-RAGE axis is implicated in heart failure and we predict that therapeutic antagonism of RAGE might be a unique target for therapeutic intervention in this disorder.     

Cecal volvulus occurring after laparoscopic appendectomy.

Less than 2% of cases of intestinal obstruction in adults is caused by cecal volvulus. Although recent abdominal surgery has been implicated, no previous case of cecal volvulus has been reported after laparoscopic appendectomy.     

A study on utilization of anti–asthmatic drugs at a medical college hospital in India

ObjectiveTo study the usage of anti-asthmatic dugs and enumerate the patients' non-compliance.MethodsThe study was conducted from 5th Feb, 2006 to 5th Mar, 2006. The samples were from the general medicine ward. All patients with respiratory tract infection who received anti–asthmatic drugs were included in the study. Data were collected from clinical notes and structured patient's data, and patient interview utilizing a piloted questionnaire data collection form. The questionnaire included patient demographics, anti–asthmatics prescribed, dose, frequency and previous treatment if any and its duration, concomitant medications etc.Results26.31% of patients were 61–70 years old. Among 57 patients, 91.23% of patients received multi–therapy, 8.77% of patients received mono–therapy, 59.65% of patients took over the counter (OTC) drugs and 57.89% of patients were non compliant. Anti–asthmatic drugs were prescribed to asthmatic patients as oral, inhalation and others (injections), and more than one route were used for administration of drugs.ConclusionThe anti-asthmatics are used to treat breathing difficulties such as allergy. Poor compliance to treatment is common among the patients, which makes it difficult to manage asthma and increases both morbidity and mortality. It is suggested that interventions have to be done by providing counseling and improving the current prescribing trend for better and rational utilization.     

Backscattered Dose Perturbation Effects at Metallic Interfaces Irradiated by High-Energy X- and Gamma-Ray Therapeutic Beams

PURPOSE: To analyze backscattered dose enhancements near different metallic interfaces for cobalt-60 ((60)Co) gamma rays and 6- and 18-MV photon beams. MATERIAL AND METHODS: Measurements were carried out with a PTW thin-window, parallel-plate ionization chamber and an RDM-1F electrometer. Thin sheets of aluminum, mild steel, copper, cadmium and lead were used as inhomogeneities. The chamber was positioned below the inhomogenities with the gantry maintained under the couch. RESULTS: It can be noticed that the backscatter dose factor (BSDF) reaches the saturation value within few millimeters of all inhomogeneities and the thickness at which the saturation value is reached depends on the atomic number of the inhomogeneity. The amount of backscattered radiation was noticed to be greater with lesser-energy photons ((60)Co) compared to the high erenergy photons. The BSDF varies across the beam when the inhomogeneity is present due to the change in beam quality. The backscattered electrons from lead inhomogeneity have a range in the order of 5-7 mm. CONCLUSION: Higher atomic number inhomogeneities result in an increase in BSDF, as they have higher scattering cross section for the secondary electrons. The increase in dose was noticed for few millimeters upstream from the metallic inhomogeneity, which suggests that the range of backscattered electrons is very small. Since the factors affecting the BSDF at the interface are energy dependent, it is expected that the variation in BSDF will also be sensitive to the beam energy.