The C-Terminal Acidic Region of Calreticulin Mediates Phosphatidylserine Binding and Apoptotic Cell Phagocytosis [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Calreticulin is a calcium-binding chaperone that is normally localized in the endoplasmic reticulum. Calreticulin is detectable on the surface of apoptotic cells under some apoptosis-inducing conditions, where it promotes the phagocytosis and immunogenicity of dying cells. However, the precise mechanism by which calreticulin, a soluble protein, localizes to the outer surface of the plasma membrane of dying cells is unknown, as are the molecular mechanisms that are relevant to calreticulin-induced cellular phagocytosis. Calreticulin comprises three distinct structural domains: a globular domain, an extended arm-like P-domain, and a C-terminal acidic region containing multiple low-affinity calcium binding sites. We show that calreticulin, via its C-terminal acidic region, preferentially interacts with phosphatidylserine (PS) compared with other phospholipids and that this interaction is calcium dependent. Additionally, exogenous calreticulin binds apoptotic cells via a higher-affinity calcium-dependent mode that is acidic region dependent. Exogenous calreticulin also binds live cells, including macrophages, via a second, lower-affinity P-domain and globular domain–dependent, but calcium-independent binding mode that likely involves its generic polypeptide binding site. Truncation constructs lacking the acidic region or arm-like P-domain of calreticulin are impaired in their abilities to induce apoptotic cell phagocytosis by murine peritoneal macrophages. Taken together, the results of this investigation provide the first molecular insights into the phospholipid binding site of calreticulin as a key anchor point for the cell surface expression of calreticulin on apoptotic cells. These findings also support a role for calreticulin as a PS-bridging molecule that cooperates with other PS-binding factors to promote the phagocytosis of apoptotic cells.

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Raftlin Controls Lipopolysaccharide-Induced TLR4 Internalization and TICAM-1 Signaling in a Cell Type-Specific Manner [INNATE IMMUNITY AND INFLAMMATION]

The clathrin-dependent endocytic pathway is crucial for endosomal TLR3- and TLR4-mediated Toll–IL-1R domain–containing adaptor molecule-1 (TICAM-1) signaling. TLR4 uses a different signaling platform, plasma membrane and endosomes, for activation of TIRAP-MyD88 and TICAM-2–TICAM-1, respectively. LPS-induced endocytosis of TLR4 is mandatory for TICAM-1–mediated signaling including IFN-β production. Several molecules/mechanisms such as CD14, clathrin, and phosphatidylinositol metabolism have been reported to act as inducers of TLR4 translocation. However, the molecular mechanism of spatiotemporal regulation of TLR4 signaling remains unresolved. We have previously shown that Raftlin is essential for clathrin-dependent endocytosis of TLR3 ligand in human epithelial cells and myeloid dendritic cells (DCs). In this article, we demonstrate that Raftlin also mediated LPS-induced TLR4 internalization and TICAM-1 signaling in human monocyte-derived DCs and macrophages (Mo-Ms). When Raftlin was knocked down, LPS-induced TLR4-mediated IFN-β promoter activation, but not NF-B activation, was decreased in HEK293 cells overexpressing TLR4/MD-2 or TLR4/MD-2/CD14. LPS-induced IFN-β production by monocyte-derived DCs and Mo-Ms was significantly decreased by knockdown of Raftlin. Upon LPS stimulation, Raftlin moved from the cytoplasm to the plasma membrane in Mo-Ms, where it colocalized with TLR4. Raftlin associated with clathrin-associated adaptor protein–2 in resting cells and transiently bound to TLR4 and clathrin at the cell surface in response to LPS. Thus, Raftlin appears to modulate cargo selection as an accessary protein of clathrin-associated adaptor protein–2 in clathrin-mediated endocytosis of TLR3/4 ligands.

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Topical Application of Fingolimod Perturbs Cutaneous Inflammation [INNATE IMMUNITY AND INFLAMMATION]

The prevalence of allergies, including rhinitis, eczema, and anaphylaxis, is rising dramatically worldwide. This increase is especially problematic in children who bear the greatest burden of this rising trend. Increasing evidence identifies neutrophils as primary perpetrators of the more severe and difficult to manage forms of inflammation. A newly recognized mechanism by which neutrophils are recruited during the early phase of histamine-induced inflammation involves the sphingosine kinase (SK)/sphingosine-1-phosphate axis. This study examines whether topical application of fingolimod, an established SK/sphingosine-1-phosphate antagonist already in clinical use to treat multiple sclerosis, may be repurposed to treat cutaneous inflammation. Using two mouse models of ear skin inflammation (histamine- and IgE-mediated passive cutaneous anaphylaxis) we topically applied fingolimod prophylactically, as well as after establishment of the inflammatory response, and examined ear swelling, SK activity, vascular permeability, leukocyte recruitment, and production of proinflammatory mediators. The present study reveals that when applied topically, fingolimod attenuates both immediate and late-phase responses to histamine with reduced extravasation of fluid, SK-1 activity, proinflammatory cytokine and chemokine production, and neutrophil influx and prevents ear swelling. Intravital microscopy demonstrates that histamine-induced neutrophil rolling and adhesion to the postcapillary venules in the mouse ears is significantly attenuated even after 24 h. More importantly, these effects are achievable even once inflammation is established. Translation into humans was also accomplished with epicutaneous application of fingolimod resolving histamine-induced and allergen-induced inflammatory reactions in forearm skin. Overall, this study demonstrates, to our knowledge for the first time, that fingolimod may be repurposed to treat cutaneous inflammation.

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A MicroRNA-Mediated Positive Feedback Regulatory Loop of the NF-{kappa}B Pathway in Litopenaeus vannamei [INNATE IMMUNITY AND INFLAMMATION]

In the evolutionarily conserved canonical NF-B pathway, degradation of the NF-B inhibitor IB in the cytoplasmic NF-B/IB complex allows the liberated NF-B to translocate into the nucleus to activate various target genes. The regulatory mechanism governing this process needs further investigation. In this study, a novel microRNA, temporarily named miR-1959, was first identified from an invertebrate Litopenaeus vannamei. miR-1959 targets the 3'-untranslated region of the IB homolog Cactus gene and reduces the protein level of Cactus in vivo, whereas the NF-B homolog Dorsal directly binds the miR-1959 promoter to activate its transcription. Therefore, miR-1959 mediates a positive feedback regulatory loop, in that Dorsal activates miR-1959 expression, and in turn, miR-1959 inhibits the expression of Cactus, further leading to enhanced activation of Dorsal. Moreover, miR-1959 regulates the expression of many antimicrobial peptides in vivo and is involved in antibacterial immunity. To our knowledge, it is the first discovery of a microRNA-mediated feedback loop that directly regulates the NF-B/IB complex. This positive feedback loop could collaborate with the known NF-B/IB negative loop to generate a dynamic balance to regulate the activity of NF-B, thus constituting an effective regulatory mechanism at the critical node of the NF-B pathway.

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TLR10 Is a Negative Regulator of Both MyD88-Dependent and -Independent TLR Signaling [INNATE IMMUNITY AND INFLAMMATION]

TLRs are central components of the innate immune system which, upon recognition of bacterial, fungal or viral components, activate intracellular signals that lead to protective inflammatory responses. Among the 10-member human TLR family, TLR10 is the only remaining orphan receptor without a known ligand or signaling function. Murine TLR10 is a disrupted pseudogene, which precludes investigation using classic gene knockout approaches. We report here that TLR10 suppressed the production of an array of cytokines in stably transfected human myelomonocytic U937 cells in response to other TLR agonists. This broad TLR suppressive activity affects both MyD88- and TRIF-inducing IFN-β–mediated signaling pathways upstream of IB and MAPK activation. Compared with nontransgenic littermate controls, monocytes of TLR10 transgenic mice exhibited blunted IL-6 production following ex vivo blood stimulation with other TLR agonists. After i.p. injection of LPS, lower levels of TNFα, IL-6, and type 1 IFN were measured in the serum of TLR10 transgenic mice compared to nontransgenic mice, but did not affect mouse survival in an LPS-induced septic shock model. Finally, treatment of human mononuclear cells with a monoclonal anti-TLR10 Ab suppressed proinflammatory cytokines released by LPS stimulation. These results demonstrate that TLR10 functions as a broad negative regulator of TLR signaling and suggests that TLR10 has a role in controlling immune responses in vivo.

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Relationship of NKG2C Copy Number with the Distribution of Distinct Cytomegalovirus-Induced Adaptive NK Cell Subsets [INFECTIOUS DISEASE AND HOST RESPONSE]

CD94/NKG2C and lack of FcR (FcR) expression are considered markers of the adaptive NK cell response to human CMV (HCMV) infection. Despite the fact that FcR^– and NKG2C^bright NK cells share some phenotypic, epigenetic, and functional features, their relationship remains unclear. To address this issue, a systematic analysis of NKG2C^bright and FcR expression was carried out in NK cells from a cohort of healthy young adults (n = 81) considering NKG2C copy number, previously related to the magnitude of NKG2C⁺ NK cell expansion. NKG2C^bright and FcR^– NK cells coincided in a subgroup of HCMV⁺ individuals, pointing to a common host–virus interaction pattern. Even though FcR loss was often confined to expanded NKG2C^bright NK cells, both markers appeared occasionally dissociated, consistent with the existence of distinct adaptive NK cell subsets. Remarkably, FcR loss was mostly accumulated within the NKG2C^bright subset in NKG2C^+/+ subjects, whereas NKG2C^–FcR^– NK cell subpopulations were more frequently detected in NKG2C^+/del donors and also in NKG2C^del/del individuals, independently of activating killer Ig–like receptor expression. The distribution of other NK receptors (i.e., killer Ig–like receptor, LILRB1, or CD57) supported a sequential differentiation from NKG2C^brightFcR⁺ to NKG2C^brightFcR^– NK cells. Noticeably, NKG2C^bright NK cells produced more TNF-α in response to Ab-dependent activation, regardless of their FcR levels. Moreover, the TNF-α response of NKG2C^–FcR^– subpopulations was lower than that of concurrent NKG2C^brightFcR^– NK cells, further supporting that FcR levels and enhanced potential for cytokine production are uncoupled. Overall, our data extend the characterization of adaptive NK cell subsets that differentiate in response to HCMV, supporting a relationship between their distribution and NKG2C copy number.

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Differentiating School-Aged Children With and Without Language Impairment Using Tense and Grammaticality Measures From a Narrative Task

Purpose

To determine the diagnostic accuracy of the finite verb morphology composite (FVMC), number of errors per C-unit (Errors/CU), and percent grammatical C-units (PGCUs) in differentiating school-aged children with language impairment (LI) and those with typical language development (TL).

Method

Participants were 61 six-year-olds (50 TL, 11 LI) and 67 eight-year-olds (50 TL, 17 LI). Narrative samples were collected using a story-generation format. FVMC, Errors/CU, and PGCUs were computed from the samples.

Results

All of the three measures showed acceptable to good diagnostic accuracy at age 6, but only PGCUs showed acceptable diagnostic accuracy at age 8 when sensitivity, specificity, and likelihood ratios were considered.

Conclusion

FVMC, Errors/CU, and PGCUs can all be used in combination with other tools to identify school-aged children with LI. However, FVMC and Errors/CU may be an appropriate diagnostic tool up to age 6. PGCUs, in contrast, may be a sensitive tool for identifying children with LI at least up to age 8 years.

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Optimization of computation efficiency in underwater acoustic navigation system

This paper presents a technique for the estimation of the relative bearing angle between the unmanned underwater vehicle (UUV) and the base station for the homing and docking operations. The key requirement of this project includes computation efficiency and estimation accuracy for direct implementation onto the UUV electronic hardware, subject to the extreme constraints of physical limitation of the hardware due to the size and dimension of the UUV housing, electric power consumption for the requirement of UUV survey duration and range coverage, and heat dissipation of the hardware. Subsequent to the design and development of the algorithm, two phases of experiments were conducted to illustrate the feasibility and capability of this technique. The presentation of this paper includes system modeling, mathematical analysis, and results from laboratory experiments and full-scale sea tests.

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Effects of corrugation shape on frequency band-gaps for longitudinal wave motion in a periodic elastic layer

The paper concerns determining frequency band-gaps for longitudinal wave motion in a periodic waveguide. The waveguide may be considered either as an elastic layer with variable thickness or as a rod with variable cross section. As a result, widths and locations of all frequency band-gaps are determined by means of the method of varying amplitudes. For the general symmetric corrugation shape, the width of each odd band-gap is controlled only by one harmonic in the corrugation series with its number being equal to the number of the band-gap. Widths of even band-gaps, however, are influenced by all the harmonics involved in the corrugation series, so that the lower frequency band-gaps can emerge. These are band-gaps located below the frequency corresponding to the lowest harmonic in the corrugation series. For the general non-symmetric corrugation shape, the mth band-gap is controlled only by one, the mth, harmonic in the corrugation series. The revealed insights into the mechanism of band-gap formation can be used to predict locations and widths of all frequency band-gaps featured by any corrugation shape. These insights are general and can be valid also for other types of wave motion in periodic structures, e.g., transverse or torsional vibration.

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Short- and long-term monitoring of underwater sound levels in the Hudson River (New York, USA)

There is a growing body of research on natural and man-made sounds that create aquatic soundscapes. Less is known about the soundscapes of shallow waters, such as in harbors, rivers, and lakes. Knowledge of soundscapes is needed as a baseline against which to determine the changes in noise levels resulting from human activities. To provide baseline data for the Hudson River at the site of the Tappan Zee Bridge, 12 acoustic data loggers were deployed for a 24-h period at ranges of 0–3000 m from the bridge, and four of the data loggers were re-deployed for three months of continuous recording. Results demonstrate that this region of the river is relatively quiet compared to open ocean conditions and other large river systems. Moreover, the soundscape had temporal and spatial diversity. The temporal patterns of underwaternoise from the bridge change with the cadence of human activity. Bridge noise (e.g., road traffic) was only detected within 300 m; farther from the bridge, boating activity increased sound levels during the day, and especially on the weekend. Results also suggest that recording near the river bottom produced lower pseudo-noise levels than previous studies that recorded in the river water column.

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HDAC6-mediated EGFR stabilization and activation restrict cell response to sorafenib in non-small cell lung cancer cells

Abstract

Sorafenib is a multi-targeted kinase inhibitor and has been the subject of extensive clinical research in advanced non-small cell lung cancer (NSCLC). However, sorafenib fails to improve overall survival of patients with advanced NSCLC. The molecular mechanisms that account for this phenomenon are unclear. Here we show that sorafenib treatment stabilizes epidermal growth factor receptor (EGFR) and activates EGFR pathway. Moreover, this is partly mediated by stabilization of histone deacetylase 6 (HDAC6), which has been shown to regulate EGFR endocytic trafficking and degradation. Overexpression of HDAC6 confers resistance to sorafenib in NSCLC cells. Inhibition of HDAC6 with selective inhibitors synergizes with sorafenib to kill NSCLC cells via inhibition of sorafenib-mediated EGFR pathway activation. Taken together, our findings might partly explain the failure of Phase III trial of sorafenib in improving overall survival of advanced NSCLC patients and bear possible implications for the improvement on the efficacy of sorafenib in treatment of NSCLC.

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Assessment of the frequency of genetic alterations (LOH/MSI) in patients with intraepithelial cervical lesions with HPV infection: a pilot study

Abstract

In the present study, we analyzed (1) the type of HPV infection and (2) the frequency of loss of heterozygosity and microsatellite imbalance (LOH/MSI) in normal cytology and cervical intraepithelial neoplasia (CIN1-3). The cytological material included: low-grade squamous intraepithelial lesions (CIN1, n = 11), high-grade lesions (CIN2 and CIN3, n = 13), and cytologically normal cells from non-neoplastic cervical samples (n = 8). HPV genotyping was done using RealLine HPV 16/18 kit. We used 20 microsatellite markers from: 1p31.2, 3p14.3, 3p21.3, 3p22.2, 3p24.2, 3p25.3, 7q32.2, 9p21.3, 11p15.5, 12q23.2, and 16q22.1. LOH/MSI was correlated with clinicopathological parameters. The presence of HPV DNA was revealed in 78.13 % samples, including normal cytology. LOH/MSI was the most frequent for: 3p25.3 (39 %), 3p22.2 (20.83 %), 3p24.2 (20 %), and 3p14.3 (16.67 %). It was demonstrated that D3S1234 (FHIT; 3p14.3), D3S1611 (MLH1; 3p22.2), D3S1583 (RARB; 3p24.2), D3S1317 and D3S3611 (VHL; 3p25.3) could differentiate patients with CIN2/CIN3 versus CIN1, showing significantly higher frequency in CIN2/CIN3. LOH/MSI frequency for other than 3p markers was lower, 10–22.2 %. The simultaneous occurrence of LOH/MSI for several markers (OFAL) was higher in CIN2/CIN3. Significant differences in OFAL were found between samples with versus without HPV infection. In HPV-positive patients, significant differences in OFAL were found between normal cytology, CIN1 and CIN2/CIN3. HPV infection influences the increase in LOH/MSI frequency, especially in tumor suppressor gene loci. Several studied microsatellite markers seem to be useful for CIN grading. Hopefully, the obtained results, if confirmed on larger patient cohort, would allow creating a panel of markers supporting clinical diagnosis in patients with HPV infection.

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Intrinsic circuits of the striatum: Complexity and clinical correlations

The striatum is the input component of the basal ganglia circuits. It provides a hub for the interaction among multiple afferents and local intrastriatal networks that regulate basal ganglia function. Via their distinct cortical connections, different components of the striatum are key elements for control of different aspects of behavior: the nucleus accumbens is primarily involved in reward-based action learning, the caudate nucleus in goal-based action selection, and the putamen in habit formation and action sequencing.

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Clinical Reasoning: A young man with acute encephalopathy, loss of vision, and upper motor neuron signs

A 22-year-old man with no significant medical history presented at the hospital emergency department with a 1-day history of confusion and gradual loss of vision. Seven days before the presentation, he started complaining of holocranial headache, which was initially mild but eventually progressed to become severe in intensity, associated with nausea and vomiting, and was not responsive to paracetamol. There were no associated seizures.

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Retinitis pigmentosa in Lafora disease: Expanding findings of progressive myoclonic epilepsy

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Teaching NeuroImages: Red ear syndrome

A 41-year-old man presented with a 3-year history of unilateral pulsatile headaches associated with nausea, vomiting, photophobia, and 1 to 2 episodes per day of red, burning, itchy, and painful left pinna, lasting 4 hours, triggered by touch, increased temperature, and sun exposure (figure). The migraine headaches and the red pinna were temporally associated. His brother has migraines only. Examination was normal. MRI of the head and cervical spine including angiogram was unremarkable. Blood and CSF analyses were normal. Ear symptoms were worse with steroids. Beta-blockers and amitriptyline were unhelpful. Gabapentin has shown some benefit in reducing the frequency of attacks. This condition is called red ear syndrome and its pathophysiology is unclear. Secondary causes such as thalamic syndrome, temporomandibular joint dysfunction, carotid body adenoma, upper cervical spine lesions including Chiari I malformations, and vertebral artery compression at C3 need to be ruled out and migraine prophylaxis considered in migraine-related attacks.^1,2

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Global cerebral edema from hypercapnic respiratory acidosis and response to hyperosmolar therapy

Hypercapnic respiratory acidosis (HRA) causes cerebral vasodilation via perivascular extracellular pH changes.¹ Its ability to precipitate global cerebral edema (GCE) in the absence of acute brain injury is rare. Treatment in these reports involves mechanical ventilation.² We describe a rare case of HRA-induced GCE in a patient without brain injury and the efficacy of hyperosmolar treatment after mechanical ventilation failed.

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Teaching Video NeuroImages: Slow upward ocular bobbing

Slow upward ocular bobbing consists of slow upward conjugate eye movement, followed by a fast downward return to midposition, previously described with pontine pathology.^1,2 Our patient had an undiagnosed CSF leak in the setting of a postoperative pseudomeningocele with decline in her level of consciousness, absent oculocephalic reflexes, and intact corneal and pupillary light reflexes. She exhibited slow upward ocular bobbing (video on the Neurology® Web site at Neurology.org), which increased in frequency with noxious stimuli. Imaging revealed brain sag with ventral pontine flattening. Despite repair of the pseudomeningocele, the patient remained comatose requiring mechanical ventilation and passed shortly after care was withdrawn.

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Punctate pattern: A promising imaging marker for the diagnosis of natalizumab-associated PML

Objective:

To evaluate the usefulness of the punctate pattern (PP) for the diagnosis and follow-up of patients with progressive multifocal leukoencephalopathy (PML).

Methods:

A cohort of 20 consecutive patients with PML, related to natalizumab (NTZ) (n = 14) or not (n = 6), underwent 3T MRI (147 MRI examinations). MRI was available at presymptomatic (n = 9 patients), symptomatic (n = 15), immune reconstitution inflammatory syndrome (IRIS), and chronic stages (n = 20). A pathologic control group of patients without PML (n = 80), with clinically definitive multiple sclerosis or a clinically isolated syndrome suggestive of CNS demyelination, underwent the same MRI protocol. Number and appearance of punctate lesions were assessed by 3 blinded readers using T2-weighted, fluid-attenuated inversion recovery (FLAIR), and postcontrast T1-weighted images.

Results:

Interobserver agreement was good ( = 0.79) (0.72–0.87). Of the 20 patients with PML, 18 had PP, including the 14 patients with NTZ-PML; none in the pathologic control group. Of the 9 presymptomatic patients with NTZ-PML, PP was observed in 7 (78% sensitive and 100% specific). Nonenhancing PP on T2-weighted/FLAIR images was detected in 13 patients with PML, exclusively at the presymptomatic or symptomatic stages (including 7 NTZ-PML), whereas enhancing PP occurred in 16 patients with PML, including 13 of the 14 patients with NTZ-PML at the IRIS stage.

Conclusions:

PP is a highly specific feature of PML and may be the first imaging feature at the presymptomatic stage with potential implications in patient care.

Classification of evidence:

This study provides Class II evidence that a PP on MRI accurately identifies patients with NTZ-PML.

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Spotlight on the April 19 Issue

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Huntington disease among the Navajo: A population-based study in the Navajo Nation

Huntington disease (HD) has a protracted course that imparts substantial personal and economic burden.¹ Disease rates vary by geographic location. In Western countries, prevalence approximates 5.7/100,000; rates are tenfold lower in Asia.² Epidemiologic studies from the United States report on mostly white populations.² Few studies give rates of HD among minorities, and there are no comprehensive descriptions of HD in American Indians. Better understanding of how the disease affects discrete populations could produce hypotheses for new approaches to treatment.

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Calming the excitement in ALS

The concept of excitotoxicity, first established by the pioneering work of John Olney,¹ traditionally has been applied to lesions of the CNS, focusing mostly on glutamate as a neurotoxic excitatory amino acid neurotransmitter. Indeed, glutamate excitotoxicity remains one of the best-supported theories for motor neuron death in amyotrophic lateral sclerosis (ALS),² and was the pharmacologic inspiration for riluzole, which remains the only drug proven to slow the course of ALS.³ The excitotoxic model of disease can be appropriately extended to the peripheral nervous system (PNS), where overactivity of peripheral axons leads to symptoms of fasciculations and cramping. However, the increased firing of peripheral axons could also result in antidromic stimulation of parent motor and sensory neurons, resulting in increased excitatory activity and possibly excitotoxic injury. In this model, therapeutic interventions are directed at reducing axonal firing, which can be accomplished by blocking sodium channels.

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Identification of cooperative genes for E2A-PBX1 to develop acute lymphoblastic leukemia

Abstract

E2A-PBX1 is a chimeric gene product detected in t(1;19)-bearing acute lymphoblastic leukemia (ALL) with B-cell lineage. To investigate the leukemogenic process, we generated conditional knock-in (cKI) mice for E2A-PBX1, in which E2A-PBX1 is inducibly expressed under the control of the endogenous E2A promoter. Despite the induced expression of E2A-PBX1, no hematopoietic disease was observed, strongly suggesting that additional genetic alterations are required to develop leukemia. To address this possibility, retroviral insertional mutagenesis was employed. Virus infection efficiently induced T-cell, B-cell and biphenotypic ALL in E2A-PBX1 cKI mice. Inverse PCR identified eight retroviral common integration sites, in which enhanced expression was observed in the Gfi1, Mycn and Pim1 genes. In addition, it is of note that viral integration and overexpression of Zfp521 gene was detected in one tumor with B-cell lineage, since we previously identified Zfp521 as a cooperative gene with E2A-HLF, another E2A-involving fusion gene with B-lineage ALL. The cooperative oncogenicity of E2A-PBX1 with overexpressed Zfp521 in B-cell tumorigenesis was demonstrated by the finding that E2A-PBX1 cKI, Zfp521 transgenic compound mice developed B-lineage ALL. Moreover, upregulation of ZNF521 the human counterpart of Zfp521, was found in several human leukemic cell lines bearing t(1;19). These results indicate that E2A-PBX1 cooperates with additional gene alterations to develop ALL, and among them, enhanced expression of ZNF521 may play a clinically relevant role in E2A fusion genes to develop B-lineage ALL.

This article is protected by copyright. All rights reserved.

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Chronic mesothelial reaction and toxicity of potassium octatitanate fibers in the pleural cavity in mice and F344 rats

Summary

Fiber shaped particles of potassium octatitanate (trade name TISMO; chemical formula K₂O･6TiO₂), which are morphologically similar to asbestos particles, were shown to induce severe proliferative reactions in the pleural mesothelium in a previous experiment conducted over 21 weeks. The present study aims to determine whether these fibers induce malignant mesotheliomas in rodents or not, and to examine chronic toxicity induced. Additionally, we investigated the specific differences observable between the biological responses to the direct infusion of the fibers alone into the pleural cavity and those induced by the co-administration of the fibers with a known carcinogen.

To detect the induction of malignant pleural mesotheliomas, two experiments were conducted. In Experiment 1, 4 strains of mice, A/J, C3H, ICR, and C57BL, were examined for 52 weeks after experimental treatment with TISMO. In Experiment 2, the F344 rats were treated with TISMO, the lung carcinogen N-bis (2-hydroxypropyl) nitrosamine (DHPN), both TISMO and DHPN, or left untreated and were then examined for 52 weeks. In this experiment, malignant lesion induction was expected in the co-administration group.

TISMO fibers were observed in the alveoli, indicating penetration through the visceral pleura in mice and rats. The histopathological detection of TISMO fibers in the liver and kidneys of mice and rats indicated migration of the fibers out of the pleural cavity. Atypical mesothelial cells with severe pleural proliferation were observed, but malignant mesotheliomas were not detected. Among the rats, there were no observed malignant alterations in the mesothelium induced by DHPN-TISMO co-administration.

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Klinik und Histologie Metallimplantat-assoziierter Hauterscheinungen

Zusammenfassung

Metallimplantatunverträglichkeit kann zu Schmerzen, Bewegungseinschränkung, Implantatlockerung und Hautreaktionen führen. Kenntnisse der Differenzialdiagnosen und der relevanten Diagnostik einschließlich Histologie sind essenziell für die richtige Diagnosestellung. Zur Erläuterung der typischen Klinik und Histologie bei Metallimplantat-assoziierten Hauterscheinungen werden 3 prototypische Patientenfälle aus der Implantatsprechstunde vorgestellt, und eine Übersicht über die aktuelle Literatur zur Problematik der Metallimplantatunverträglichkeit wird gegeben. Selbst bei negativer Epikutantestung kann ein Lymphozytentransformationstest (LTT) Metallsensibilisierungen anzeigen. Und auch „reine" Titanlegierungen können Nickelkontamination aufweisen. Die Histologie des Spektrums an Implantat-assoziierten Hautveränderungen reicht von teleangiektatischem Postimplantationserythem über Ekzem zu Vaskulitis. In Zusammenschau von Anamnese, Symptomatik, klinischem Bild, Allergiediagnostik und Histologie kann eine Metallimplantatunverträglichkeit genauer diagnostiziert werden.

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Rolle des Lymphozytentransformationstests zur Beurteilung einer Metallsensibilisierung

Zusammenfassung

Hintergrund

Der Lymphozytentransformationstest (LTT) dient dem Nachweis einer T‑zellulären Sensibilisierung. Sein Nutzen wurde in der Vergangenheit kontrovers diskutiert.

Fragestellung

Welche Rolle kann der LTT beim Nachweis einer Metallsensibilisierung spielen?

Methoden

Der Stand des Wissens zum Thema LTT wird anhand der aktuellen Literatur und auch eigener Arbeiten dargestellt.

Ergebnisse

In einigen Studien konnte nachgewiesen werden, dass der LTT – gerade was Metalle betrifft – eine ausreichende Spezifität bzw. Sensitivität besitzt. Dabei wurden in der Vergangenheit auch verschiedene modifizierte Testprotokolle entwickelt. Er stellt einen wissenschaftlichen Ansatz dar, der jeweils von den durchführenden Laboren entsprechend evaluiert werden muss.

Schlussfolgerungen

Zum Nachweis einer Metallsensibilisierung kann der LTT ein sinnvolles Hilfsmittel darstellen, v. a. bei Situationen, bei denen die Exposition nicht über die Haut, sondern im Inneren des Körpers stattfindet (z. B. Metallimplantate).

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Equol inhibits prostate cancer growth via degradation of the androgen receptor by Skp2

Summary

Chemo-preventative and potential therapeutic effects of soy isoflavones have been shown to be effective in numerous pre-clinical studies as well as clinical studies in prostate cancer. Although the inhibition of androgen receptor signaling has been supposed as one mechanism underlying their effects, the precise mechanism of androgen receptor inhibition remains unclear. Thus, this study aimed to clarify their mechanism. Among soy isoflavones, equol suppressed androgen receptor as well as prostate-specific antigen expression most potently in androgen-dependent LNCaP cells. However, the inhibitory effect on androgen receptor expression and activity was less prominent in castration-resistant CxR and 22Rv1 cells. Consistently, cell proliferation was suppressed and cellular apoptosis was induced by equol in LNCaP cells, but less in CxR and 22Rv1 cells. We revealed that the proteasome pathway via Skp2 was responsible for androgen receptor suppression. Taken together, soy isoflavones, especially equol, appear to be promising as chemopreventative and therapeutic agents for prostate cancer based on the fact that equol augments Skp2-mediated androgen receptor degradation. Moreover, because Skp2 expression was indicated to be crucial for the effect of soy isoflavones, soy isoflavones may be applicable for pre-cancerous and cancerous prostates.

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Prognosis of metastatic renal cell carcinoma with first-line Interferon-α therapy in the era of molecular-targeted therapy

Abstract

The RCC-SELECT study showed the correlation between single nucleotide polymorphisms (SNPs) in STAT3 gene and survival in metastatic renal cell carcinoma (mRCC) patients with first-line interferon-α (IFN-α). In that study, even patients with STAT3 SNPs linked to shorter overall survival (OS) exhibited remarkably improved prognosis. All 180 patients evaluated in the above study were further analysed for correlation between OS and demographics/clinicopathological parameters. OS was estimated using the Kaplan-Meier method. Associations between OS and potential prognostic factors were assessed using the log-rank test and the Cox proportional hazards model. The median OS was 42.8 months. Univariate analysis showed that worse Eastern Cooperative Oncology Group-performance status (ECOG-PS), high T stage, regional lymph node metastasis, distant metastasis, higher grade, infiltrative growth pattern, the presence of microscopic vascular invasion (MVI), hypercalcemia, anemia, thrombocytopenia and elevated C-reactive protein were significantly associated with OS. Multivariate analysis revealed that ECOG-PS [hazard ratio (HR) = 3.665, P = 0.0004], hypercalcemia [HR = 6.428, P = 0.0005] and the presence of MVI [HR = 2.668, P = 0.0109] were jointly significant poor prognostic factors. This is the first study analysing prognostic factors of mRCC patients with first-line IFN-α using large cohort of the prospective study. The present study suggests that first-line IFN-α is still a useful therapy for mRCC even in the era of molecular targeted therapy.

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Prognostic and predictive value of extended RAS mutation and mismatch repair status in stage III colorectal cancer

Abstract

The prognostic and predictive value of KRAS gene mutations in stage III colorectal cancer is controversial because many recent clinical trials have not involved a surgery-alone arm.　Additionally, data on the significance of extended RAS (KRAS/NRAS) mutations in stage　III cancer are not available. Hence, we performed a combined analysis of two phase 3　randomized trials, in which the usefulness of adjuvant chemotherapy with UFT was　evaluated, as compared with surgery alone. We determined the association of extended　RAS and mismatch repair (MMR) status with the effectiveness of adjuvant chemotherapy.　Mutations in KRAS exons 2, 3, 4 and NRAS exons 2, 3 were detected by direct DNA　sequencing. Tumor MMR status was determined by immunohistochemistry. Total RAS mutations were detected in 134/304 (44%) patients. In patients with RAS mutations, a significant benefit was associated with adjuvant UFT in RFS (HR=0.49 (0.27-0.91); p=0.02) and OS (HR=0.51 (0.26-0.97); p=0.03). In contrast, among patients without RAS mutations, there was no difference in RFS and OS between the adjuvant UFT group and surgery-alone group. MMR deficiency (dMMR) was detected in 23/304 (8%) patients. MMR status was neither prognostic nor predictive for adjuvant chemotherapy, although the small number of dMMR tumors might have affected. An interaction analysis showed that there was a better RFS among patients treated with UFT with RAS mutations, but not for those without RAS mutations. Extended RAS (KRAS/NRAS) mutations are proposed be predictive indicators with respect to the efficacy of adjuvant UFT chemotherapy in patients with resected stage III colorectal cancer.

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B7-H4 facilitates proliferation of esophageal squamous cell carcinoma cells through promoting IL-6/STAT3 pathway activation

Summary

B7-H4, one of the costimulatory molecules of B7 family, has been found to be widely expressed in many kinds of tumor tissues and to play an important part in tumor progression and poor prognosis. However, the role of B7-H4 in esophageal squamous cell carcinoma (ESCC) cells has not been elucidated. In this study, we found that, compared with normal esophageal tissue, B7-H4 was highly expressed in three ESCC cell lines, Eca109, TE1 and TE13. Besides, B7-H4 silence suppressed cells proliferation and colony formation. Additionally, compared with control cells, B7-H4 silence cells showed higher apoptosis rate, Bcl-2 and Survivin upregulation as well as BAX downregulation. Further study demonstrated that B7-H4 silence cells also exhibited reduction of IL-6 secretion, STAT3 activation and p-STAT3 translocation from cytoplasm to nucleus. Moreover, B7-H4 depletion inhibited the IL-6 secretion of control cells but not JAK2/STAT3 inhibitor FLLL32 treated cells. IL-6 receptor antagonist Tocilizumab didn't block the p-JAK2 and p-STAT3 downregulation induced by B7-H4 silence. It was suggested that B7-H4 silence suppressed IL-6 secretion through JAK2/STAT3 inactivation. Furthermore, cells proliferation and colony formation were downregulated by Tocilizumab in control cells but not B7-H4 silence cells demonstrating that IL-6 upregulation induced by B7-H4 was necessary for cells growth. On the other hand, B7-H4 expression was downregulated by Tocilizumab. In all, our study provided the first evidence that B7-H4 facilitated ESCC cells proliferation through promoting IL-6/STAT3 positive loopback pathway activation.

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miR-124-3p regulates cell proliferation, invasion, apoptosis and bioenergetics by targeting PIM1 in astrocytoma

Abstract

PIM1 is an important regulator of cell proliferation, the cell cycle, apoptosis, and metabolism in various human cancers. MicroRNAs (miRNAs) are powerful post-transcriptional gene regulators that function via translational repression or transcript destabilization. Therefore, we aimed to identify whether a close relationship exists between PIM1 and miRNAs. The PIM1 protein levels and mRNA levels were significantly upregulated in astrocytoma tissues, indicating the oncogenic role of PIM1 in astrocytoma. Further bioinformatics analysis indicated that miR-124-3p targeted the 3′-untranslated region (3′-UTR) of PIM1. We also observed an inverse correlation between the miR-124-3p levels and PIM1 protein or mRNA levels in astrocytoma samples. Next, we experimentally confirmed that miR-124-3p directly recognizes the 3′-UTR of the PIM1 transcript and regulates PIM1 expression at both the protein and mRNA levels. Furthermore, we examined the biological consequences of miR-124-3p targeting PIM1 in vitro. We demonstrated that the repression of PIM1 in astrocytoma cancer cells by miR-124-3p suppressed proliferation, invasion, and aerobic glycolysis and promoted apoptosis. We observed that the restoration or inhibition of PIM1 activity resulted in effects that were similar to those induced by miR-124-3p inhibitors or mimics in cancer cells. Finally, overexpression of PIM1 rescued the inhibitory effects of miR-124-3p. In summary, these findings aid in understanding the tumor suppressive role of miR-124-3p in astrocytoma pathogenesis through the inhibition of PIM1 translation.

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Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis

Abstract

Asbestos-induced mesothelial carcinogenesis is currently a profound social issue due to its extremely long incubation period and high mortality rate. Therefore, procedures to prevent malignant mesothelioma in people already exposed to asbestos are important. In previous experiments, we established an asbestos-induced rat peritoneal mesothelioma model, which revealed that local iron overload is a major cause of pathogenesis and that the induced genetic alterations were similar to human counterparts. Furthermore, we showed that oral administration of deferasirox modified the histology from sarcomatoid to the more favorable epithelioid subtype. Here, we used intraperitoneal administration of desferal to evaluate its effects on asbestos-induced peritoneal inflammation and iron deposition, as well as oxidative stress. Nitrilotriacetate (NTA) was used to promote an iron-catalyzed Fenton reaction as a positive control. Desferal significantly decreased peritoneal fibrosis, iron deposition and nuclear 8-hydroxy-2′-deoxyguanosine levels in mesothelial cells, whereas NTA significantly increased all of them. Desferal was more effective in rat peritoneal mesothelial cells (RPMCs) to counteract asbestos-induced cytotoxicity than in RAW264.7. Furthermore, rat sarcomatoid mesothelioma cells were more dependent on iron for proliferation than RPMCs. Because inflammogenicity of a fiber is proportionally associated with subsequent mesothelial carcinogenesis, iron elimination from the mesothelial environment can confer dual merits for preventing asbestos-induced mesothelical carcinogenesis by suppressing inflammation and mesothelial proliferation simultaneously.

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Identification of cooperative genes for E2A-PBX1 to develop acute lymphoblastic leukemia

Abstract

E2A-PBX1 is a chimeric gene product detected in t(1;19)-bearing acute lymphoblastic leukemia (ALL) with B-cell lineage. To investigate the leukemogenic process, we generated conditional knock-in (cKI) mice for E2A-PBX1, in which E2A-PBX1 is inducibly expressed under the control of the endogenous E2A promoter. Despite the induced expression of E2A-PBX1, no hematopoietic disease was observed, strongly suggesting that additional genetic alterations are required to develop leukemia. To address this possibility, retroviral insertional mutagenesis was employed. Virus infection efficiently induced T-cell, B-cell and biphenotypic ALL in E2A-PBX1 cKI mice. Inverse PCR identified eight retroviral common integration sites, in which enhanced expression was observed in the Gfi1, Mycn and Pim1 genes. In addition, it is of note that viral integration and overexpression of Zfp521 gene was detected in one tumor with B-cell lineage, since we previously identified Zfp521 as a cooperative gene with E2A-HLF, another E2A-involving fusion gene with B-lineage ALL. The cooperative oncogenicity of E2A-PBX1 with overexpressed Zfp521 in B-cell tumorigenesis was demonstrated by the finding that E2A-PBX1 cKI, Zfp521 transgenic compound mice developed B-lineage ALL. Moreover, upregulation of ZNF521 the human counterpart of Zfp521, was found in several human leukemic cell lines bearing t(1;19). These results indicate that E2A-PBX1 cooperates with additional gene alterations to develop ALL, and among them, enhanced expression of ZNF521 may play a clinically relevant role in E2A fusion genes to develop B-lineage ALL.

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Chronic mesothelial reaction and toxicity of potassium octatitanate fibers in the pleural cavity in mice and F344 rats

Summary

Fiber shaped particles of potassium octatitanate (trade name TISMO; chemical formula K₂O･6TiO₂), which are morphologically similar to asbestos particles, were shown to induce severe proliferative reactions in the pleural mesothelium in a previous experiment conducted over 21 weeks. The present study aims to determine whether these fibers induce malignant mesotheliomas in rodents or not, and to examine chronic toxicity induced. Additionally, we investigated the specific differences observable between the biological responses to the direct infusion of the fibers alone into the pleural cavity and those induced by the co-administration of the fibers with a known carcinogen.

To detect the induction of malignant pleural mesotheliomas, two experiments were conducted. In Experiment 1, 4 strains of mice, A/J, C3H, ICR, and C57BL, were examined for 52 weeks after experimental treatment with TISMO. In Experiment 2, the F344 rats were treated with TISMO, the lung carcinogen N-bis (2-hydroxypropyl) nitrosamine (DHPN), both TISMO and DHPN, or left untreated and were then examined for 52 weeks. In this experiment, malignant lesion induction was expected in the co-administration group.

TISMO fibers were observed in the alveoli, indicating penetration through the visceral pleura in mice and rats. The histopathological detection of TISMO fibers in the liver and kidneys of mice and rats indicated migration of the fibers out of the pleural cavity. Atypical mesothelial cells with severe pleural proliferation were observed, but malignant mesotheliomas were not detected. Among the rats, there were no observed malignant alterations in the mesothelium induced by DHPN-TISMO co-administration.

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Pyomyositis in a patient with systemic lupus erythaematosus and a review of the literature

Pyomyositis (PM) is a common masquerading disease that is frequently misdiagnosed. A concurrent state of immunodeficiency is observed in up to 75% of tropical PM cases. PM in systemic lupus erythaematosus (SLE) is a relatively rare disease. I report a case of PM that was caused by Klebsiella pneumoniae in a patient with SLE who presented with leg pain, fever and a lupus flare-up. The patient was correctly diagnosed using a CT scan. Immediate surgical drainage was performed, and empirical antibiotics were administered. The patient was discharged while in a recovering condition. The clinical features, the results of radiographic investigations and the management of PM in SLE are synopsised in this article to underscore the importance of considering this relatively rare disease during differential diagnosis in patients with SLE with muscle pain with or without fever. I also emphasise the need to exclude mycobacterial infection in patients with SLE with PM.

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Dentigerous cyst arising from a complex odontoma: an unusual presentation

Description

A 21-year-old man presented with pain in the right posterior region of the jaw for 10–15 days. The pain was mild, dull and non-radiating in nature, beginning with slight pressure and relieved within seconds. Clinically, the patient was healthy with an unremarkable medical history. On inspection, the patient had congenitally missing mandibular molar teeth along with absence of clinical swelling intraorally. Panoramic radiograph showed an amorphous, dense, irregularly shaped radio-opacity surrounded by a well-defined radiolucency in the apical region of 46, 47 and 48, which extended anteriorly to involve an impacted mandibular first molar tooth (figure 1). Complete surgical excision was performed and tissue sent for histopathological examination. The soft tissue was separated from the calcified mass during the surgical removal. The cystic and calcified components needed different processing techniques for further investigations and hence each tissue sample was processed separately.

Figure 1

Panoramic radiograph...

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Severe transaminitis in a paediatric patient with systemic lupus erythaematosus and a discussion of the literature

A 15-year-old African-American girl with known systemic lupus erythaematosus (SLE) presented to the emergency room with fever, abdominal distension, pain and vomiting. She was found to have severe transaminitis on laboratory examination, which prompted further work up including imaging and liver biopsy. Although complete diagnostic criteria were not met, histology was suggestive of autoimmune hepatitis (AIH). She was treated with steroids and azathioprine with good response and resolution of liver function tests. Availability of the literature discussing patients of any age with SLE and AIH is minimal, and consists mostly of small case series and some case reports. The juvenile literature on SLE and AIH occurring in the same patient is even scarcer and should be further studied at a multicentre level.

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Synchronous presentation of two rare forms of extrapulmonary tuberculosis

Tuberculosis (TB) remains one of the leading infectious causes of death throughout the world. Extrapulmonary forms, namely adrenalitis and prostatitis, are rare presentations of TB and pose a difficult diagnostic challenge, given their non-specific manifestations. The authors present a case of a 42-year-old man with long-standing symptoms of fatigue, anorexia, weight loss, nightly fever and sudoresis. He also suffered from sporadic vomiting and episodic hypotension, and had skin hyperpigmentation, as well as frequent urination, perineal discomfort and pain at ejaculation. Laboratory investigation confirmed primary adrenal failure. On CT scan there were two hypodense right adrenal nodules and bilateral lung condensations with a tree-in-bud pattern. Another hypodense nodule was seen in the prostate. TB was diagnosed by isolating Mycobacterium tuberculosis following cultures of bronchoalveolar lavage, bronchial secretions, urine and ejaculate. Antibacillary treatment resolved the infectious lesions but the patient remained on corticosteroid replacement therapy for ongoing adrenal failure.

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Zellweger syndrome with severe malnutrition, immunocompromised state and opportunistic infections

Peroxisome biogenesis disorders are related to a spectrum of genetic diseases that range from severe Zellweger syndrome to milder infantile Refsum disease. Zellweger syndrome is characterised by dysmorphic features, severe hypotonia, seizures, failure to thrive, liver dysfunction and skeletal defects. Increased levels of very long chain fatty acids are the biochemical hallmark and the most common mutations found in the PEX1 gene. We report an unusual presentation of Zellweger syndrome in a 2-month-old female infant with severe malnutrition, opportunistic infections, lymphopaenia and a small thymic shadow on chest radiography. With this clinical picture, an initial hypothesis of primary immunodeficiency was considered. It was later confirmed to not be the case. On follow-up, global developmental delay, bilateral optic nerve atrophy and moderate bilateral sensorineural deafness grade II were documented. There were no further infectious complications and we concluded malnutrition was the cause of the infant's immunocompromised state.

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Lymphoedema of the upper limb: a rare complication of thyroid surgery?

A 40-year-old woman underwent an elective thyroidectomy for a non-toxic, multinodular goitre. In the early postoperative period, the patient developed a significant unilateral swelling of the right upper limb, which was subsequently confirmed to be lymphoedema. This was eventually treated successfully using liposuction and compression garment therapies. We report the case due to its rarity and present a possible explanation for such an unexpected complication based on known anatomical variations of lymphatic drainage of the upper limb.

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Migratory pushpin in the tracheobronchial tree

Description

A healthy 10-year-old boy presented to the emergency department, with a 3-day history of cough and odynophagia, which started after eating squid. On examination, he had decreased breath sounds in the lower half of the right lung. The physical examination was otherwise unremarkable. Chest X-ray showed a consolidation of the right lower lobe with small pleural effusion, and a foreign body in the right bronchus (figure 1A). The patient was admitted for antibiotic treatment and bronchoscopy, but had a sudden onset of coughing with respiratory distress, pale skin and cold extremities, for a few seconds. A subsequent chest X-ray performed after this episode showed that the foreign body had migrated to the left bronchus (figure 1B). Rigid bronchoscopy revealed a pushpin in the left main bronchus, which was removed. Recovery was uneventful. Follow-up X-ray was normal.

Figure 1

(A) Chest radiograph of...

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A mild phenotype associated with a de novo microdeletion 10q23.1-q23.2: a new patient with a novel feature

Chromosome 10q23 contains several genes, including PTEN and BMPR1A, the mutations or microdeletion of which are associated with aggressive polyposis and malignancies in children. Deletions in this chromosomal region have also been associated with heart anomalies, developmental delay and macrocephaly. Most of the cases reported involve the PTEN and BMPR1A genes, usually associated with complex and severe anomalies. We report a case of a boy with a de novo interstitial microdeletion in 10q23.1-q23.2 spanning 6.7 Mb with boundaries from 82 087 077 to 88 847 906, not including PTEN and BMPR1A. Clinical features consisted of mildly dysmorphic facies, frontal telangiectasias, poor scholastic performance and hyperactivity. Furthermore, the boy presented toe anomalies, which appeared to be novel features associated with 10q23 deletion. Further observations of 10q23.1-q23.2 deletions are necessary to confirm the clinical features observed in the proband, and to show that deletion or mutations not involving PTEN and BMPR1A may not be associated with severe neurological impairment and malformation anomalies.

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A diagnostic dilemma in a case of pulmonary inflammatory myofibroblastic tumour

An 18-year-old man presented to the local hospital in Malta, with dyspnoea, cough, mild haemoptysis, chest pain and night sweats. CT revealed a right hilar mass. Pleural tap, bronchoscopy and open lung biopsy were inconclusive. Biopsies obtained at repeat bronchoscopy and endobronchial ultrasound (EBUS) revealed a likely diagnosis of inflammatory myofibroblastic tumour (IMT). The patient subsequently underwent right pneumonectomy, and histology revealed the presence of two further nodules apart from the main tumour. Follow-up with positron emission tomography (PET)/CT showed the development of a right basal paracardial lesion due to recurrence and the presence of lymph node, pleural and skeletal disease. Despite radiotherapy to the recurrent nodule and chemotherapy, there was skeletal disease progression. Treatment with an anaplastic lymphoma kinase inhibitor, ceritinib, resulted in very good metabolic response. This case report highlights the importance of keeping IMT in mind when the diagnosis of lung tumours is difficult, as delayed diagnosis may lead to worsened prognosis.

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Acute idiopathic blue fingers: a young man with Achenbach's syndrome

We report a case of a 20-year-old man presenting with acute painful blue fingers. All physical findings, including an Allen test, were normal, and systematic symptoms frequently seen in collagen diseases were absent. Although we performed a wide variety of investigations including medical imaging, no specific abnormal findings were observed. Skin biopsy pathology was an important reference. The patient's symptoms gradually improved and were completely resolved without specific treatment. Based on the clinical presentation and course, we gave a diagnosis of Achenbach's syndrome, developed in a young male. Achenbach's syndrome is rare, but still may be encountered in clinical practice. The symptoms can be startling to the patient, eliciting fear of something terrible when, in fact, the syndrome is relatively benign and has a good prognosis. Recognising this disease quickly after presentation helps to eliminate the anxiety of the patient, as well as reducing excessively invasive investigations. We present a case report to enlighten Achenbach's syndrome.

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Comparison of the Oral Microbiome of Siblings Using Next-generation Sequencing: a Pilot Study

Abstract

Objective

The purpose of this study was to compare the oral microbiome of siblings with and without dental caries using next-generation sequencing.

Materials and Methods

To investigate the oral microbiome composition, 14 young siblings, 7 with caries and 7 without, were enrolled from seven sibling-pair families. Supragingival plaque samples were collected from the cervicobuccal area of posterior teeth. All samples were analyzed by pyrosequencing, based on the 16S rRNA gene hypervariable regions, V1-V4.

Results

The organisms identified belonged to 65 genera. Fifty-two genera were identified in the subjects with caries and 58 in those without; 45 genera were shared by both groups. In the Shannon index, the caries group showed lower bacterial diversity than the caries-free group and the difference was significant (Wilcoxon signed-rank test, p < 0.05). Additionally, similarities between siblings were evident in analyses based on weighted UniFrac distances (p < 0.05).

Conclusions

In this study, the diversity of the microbiome was reduced in subjects with dental caries, while similarity between siblings seemed to be retained.

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Histological validation of ICDAS II and radiological assessment of occlusal carious lesions in permanent teeth

Abstract

The International Caries Detection and Assessment System (ICDAS) was introduced for a detailed evaluation of dental caries. The aim of the present study was to compare the ICDAS scores and radiologically evaluated caries depths to the histologically evaluated carious lesions in permanent teeth. 84 freshly extracted human teeth were included. Visual examination and scoring of the occlusal aspect were performed according to the ICDAS II criteria after completing a respective e-learning programme to support training in the use of ICDAS. Bucco-lingual digital X-ray images of the teeth were taken. Specimens were then fixed in formalin and embedded in a photocuring one-component methacrylate-based resin. Longitudinal sections were cut and stained with rhodamine B, fuchsin and acetic light green dye to assess the caries extension by light microscopic analysis. Assessing ICDAS II scores and histological findings, a rank correlation coefficient of r = 0.890 could be found. ICDAS II/radiology and histology/radiology showed correlation coefficients of r = 0.658 and 0.661, respectively. Evaluating receiver operating characteristic (ROC) curves, no exact predictability could be found for caries lesions in enamel for both ICDAS II and radiological evaluation. Focussing on deep dentin lesions, values of 0.940 (ICDAS II) and 0.845 (radiology) showed high predictability with respect to the histologically observed caries extension. The present study indicates an acceptable validity of the ICDAS II criteria when applied to permanent teeth. Especially, dentin lesions can be reliably detected. Thus, ICDAS assessment provides the possibility of reducing X-ray exposure for caries detection.

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Comparison of the Oral Microbiome of Siblings Using Next-generation Sequencing: a Pilot Study

Abstract

Objective

The purpose of this study was to compare the oral microbiome of siblings with and without dental caries using next-generation sequencing.

Materials and Methods

To investigate the oral microbiome composition, 14 young siblings, 7 with caries and 7 without, were enrolled from seven sibling-pair families. Supragingival plaque samples were collected from the cervicobuccal area of posterior teeth. All samples were analyzed by pyrosequencing, based on the 16S rRNA gene hypervariable regions, V1-V4.

Results

The organisms identified belonged to 65 genera. Fifty-two genera were identified in the subjects with caries and 58 in those without; 45 genera were shared by both groups. In the Shannon index, the caries group showed lower bacterial diversity than the caries-free group and the difference was significant (Wilcoxon signed-rank test, p < 0.05). Additionally, similarities between siblings were evident in analyses based on weighted UniFrac distances (p < 0.05).

Conclusions

In this study, the diversity of the microbiome was reduced in subjects with dental caries, while similarity between siblings seemed to be retained.

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Treatment response with mepolizumab in severe eosinophilic asthma patients with previous omalizumab treatment

Abstract

Background

We performed post-hoc analyses to evaluate the effect of humanized monoclonal antibody mepolizumab in patients with severe eosinophilic asthma previously treated with omalizumab.

Methods

Data were collected from two randomized double-blind, placebo-controlled studies: MENSA (NCT01691521: 32-week treatment phase) and SIRIUS (NCT01691508: 24-week treatment phase). Active treatment was 75 mg intravenous mepolizumab (MENSA) or 100 mg subcutaneous mepolizumab (MENSA, SIRIUS). Patients had evidence of eosinophilic inflammation ≥150 cells/μl (at screening) or ≥300 cells/μl (during the previous year). Primary outcomes were rate of exacerbations (MENSA) and percentage reduction in oral corticosteroid (OCS) dose (SIRIUS). Other outcomes included lung function (forced expiratory volume in 1 second and morning peak expiratory flow), Asthma Control Questionnaire (ACQ-5), St George's Respiratory Questionnaire (SGRQ) scores, and safety.

Results

Overall, 576 patients were included from MENSA and 135 from SIRIUS, with 13% and 33% previously receiving omalizumab, respectively. In MENSA, mepolizumab reduced the rate of exacerbations by 57% (prior omalizumab) and 47% (no prior omalizumab) vs placebo. In SIRIUS, reductions in OCS use were comparable regardless of prior omalizumab use. Despite reducing chronic OCS use, mepolizumab also resulted in similar reductions in exacerbation rate relative to placebo in both subgroups. Asthma control and quality of life improved with mepolizumab vs placebo in both studies independent of prior omalizumab use, as shown by ACQ-5 and SGRQ scores. Adverse events were also comparable irrespective of prior omalizumab use.

Conclusions

These post-hoc analyses indicate that patients with severe eosinophilic asthma respond positively to mepolizumab regardless of prior use of omalizumab.

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Residential greenness is differentially associated with childhood allergic rhinitis and aeroallergen sensitization in seven birth cohorts

Abstract

Background

The prevalence of allergic rhinitis is high but the role of environmental factors remains unclear. We examined cohort-specific and combined associations of residential greenness with allergic rhinitis and aeroallergen sensitization based on individual data from Swedish (BAMSE), Australian (MACS), Dutch (PIAMA), Canadian (CAPPS and SAGE) and German (GINIplus and LISAplus) birth cohorts (N=13,016).

Methods

Allergic rhinitis (doctor diagnosis/symptoms) and aeroallergen sensitization were assessed in children aged 6-8 years in six cohorts and 10-12 years in five cohorts. Residential greenness was defined as the mean Normalized Difference Vegetation Index (NDVI) in a 500m buffer around the home address at the time of health assessment. Cohort-specific associations per 0.2 unit increase in NDVI were assessed using logistic regression models and combined in a random-effects meta-analysis.

Results

Greenness in a 500m buffer was positively associated with allergic rhinitis at 6-8 years in BAMSE (odds ratio=1.42, 95% confidence interval [1.13, 1.79]) and GINI/LISA South (1.69 [1.19, 2.41]) but inversely associated in GINI/LISA North (0.61 [0.36, 1.01]) and PIAMA (0.67 [0.47, 0.95]). Effect estimates in CAPPS and SAGE were also conflicting but not significant (0.63 [0.32, 1.24] and 1.31 [0.81, 2.12], respectively). All meta-analyses were non-significant. Results were similar for aeroallergen sensitization at 6-8 years and both outcomes at 10-12 years. Stratification by NO₂ concentrations, population density, an urban versus rural marker and moving did not reveal consistent trends within subgroups.

Conclusion

Although residential greenness appears to be associated with childhood allergic rhinitis and aeroallergen sensitization, the effect direction varies by location.

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Cognitive screening in patients with intracranial tumors: validation of the BCSE

Abstract

This study presents the first validation of the Brief Cognitive Status Exam (BCSE) against two other screening tools for cognitive impairment in patients with intracranial tumors. 58 patients and 22 matched healthy controls completed the BCSE, the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Patients were additionally tested with a comprehensive neuropsychological battery. Based on this assessment, they were classified as cognitively impaired or unimpaired on five cognitive domains. Analyses revealed a comparable feasibility of the BCSE relative to the MoCA and the MMSE, but a smaller range of assessed functions (e.g., no correlation with the domain visual-spatial functions). The ability to separate patients and healthy controls was extremely poor for BCSE and MMSE (sensitivity of 38.6 % and less), but moderate for MoCA (sensitivity 68.97 %). Detection of cognitive impairment in patients was worst with BCSE (sensitivity 37 %; MoCA 92.9 %, MMSE 44.4 %) as compared to neuropsychological testing. Moreover, prediction of cognitive outcome was also worst for the BCSE (AUC = .713, NPV = 50 %). An optimal cut-off of 50.5 increased the results slightly. In summary, the BCSE showed good feasibility but no sufficient results in separating healthy individuals from patients or detecting cognitive impairment in patients. Consequently, as a screening measure, we would recommend the MoCA instead of the BCSE. However, since even the MoCA failed to detect cognitive impairment, our study supports the view that reliable results could only be obtained with a comprehensive neuropsychological battery.

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