Triple-Quadrupole Inductively Coupled Plasma-Mass Spectrometry with a High-Efficiency Sample Introduction System for Ultratrace Determination of 135Cs and 137Cs in Environmental Samples at Femtogram Levels

Analytical Chemistry

DOI: 10.1021/acs.analchem.6b02150

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Transient Heat and Solute Transfers in Liquid-Saturated Porous Media

Abstract

We investigate transient heat and solute transfers in liquid-saturated porous media. The macroscopic equivalent models are obtained by a homogenization process from the pore-scale description. The large value of the Lewis number in liquid mixtures introduces a possible separation of scales between the heat and solute diffusion wavelengths \(L^{\mathrm{heat}}\) and \(L^{\mathrm{solute}}\) at a given excitation time. Thus, two separations of scales could be present between the pore scale of characteristic length l and \(L^{\mathrm{heat}}\) and \(L^{\mathrm{solute}}\) . Depending on the ratio of these two separations of scales results in different equivalent macroscopic models or in non-homogenizable situations. Among numerous possibilities, we present two different homogenizable problems and a non-homogenizable situation. As the characteristic excitation time is decreased, the solute pseudo-wavelength and the heat pseudo-wavelength increase; a unique separation of scales between both solute and heat transfers and the pore scale appears, and we recover the classical macroscopic thermodiffusion model.

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Biocompatible Silk Noil-Based Three-Dimensional Carded-Needled Nonwoven Scaffolds Guide the Engineering of Novel Skin Connective Tissue

Tissue Engineering Part A Aug 2016, Vol. 22, No. 15-16: 1047-1060.


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Three-Dimensional Adult Cardiac Extracellular Matrix Promotes Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Tissue Engineering Part A Aug 2016, Vol. 22, No. 15-16: 1016-1025.


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Fibroblast Growth Factor Ligand Dependent Proliferation and Chondrogenic Differentiation of Synovium-Derived Stem Cells and Concomitant Adaptation of Wnt/Mitogen-Activated Protein Kinase Signals

Tissue Engineering Part A Aug 2016, Vol. 22, No. 15-16: 1036-1046.


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A Simple, Versatile Antibody-Based Barcoding Method for Flow Cytometry [NOVEL IMMUNOLOGICAL METHODS]

Barcoding of biological samples is a commonly used strategy to mark or identify individuals within a complex mixture. However, cell barcoding has not yet found wide use in flow cytometry that would benefit greatly from the ability to analyze pooled experimental samples simultaneously. This is due, in part, to technical and practical limitations of current fluorescent dye-based methods. In this study, we describe a simple, versatile barcoding strategy that relies on combinations of a single Ab conjugated to different fluorochromes and thus in principle can be integrated into any flow cytometry application. To demonstrate the efficacy of the approach, we describe the results of a variety of experiments using live cells as well as fixed and permeabilized cells. The results of these studies show that Ab-based barcoding provides a simple, practical method for identifying cells from individual samples pooled for analysis by flow cytometry that has broad applications in immunological research.

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Chemoattractant Receptors BLT1 and CXCR3 Regulate Antitumor Immunity by Facilitating CD8+ T Cell Migration into Tumors [TUMOR IMMUNOLOGY]

Immunotherapies have shown considerable efficacy for the treatment of various cancers, but a multitude of patients remain unresponsive for various reasons, including poor homing of T cells into tumors. In this study, we investigated the roles of the leukotriene B₄ receptor, BLT1, and CXCR3, the receptor for CXCL9, CXCL10, and CXCL11, under endogenous as well as vaccine-induced antitumor immune response in a syngeneic murine model of B16 melanoma. Significant accelerations in tumor growth and reduced survival were observed in both BLT1^–/– and CXCR3^–/– mice as compared with wild-type (WT) mice. Analysis of tumor-infiltrating leukocytes revealed significant reduction of CD8⁺ T cells in the tumors of BLT1^–/– and CXCR3^–/– mice as compared with WT tumors, despite their similar frequencies in the periphery. Adoptive transfer of WT but not BLT1^–/– or CXCR3^–/– CTLs significantly reduced tumor growth in Rag2^–/– mice, a function attributed to reduced infiltration of knockout CTLs into tumors. Cotransfer experiments suggested that WT CTLs do not facilitate the infiltration of knockout CTLs to tumors. Anti–programmed cell death-1 (PD-1) treatment reduced the tumor growth rate in WT mice but not in BLT1^–/–, CXCR3^–/–, or BLT1^–/–CXCR3^–/– mice. The loss of efficacy correlated with failure of the knockout CTLs to infiltrate into tumors upon anti–PD-1 treatment, suggesting an obligate requirement for both BLT1 and CXCR3 in mediating anti–PD-1 based antitumor immune response. These results demonstrate a critical role for both BLT1 and CXCR3 in CTL migration to tumors and thus may be targeted to enhance efficacy of CTL-based immunotherapies.

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Correction: LFA-1/ICAM-1 Ligation in Human T Cells Promotes Th1 Polarization through a GSK3{beta} Signaling-Dependent Notch Pathway [CORRECTIONS]

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Enhanced Requirement for TNFR2 in Graft Rejection Mediated by Low-Affinity Memory CD8+ T Cells during Heterologous Immunity [TRANSPLANTATION]

The affinity of a TCR binding to peptide:MHC profoundly impacts the phenotype and function of effector and memory cell differentiation. Little is known about the effect of low-affinity priming on memory cell generation and function, which is particularly important in heterologous immunity, when microbe-specific T cells cross-react with allogeneic Ag and mediate graft rejection. We found that low-affinity–primed memory CD8⁺ T cells produced high levels of TNF ex vivo in response to heterologous rechallenge compared with high-affinity–primed memory T cells. Low-affinity secondary effectors significantly upregulated TNFR2 on the cell surface and contained a higher frequency of TNFR2^hi proliferating cells. Low-affinity–primed secondary effectors concurrently downregulated TNF production. Importantly, blockade of TNFR2 attenuated graft rejection in low- but not high-affinity–primed animals. These data establish a functional connection between TNF signaling and TCR-priming affinity and have implications for the immunomodulation of pathogenic T cell responses during transplantation.

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Innate Allorecognition Results in Rapid Accumulation of Monocyte-Derived Dendritic Cells [TRANSPLANTATION]

Although the mechanisms governing the innate recognition of pathogen-associated molecular patterns have been well defined, how allogeneic cellular stimuli evoke innate responses remains less so. In this article, we report that upon i.v. transfer (to avoid major iatrogenic interference), allogeneic but not syngeneic leukocytes could induce a rapid (after 1 d) accumulation of host monocyte–derived dendritic cells (moDCs) without any increase in conventional DCs. This occurred in various donor–host strain combinations, did not require MHC mismatch, and could be induced by various donor cell types including B cells, T cells, or NK cells. Using RAG^–/–c^–/– and scid c^–/–mice with different MHC, we found that the presence of either donor or host lymphoid cells was required. Alloinduced moDC accumulation was significantly reduced when splenocytes from mice deficient in NK cells by genetic ablation were used as donors. A major component of this moDC accumulation appears to be recruitment. Our findings provide new insights into how the innate and adaptive immune system may interact during allogeneic encounters and thus transplant rejection.

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The Repair of Skeletal Muscle Requires Iron Recycling through Macrophage Ferroportin [INNATE IMMUNITY AND INFLAMMATION]

Macrophages recruited at the site of sterile muscle damage play an essential role in the regeneration of the tissue. In this article, we report that the selective disruption of macrophage ferroportin (Fpn) results in iron accumulation within muscle-infiltrating macrophages and jeopardizes muscle healing, prompting fat accumulation. Macrophages isolated from the tissue at early time points after injury express ferritin H, CD163, and hemeoxygenase-1, indicating that they can uptake heme and store iron. At later time points they upregulate Fpn expression, thus acquiring the ability to release the metal. Transferrin-mediated iron uptake by regenerating myofibers occurs independently of systemic iron homeostasis. The inhibition of macrophage iron export via the silencing of Fpn results in regenerating muscles with smaller myofibers and fat accumulation. These results highlight the existence of a local pathway of iron recycling that plays a nonredundant role in the myogenic differentiation of muscle precursors, limiting the adipose degeneration of the tissue.

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In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity [ALLERGY AND OTHER HYPERSENSITIVITIES]

Contact hypersensitivity (CHS) of murine skin serves as a model of allergic contact dermatitis. Hapten-specific CD8 T cells and neutrophils represent the major effector cells driving this inflammatory reaction whereas Foxp3⁺ regulatory T cells (Tregs) control the severity of inflammation. However, whether in vivo expansion of endogenous Tregs can downregulate CHS-mediated inflammation remains to be elucidated. In this study, we addressed this issue by using injection of an IL-2/anti–IL-2 mAb JES6-1 complex (IL-2/JES6-1) as a means of Treg induction in 2,4,6-trinitrochlorobenzene–induced CHS. IL-2/JES6-1 injection before or after hapten sensitization led to a considerable reduction of skin inflammation, even when rechallenged up to 3 wk after the last treatment. Conversely, Treg depletion re-established the CHS response in IL-2/JES6-1–treated mice. IL-2/JES6-1 injection resulted in increased frequencies of natural and peripheral Tregs in spleen and draining lymph nodes (LNs), elevated IL-10 and TGF-β production by CD4 T cells, reduced CD86 expression by dendritic cells, and led to lower numbers of hapten-specific IFN-–producing CD8 T effector cells in LNs. Neutrophil and CD8 T cell infiltration was reduced in inflamed ear tissue, whereas CTLA-4⁺Foxp3⁺ Treg frequencies were augmented. Adoptive transfer of LN cells of sensitized mice into recipients treated with IL-2/JES6-1 showed impaired CHS. Our results show that in vivo Treg expansion results in a prolonged CHS suppression, a sustained reduction of hapten-specific CD8 T cells, and a decrease in effector cell influx in inflamed tissue.

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Induction of Th1-Biased T Follicular Helper (Tfh) Cells in Lymphoid Tissues during Chronic Simian Immunodeficiency Virus Infection Defines Functionally Distinct Germinal Center Tfh Cells [INFECTIOUS DISEASE AND HOST RESPONSE]

Chronic HIV infection is associated with accumulation of germinal center (GC) T follicular helper (Tfh) cells in the lymphoid tissue. The GC Tfh cells can be heterogeneous based on the expression of chemokine receptors associated with T helper lineages, such as CXCR3 (Th1), CCR4 (Th2), and CCR6 (Th17). However, the heterogeneous nature of GC Tfh cells in the lymphoid tissue and its association with viral persistence and Ab production during chronic SIV/HIV infection are not known. To address this, we characterized the expression of CXCR3, CCR4, and CCR6 on GC Tfh cells in lymph nodes following SIVmac251 infection in rhesus macaques. In SIV-naive rhesus macaques, only a small fraction of GC Tfh cells expressed CXCR3, CCR4, and CCR6. However, during chronic SIV infection, the majority of GC Tfh cells expressed CXCR3, whereas the proportion of CCR4⁺ cells did not change, and CCR6⁺ cells decreased. CXCR3⁺, but not CXCR3^–, GC Tfh cells produced IFN- (Th1 cytokine) and IL-21 (Tfh cytokine), whereas both subsets expressed CD40L following stimulation. Immunohistochemistry analysis demonstrated an accumulation of CD4⁺IFN-⁺ T cells within the hyperplastic follicles during chronic SIV infection. CXCR3⁺ GC Tfh cells also expressed higher levels of ICOS, CCR5, and α4β7 and contained more copies of SIV DNA compared with CXCR3^– GC Tfh cells. However, CXCR3⁺ and CXCR3^– GC Tfh cells delivered help to B cells in vitro for production of IgG. These data demonstrate that chronic SIV infection promotes expansion of Th1-biased GC Tfh cells, which are phenotypically and functionally distinct from conventional GC Tfh cells and contribute to hypergammaglobulinemia and viral reservoirs.

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Prostaglandin I2 Suppresses Proinflammatory Chemokine Expression, CD4 T Cell Activation, and STAT6-Independent Allergic Lung Inflammation [ALLERGY AND OTHER HYPERSENSITIVITIES]

Allergic airway diseases are immune disorders associated with heightened type 2 immune responses and IL-5 and IL-13 production at the site of inflammation. We have previously reported that cyclooxygenase (COX) inhibition by indomethacin augmented allergic airway inflammation in a STAT6-independent manner. However, the key COX product(s) responsible for restraining indomethacin-mediated STAT6-independent allergic inflammation is unknown. In this study, using the mouse model of OVA-induced allergic airway inflammation, we identified that PGI₂ receptor (IP) signaling was critical for indomethacin-induced, STAT6-independent proallergic effects. We demonstrated that IP deficiency increased inflammatory cell infiltration, eosinophilia, and IL-5 and IL-13 expression in the lung in a STAT6-independent manner. The augmented STAT6-independent allergic inflammation correlated with enhanced primary immune responses to allergic sensitization and elevated production of multiple inflammatory chemokines (CCL11, CCL17, CCL22, and CXCL12) in the lung after allergen challenge. We also showed that the PGI₂ analogue cicaprost inhibited CD4 T cell proliferation and IL-5 and IL-13 expression in vitro, and IP deficiency diminished the stimulatory effect of indomethacin on STAT6-independent IL-5 and IL-13 responses in vivo. The inhibitory effects of PGI₂ and the IP signaling pathway on CD4 T cell activation, inflammatory chemokine production, and allergic sensitization and airway inflammation suggest that PGI₂ and its analogue iloprost, both Food and Drug Administration–approved drugs, may be useful in treating allergic diseases and asthma. In addition, inhibiting PGI₂ signaling by drugs that either block PGI₂ production or restrain IP signaling may augment STAT6-independent pathways of allergic inflammation.

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The Essential Role of Neutrophils during Infection with the Intracellular Bacterial Pathogen Listeria monocytogenes [BRIEF REVIEWS]

Neutrophils have historically been characterized as first responder cells vital to host survival because of their ability to contain and eliminate bacterial and fungal pathogens. However, recent studies have shown that neutrophils participate in both protective and detrimental responses to a diverse array of inflammatory and infectious diseases. Although the contribution of neutrophils to extracellular infections has been investigated for decades, their specific role during intracellular bacterial infections has only recently been appreciated. During infection with the Gram-positive intracellular pathogen Listeria monocytogenes, neutrophils are recruited from the bone marrow to sites of infection where they use novel bacterial-sensing pathways leading to phagocytosis and production of bactericidal factors. This review summarizes the requirement of neutrophils during L. monocytogenes infection by examining both neutrophil trafficking and function during primary and secondary infection.

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Fc{gamma}RIIB-Independent Mechanisms Controlling Membrane Localization of the Inhibitory Phosphatase SHIP in Human B Cells [ANTIGEN RECOGNITION AND RESPONSES]

SHIP is an important regulator of immune cell signaling that functions to dephosphorylate the phosphoinositide phosphatidylinositol 3,4,5-trisphosphate at the plasma membrane and mediate protein–protein interactions. One established paradigm for SHIP activation involves its recruitment to the phospho-ITIM motif of the inhibitory receptor FcRIIB. Although SHIP is essential for the inhibitory function of FcRIIB, it also has critical modulating functions in signaling initiated from activating immunoreceptors such as B cell Ag receptor. In this study, we found that SHIP is indistinguishably recruited to the plasma membrane after BCR stimulation with or without FcRIIB coligation in human cell lines and primary cells. Interestingly, fluorescence recovery after photobleaching analysis reveals differential mobility of SHIP–enhanced GFP depending on the mode of stimulation, suggesting that although BCR and FcRIIB can both recruit SHIP, this occurs via distinct molecular complexes. Mutagenesis of a SHIP–enhanced GFP fusion protein reveals that the SHIP–Src homology 2 domain is essential in both cases whereas the C terminus is required for recruitment via BCR stimulation, but is less important with FcRIIB coligation. Experiments with pharmacological inhibitors reveal that Syk activity is required for optimal stimulation-induced membrane localization of SHIP, whereas neither PI3K or Src kinase activity is essential. BCR-induced association of SHIP with binding partner Shc1 is dependent on Syk, as is tyrosine phosphorylation of both partners. Our results indicate that FcRIIB is not uniquely able to promote membrane recruitment of SHIP, but rather modulates its function via formation of distinct signaling complexes. Membrane recruitment of SHIP via Syk-dependent mechanisms may be an important factor modulating immunoreceptor signaling.

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Critical Role of IL-22/IL22-RA1 Signaling in Pneumococcal Pneumonia [INFECTIOUS DISEASE AND HOST RESPONSE]

IL-22–IL-22R signaling plays a crucial role in regulating host defenses against extracellular pathogens, particularly in the intestine, through the induction of antimicrobial peptides and chemotactic genes. However, the role of IL-22–IL-22R is understudied in Streptococcus pneumoniae lung infection, a prevalent pathogen of pneumonia. This paper presents the findings of IL-22 signaling during a murine model of pneumococcal pneumonia and improvement of bacterial burden upon IL-22 administration. IL-22 was rapidly induced in the lung during pneumococcal infection in wild-type mice, and Il22^–/– mice had higher pneumococcal burdens compared with controls. Additionally, mice with hepatic-specific deletion of Il22ra1 also had higher bacterial burdens in lungs compared with littermate controls after intrapulmonary pneumococcal infection, suggesting that IL-22 signaling in the liver is important to control pneumococcal pneumonia. Thus, we hypothesized that enhancement of IL-22 signaling would control pneumococcal burden in lung tissues in an experimental pneumonia model. Administration of rIL-22 systemically to infected wild-type mice decreased bacterial burden in lung and liver at 24 h postinfection. Our in vitro studies also showed that mice treated with IL-22 had increased C3 expression in the liver compared with the isotype control group. Furthermore, serum from mice treated with IL-22 had improved opsonic capacity by increasing C3 binding on S. pneumoniae. Taken together, endogenous IL-22 and hepatic IL-22R signaling play critical roles in controlling pneumococcal lung burden, and systemic IL-22 decreases bacterial burden in the lungs and peripheral organs by potentiating C3 opsonization on bacterial surfaces, through the increase of hepatic C3 expression.

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Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells [ANTIGEN RECOGNITION AND RESPONSES]

Telomerase is a prototype-shared tumor Ag and represents an attractive target for anticancer immunotherapy. We have previously described promiscuous and immunogenic HLA-DR–restricted peptides derived from human telomerase reverse transcriptase (hTERT) and referred as universal cancer peptide (UCP). In nonsmall cell lung cancer, the presence of spontaneous UCP-specific CD4 T cell responses increases the survival of chemotherapy-responding patients. However, the precise mechanisms of hTERT's uptake, processing, and presentation on MHC-II molecules to stimulate CD4 T cells are poorly understood. In this work, by using well-characterized UCP-specific CD4 T cell clones, we showed that hTERT processing and presentation on MHC-II involve both classical endolysosomal and nonclassical cytosolic pathways. Furthermore, to our knowledge, we demonstrated for the first time that hTERT's internalization by dendritic cells requires its interaction with surface heparan sulfate proteoglycans. Altogether, our findings provide a novel mechanism of tumor-specific CD4 T cell activation and will be useful for the development of novel cancer immunotherapies that harness CD4 T cells.

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Bimodal Expansion of the Lymphatic Vessels Is Regulated by the Sequential Expression of IL-7 and Lymphotoxin {alpha}1{beta}2 in Newly Formed Tertiary Lymphoid Structures [MUCOSAL IMMUNOLOGY]

Lymphangiogenesis associated with tertiary lymphoid structure (TLS) has been reported in numerous studies. However, the kinetics and dynamic changes occurring to the lymphatic vascular network during TLS development have not been studied. Using a viral-induced, resolving model of TLS formation in the salivary glands of adult mice we demonstrate that the expansion of the lymphatic vascular network is tightly regulated. Lymphatic vessel expansion occurs in two distinct phases. The first wave of expansion is dependent on IL-7. The second phase, responsible for leukocyte exit from the glands, is regulated by lymphotoxin (LT)βR signaling. These findings, while highlighting the tight regulation of the lymphatic response to inflammation, suggest that targeting the LTα₁β₂/LTβR pathway in TLS-associated pathologies might impair a natural proresolving mechanism for lymphocyte exit from the tissues and account for the failure of therapeutic strategies that target these molecules in diseases such as rheumatoid arthritis.

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Clonal Characteristics of Circulating B Lymphocyte Repertoire in Primary Biliary Cholangitis [AUTOIMMUNITY]

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by elevated serum anti-mitochondrial Ab and lymphocyte-mediated bile duct damage. This study was designed to reveal the clonal characteristics of B lymphocyte repertoire in patients with PBC to facilitate better understanding of its pathogenesis and better management of these patients. Using high-throughput sequencing of Ig genes, we analyzed the repertoire of circulating B lymphocytes in 43 patients with PBC, and 34 age- and gender-matched healthy controls. Compared with healthy controls, PBC patients showed 1) a gain of 14 new clones and a loss of 8 clones; 2) a significant clonal expansion and increased relative IgM abundance, which corresponded with the elevated serum IgM level; 3) a significant reduction of clonal diversity and somatic hypermutations in class-switched sequences, which suggested a general immunocompromised status; 4) the reduction of clonal diversity and enhancement of clonal expansion were more obvious at the cirrhotic stage; and 5) treatment with ursodeoxycholic acid could increase the clonal diversity and reduce clonal expansion of the IgM repertoire, with no obvious effect on the somatic hypermutation level. Our data suggest that PBC is a complex autoimmune disease process with evidence of B lymphocyte clonal gains and losses, Ag-dependent ogligoclonal expansion, and a generally compromised immune reserve. This new insight into the pathogenesis of PBC opens up the prospect of studying disease-relevant B cells to better diagnose and treat this devastating disease.

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Immediate Dysfunction of Vaccine-Elicited CD8+ T Cells Primed in the Absence of CD4+ T Cells [INFECTIOUS DISEASE AND HOST RESPONSE]

CD4⁺ T cell help is critical for optimal CD8⁺ T cell memory differentiation and maintenance in many experimental systems. In addition, many reports have identified reduced primary CD8⁺ T cell responses in the absence of CD4⁺ T cell help, which often coincides with reduced Ag or pathogen clearance. In this study, we demonstrate that absence of CD4⁺ T cells at the time of adenovirus vector immunization of mice led to immediate impairments in early CD8⁺ T cell functionality and differentiation. Unhelped CD8⁺ T cells exhibited a reduced effector phenotype, decreased ex vivo cytotoxicity, and decreased capacity to produce cytokines. This dysfunctional state was imprinted within 3 d of immunization. Unhelped CD8⁺ T cells expressed elevated levels of inhibitory receptors and exhibited transcriptomic exhaustion and anergy profiles by gene set enrichment analysis. Dysfunctional, impaired effector differentiation also occurred following immunization of CD4⁺ T cell–deficient mice with a poxvirus vector. This study demonstrates that following priming with viral vectors, CD4⁺ T cell help is required to promote both the expansion and acquisition of effector functions by CD8⁺ T cells, which is accomplished by preventing immediate dysfunction.

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Involvement of NK Cells and NKp30 Pathway in Antisynthetase Syndrome [AUTOIMMUNITY]

Antisynthetase syndrome (aSS) is characterized by the association of interstitial lung disease and myositis with anti–tRNA synthetase autoantibodies. Immune mechanisms leading to aSS could be initiated in the lungs, but the role of NK cells has not yet been studied. Both extensive NK cell phenotype and functions were compared between 33 patients and 26 controls. Direct and redirected polyfunctionality assays (degranulation and intracellular production of TNF-α and IFN-) were performed spontaneously or after IL-12 plus IL-18 stimulation in the presence of K562 or P815 target cells, respectively. NK cells from inactive patients showed normal phenotype, whereas active aSS revealed a differentiated NK cell profile, as indicated by increased CD57 and Ig-like transcript 2 and an inability to produce IFN- (p = 0.002) compared with controls. Importantly, active aSS was more specifically associated with a significant NKp30 decrease (p = 0.009), although levels of mRNA and intracellular protein were similar in aSS and healthy controls. This NKp30 decrease was strongly correlated with reduced NK cell polyfunctionality in both direct and redirected killing assays with anti-NKp30 Abs (p = 0.009 and p = 0.03, respectively), confirming its important impact in aSS. Histological studies revealed massive infiltrations of NK cells inside the lungs of aSS patients (148 versus 11/mm²). Taken together, these data suggest that NK cells and NKp30 could play a role in aSS pathogenesis.

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Lack of IL-1 Receptor-Associated Kinase-4 Leads to Defective Th1 Cell Responses and Renders Mice Susceptible to Mycobacterial Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

The Toll-like and IL-1 family receptors play critical roles in innate and adaptive immunity against intracellular pathogens. Although previous data demonstrated the importance of TLRs and IL-1R signaling events for the establishment of an effective immune response to mycobacteria, the possible function of the adaptor molecule IL-1R–associated kinase (IRAK)-4 against this pathogen has not been addressed. In this study, we determined the role of IRAK-4 in signaling pathways responsible for controlling mycobacterial infections. This kinase is important for the production of IL-12 and TNF-α by macrophages and dendritic cells exposed to mycobacteria. Moreover, Mycobacterium bovis–infected IRAK-4–knockout macrophages displayed impaired MAPK and NF-B activation. IL-1β secretion and caspase-1 activation were also dependent on IRAK-4 signaling. Mice lacking IRAK-4 showed increased M. bovis burden in spleen, liver, and lungs and smaller liver granulomas during 60 d of infection compared with wild-type mice. Furthermore, 80% of IRAK-4^–/– mice succumbed to virulent M. tuberculosis within 100 d following low-dose infection. This increased susceptibility to mycobacteria correlated with reduced IFN-/TNF-α recall responses by splenocytes, as well as fewer IL-12p70–producing APCs. Additionally, we observed that IRAK-4 is also important for the production of IFN- by CD4⁺ T cells from infected mice. Finally, THP-1 cells treated with an IRAK-4 inhibitor and exposed to M. bovis showed reduced TNF-α and IL-12, suggesting that the results found in mice can be extended to humans. In summary, these data demonstrate that IRAK-4 is essential for innate and adaptive immunity and necessary for efficient control of mycobacterial infections.

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Targeting T Cell Bioenergetics by Modulating P-Glycoprotein Selectively Depletes Alloreactive T Cells To Prevent Graft-versus-Host Disease [CLINICAL AND HUMAN IMMUNOLOGY]

T lymphocytes play a central role in many human immunologic disorders, including autoimmune and alloimmune diseases. In hematopoietic stem cell transplantation, acute graft-versus-host-disease (GVHD) is caused by an attack on the recipient's tissues from donor allogeneic T cells. Selectively depleting GVHD-causing cells prior to transplant may prevent GVHD. In this study, we evaluated 24 chalcogenorhodamine photosensitizers for their ability to selectively deplete reactive T lymphocytes and identified the photosensitizer 2-Se-Cl, which accumulates in stimulated T cells in proportion to oxidative phosphorylation. The photosensitizer is also a potent stimulator of P-glycoprotein (P-gp). Enhanced P-gp activity promotes the efficient removal of photosensitizer not sequestered in mitochondria and protects resting lymphocytes that are essential for antipathogen and antitumor responses. To evaluate the selective depletion of alloimmune responses, donor C57BL/6 splenocytes were cocultured for 5 d with irradiated BALB/c splenocytes and then photodepleted (PD). PD-treated splenocytes were infused into lethally irradiated BALB/c (same-party) or C3H/HeJ (third-party) mice. Same-party mice that received PD-treated splenocytes at the time of transplant lived 100 d without evidence of GVHD. In contrast, all mice that received untreated primed splenocytes and third-party mice that received PD-treated splenocytes died of lethal GVHD. To evaluate the preservation of antiviral immune responses, acute lymphocytic choriomeningitis virus infection was used. After photodepletion, expansion of Ag-specific naive CD8⁺ T cells and viral clearance remained fully intact. The high selectivity of this novel photosensitizer may have broad applications and provide alternative treatment options for patients with T lymphocyte–mediated diseases.

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Zebrafish IRF1, IRF3, and IRF7 Differentially Regulate IFN{Phi}1 and IFN{Phi}3 Expression through Assembly of Homo- or Heteroprotein Complexes [INNATE IMMUNITY AND INFLAMMATION]

In mammals, IFN regulatory factor (IRF)1, IRF3, and IRF7 are three critical transcription factors that are pivotal for cooperative regulation of the type I IFN response. In this study, we explored the relative contribution of zebrafish (Danio rerio) IRF1 (DrIRF1), IRF3 (DrIRF3), and IRF7 (DrIRF7) (DrIRF1/3/7) to zebrafish IFN1 (DrIFN1) and IFN3 (DrIFN3) (DrIFN1/3) activation. Following spring viremia of carp virus infection, DrIFN1/3 and DrIRF1/3/7 transcripts are significantly induced in zebrafish tissues, which correlates with the replication of spring viremia of carp virus. DrIRF1/3/7 selectively bind to the IRF-binding element/IFN-stimulated regulatory element sites of DrIFN1/3 promoters, with the exception that DrIRF3 has no preference for two IRF-binding element/IFN-stimulated regulatory element motifs within the DrIFN3 promoter. Consistently, DrIRF3 alone activates DrIFN1, but not DrIFN3; DrIRF7 predominantly stimulates DrIFN3; and DrIRF1 has similar potential to DrIFN1 and DrIFN3. Strikingly, DrIRF3 facilitates the binding of DrIRF1 and DrIRF7 to both zebrafish IFN promoters, and so does DrIRF7 for the binding of DrIRF1, particularly to the DrIFN3 promoter. These binding properties correlate with differential responses of DrIFN1 and DrIFN3 to the combinatory stimulation of DrIRF1/3/7, depending on their relative amounts. Similar to the dual roles of human IRF3 in regulating IRF7-activated IFNα genes, DrIRF3 exerts dual effects on DrIRF1-mediated DrIFN3 gene expression: an inhibitory effect at lower concentrations and a synergistic effect at higher concentrations. These data provide evidence that fish and mammals have evolved a similar IRF-dependent regulatory mechanism fine-tuning IFN gene activation.

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Trends in CPAP adherence over twenty years of data collection: a flattened curve

Obstructive sleep apnea (OSA) is a common disorder, and continuous airway positive pressure (CPAP) is considered to be the gold standard of therapy. CPAP however is known to have problems with adherence, with ...

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Association between type 1, type 2 cytokines, diabetic autoantibodies and 25-hydroxyvitamin D in children with type 1 diabetes

Abstract

Purpose

Vitamin D may play a role in the pathogenesis of type 1 diabetes (T1D). The aim of the current study was to determine the possible association between 25-hydroxyvitamin D [25(OH)D] levels and circulating levels of type 1 and type 2 cytokines, as well as the pathophysiology of T1D in children.

Methods

A total of 250 T1D patients and 250 sex- and age-matched T1D-free controls were screened for 25(OH)D, hemoglobin A1c (HbA1c), type 1 and type 2 cytokines, C-reactive protein (CRP) and bone mineral metabolism, as well as antibodies against insulin, glutamic acid decarboxylase (anti-GAD 65) and islet cells.

Results

Our data showed that the plasma level of 25(OH)D was significantly lower in T1D patients and that there was a significant negative correlation between 25(OH)D levels and HbA1c values. There was a significant association between deficient levels of 25(OH)D and higher levels of cytokines (IFN-γ, TNF-α, IL-6, IL-1β, IL-4 and IL-10) and CRP. Total blood hemoglobin, the hematocrit percentage, body mass index SDS values, phosphate and magnesium levels were significantly lower in T1D patients than in T1D-free subjects. The levels of parathyroid hormone and alkaline phosphatase were significantly higher in T1D patients. Higher levels of cytokines were significantly associated with deficient levels of 25(OH)D. Moreover, in T1D patients, higher levels of islet antibodies, anti-GAD antibodies and anti-insulin antibodies were significantly associated with deficient levels of 25(OH)D.

Conclusions

In type 1 diabetic children, deficient levels of 25(OH)D are associated with high levels of HbA1c, circulatory cytokines and antibody markers.

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Using discrete choice experiments as a decision aid in total knee arthroplasty: study protocol for a randomised controlled trial

Osteoarthritis (OA) is a leading cause of disability in developed nations. Total knee arthroplasty (TKA) is a clinically effective treatment for people with end-stage knee OA, and represents one of the highest...

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Baclofen to prevent agitation in alcohol-addicted patients in the ICU: study protocol for a randomised controlled trial

Alcohol is the leading psychoactive substance consumed in France, with about 15 million regular consumers. The National institute on Alcohol Abuse and Alcoholism (NIAAA) considers alcohol abuse to be more than...

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The Da Vinci Xi and robotic radical prostatectomy—an evolution in learning and technique

Abstract

The da Vinci Xi robot has been introduced as the successor to the Si platform. The promise of the Xi is to open the door to new surgical procedures. For robotic-assisted radical prostatectomy (RARP)/pelvic surgery, the potential is better vision and longer instruments. How has the Xi impacted on operative and pathological parameters as indicators of surgical performance? This is a comparison of an initial series of 42 RARPs with the Xi system in 2015 with a series using the Si system immediately before Xi uptake in the same calendar year, and an Si series by the same surgeon synchronously as the Xi series using operative time, blood loss, and positive margins as surrogates of surgical performance. Subjectively and objectively, there is a learning curve to Xi uptake in longer operative times but no impact on T2 positive margins which are the most reflective single measure of RARP outcomes. Subjectively, the vision of the Xi is inferior to the Si system, and the integrated diathermy system and automated setup are quirky. All require experience to overcome. There is a learning curve to progress from the Si to Xi da Vinci surgical platforms, but this does not negatively impact the outcome.

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Oligo-recurrence predicts favorable prognosis of brain-only oligometastases in patients with non-small cell lung cancer treated with stereotactic radiosurgery or stereotactic radiotherapy: a multi-institutional study of 61 subjects

Abstract

Background

To investigate the prognostic value of oligo-recurrence in patients with brain-only oligometastases of non-small cell lung cancer (NSCLC) treated with stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT).

Methods

Patients treated with SRS or SRT for brain-only NSCLC oligometastases in 6 high-volume institutions in Japan between 1996 and 2008 were reviewed. Eligible patients met 1), 2), and 4) or 1), 3), and 4) of the following: 1) NSCLC with 1 to 4 brain metastases on magnetic resonance imaging (MRI) treated with SRS or SRT; 2) control of the primary lesions (thorax) at the time of SRS or SRT for brain metastases (patients meeting this criterion formed the oligo-recurrence group); 3) with SRS or SRT for brain metastases, concomitant treatment for active primary lesions (thorax) with curative surgery or curative stereotactic body radiotherapy (SBRT), or curative chemoradiotherapy (sync-oligometastases group); and 4) Karnofsky performance status (KPS) ≥70.

Results

The median overall survival (OS) of all 61 patients was 26 months (95 % CI: 17.5–34.5 months). The 2-year and 5-year overall survival rates were 60.7 and 15.7 %, respectively. Stratified by oligostatus, the sync-oligometastases group achieved a median OS of 18 months (95 % CI: 14.8–21.1 months) and a 5-year OS of 0 %, while the oligo-recurrence group achieved a median OS of 41 months (95 % CI: 27.8–54.2 months) and a 5-year OS of 18.6 %. On multivariate analysis, oligo-recurrence was the only significant independent factor related to a favorable prognosis (hazard ratio: 0.253 (95 % CI: 0.082–0.043) (p = 0.025).

Conclusions

The presence of oligo-recurrence can predict a favorable prognosis of brain-only oligometastases in patients with NSCLC treated with SRS or SRT.

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Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma

Abstract

Background

Pembrolizumab is an anti- Programmed Death 1 (PD-1) antibody approved in melanoma, non-small cell lung cancer and investigated in malignant pleural mesothelioma.

The most frequent immunotherapy related autoimmune reactions include dermatitis, pneumonitis, colitis, hypophysitis, uveitis, hypothyreodism, hepatitis and interstitial nephritis.

Case presentation

We describe a 62-year old patient diagnosed with malignant pleural mesothelioma who experienced ten days after the second dose of third line therapy with pembrolizumab sudden onset of generalized edema including legs and eyelids and weight gain of 15 kg resulting from nephrotic syndrome and acute renal failure. Pembrolizumab was discontinued and prednisone, diuretics and angiotensin II receptor blocker were initiated with full recovery of symptoms and renal function. Pembrolizumab-associated minimal change disease (MCD) was confirmed by electron microscopy in the renal biopsy.

Conclusion

We are the first to describe pembrolizumab-related minimal change disease (MCD).

Physicians should be aware of this side effect in patients presenting with edema and weight gain and initiate prompt renal function testing, serum albumin and urinalysis followed by steroid treatment if pembrolizumab-related MCD is suspected.

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Dactolisib (NVP-BEZ235) toxicity in murine brain tumour models

Abstract

Background

Glioblastomas (GBMs) are highly malignant brain tumours with a poor prognosis, and current cytotoxic regimens provide only a limited survival benefit. The PI3K/Akt/mTOR pathway has been an attractive target for therapy due to its high activation in GBMs as well as other cancers. The dual pan-PI3K/mTOR kinase inhibitor dactolisib (NVP-BEZ235) is an anti-neoplastic compound currently under investigation. However, little is known about its efficacy in human GBMs. We aimed at evaluating the efficacy of dactolisib in human glioblastoma cells, as well as in murine models carrying human GBM xenografts.

Methods

To assess the effect of dactolisib in vitro, MTS assay, manual cell count, BrdU incorporation and Annexin V staining experiments were used to observe growth and apoptosis. Furthermore, Akt phosphorylation (S473), a downstream target of PI3K, was explored by western blotting. Animal studies utilizing orthotopic xenograft models of glioblastoma were performed in nude rats and NOD/SCID mice to monitor survival benefit or inhibition of tumor growth.

Results

We found that dactolisib in vitro shows excellent dose dependent anti-growth properties and increase in apoptosis. Moreover, dose dependent inhibition of Akt phosphorylation (S473), a downstream effect of PI3K, was observed by western blotting. However, in two independent animal studies utilizing nude rats and NOD/SCID mice in orthotopic xenograft models of glioblastoma, we observed no survival benefit or inhibition of tumour growth. Severe side effects were observed, such as elevated levels of blood glucose and the liver enzyme alanine transaminase (ALT), in addition to diarrhoea, hair loss (alopecia), skin rash and accumulation of saliva in the oral cavity.

Conclusion

Taken together, our results suggest that despite the anti-neoplastic efficacy of dactolisib in glioma treatment in vitro, its utility in vivo is questionable due to toxicity.

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Dynamic changes of tumor gene expression during repeated pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with peritoneal cancer

Abstract

Background

Intraperitoneal chemotherapy is used to treat peritoneal cancer. The pattern of gene expression changes of peritoneal cancer during intraperitoneal chemotherapy has not been studied before. Pressurized intraperitoneal aerosol chemotherapy is a new form of intraperitoneal chemotherapy using repeated applications and allowing repeated tumor sampling during chemotherapy. Here, we present the analysis of gene expression changes during pressurized intraperitoneal aerosol chemotherapy with doxorubicin and cisplatin using a 22-gene panel.

Methods

Total RNA was extracted from 152 PC samples obtained from 63 patients in up to six cycles of intraperitoneal chemotherapy. Quantitative real-time PCR was used to determine the gene expression levels. For select genes, immunohistochemistry was used to verify gene expression changes observed on the transcript level on the protein level. Observed (changes in) expression levels were correlated with clinical outcomes.

Results

Gene expression profiles differed significantly between peritoneal cancer and non- peritoneal cancer samples and between ascites-producing and non ascites-producing peritoneal cancers. Changes of gene expression patterns during repeated intraperitoneal chemotherapy cycles were prognostic of overall survival, suggesting a molecular tumor response of peritoneal cancer. Specifically, downregulation of the whole gene panel during intraperitoneal chemotherapy was associated with better treatment response and survival.

Conclusions

In summary, molecular changes of peritoneal cancer during pressurized intraperitoneal aerosol chemotherapy can be documented and may be used to refine individual treatment and prognostic estimations.

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Increased long noncoding RNA SNHG20 predicts poor prognosis in colorectal cancer

Abstract

Background

Long noncoding RNAs (lncRNAs) have been suggested to be involved in the development and progression of malignancies. However, the investigation of small nucleolar RNA host gene 20 (SNHG20) on cancer progression remains unknown. The present study aims to explore the clinical significance of SNHG20 and its potential molecular mechanism in colorectal cancer (CRC).

Methods

Quantitative real-time PCR (qRT-PCR) was used to measure the SNHG20 expression in a total of 107 CRC tissues and CRC cell lines. Loss of function approach was employed to explore the biological roles of SNHG20 in vitro. Its potential molecular mechanism was further verified by western blotting and qRT-PCR.

Results

The results suggested that SNHG20 expression was significantly upregulated in CRC tissues compared to corresponding normal tissues from 107 CRC patients. High expression of SNHG20 was remarkably associated with advanced TNM stage in patients with CRC. Multivariate analyses unraveled that SNHG20 expression was an independent prognostic factor for overall survival in CRC patients. Further functional assays revealed that knockdown of SNHG20 suppressed cell proliferation, invasion and migration, and cell cycle progression in CRC cells. Moreover, SNHG20 regulated cell growth through modulation of a series of cell cycle-associated genes.

Conclusions

Our findings suggest that dysregulation of SNHG20 participates in CRC progression and may serve as a potential therapeutic target in CRC patients.

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Distribution, diffusive fluxes, and toxicity of heavy metals and PAHs in pore water profiles from the northern bays of Taihu Lake

Abstract

Pore water plays a more significant role than do sediments in pollutant cycling dynamics. Also, concentrations of pollutants in pore water provide important information about their bioavailability or eco-toxicity; however, very few studies have focused on this topic. In this study, four duplicate sediment cores from three typical northern bays as well as the central part of Taihu Lake were collected to investigate the distribution, diffusive fluxes, and toxicity of heavy metals and polycyclic aromatic hydrocarbons (PAHs) in pore water profiles, which will be good in understanding the mobility and toxicity of these toxic pollutants and achieving better environmental management. The diffusive fluxes of heavy metals across the sediment-water interface was estimated through Fick's First Law, and the toxicity of heavy metals and PAHs in pore water was assessed by applying a water quality index (interstitial water toxicity criteria unit, IWCTU) and a hazard index (HI), respectively. The average concentrations of Cr, Cu, Ni, Pb, and Zn in surface pore water were 18.8, 23.4, 12.0, 13.5, and 42.5 μg L⁻¹, respectively. Also, concentrations of the selected heavy metals in both overlying water and pore water from Taihu Lake were all lower than the standard values of the environmental quality standards for surface water. The concentrations as the pore water depth increased, and the highest detected concentrations of heavy metals were recorded between 3 and 5 cm below the sediment surface. The average diffusive fluxes of these metals were 27.3, 24.8, 7.03, 7.81, and −3.32 μg (m² day)⁻¹, respectively, indicating export from sediment into overlying water, with the exception of Zn. There was a potential risk of toxicity, mainly from Pb and Cu, indicating that heavy metals in pore water had slight to moderate impact on sediment-dwelling organisms by values of the IWCTU and the Nemeraw index. The total PAH concentrations in pore water were higher than those in overlying water, and such gradient implies a potential flux of PAHs from pore water to overlying water. The average HI value of PAHs in surface pore water showed no or low ecological risk. While there may be occasional risk due to the HI values in some sites being greater than 1, the dominant contributors were carcinogenic PAHs. Because of their potential biological impact, heavy metals and PAHs and their comprehensive toxic effects in pore water should be given priority attention to keep the safety of Taihu Lake.

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Mercury accumulation and its effects on molecular, physiological, and histopathological responses in the peacock blenny Salaria pavo

Abstract

For humans, fish consumption is the major source of mercury (Hg) exposure. The aim of this study was to assess the effect of Hg in the peacock blenny Salaria pavo, a species of the family of blennies that was used as indicator of water pollution. We performed a sublethal contamination of fish to 66 μg HgCl₂ L⁻¹ during 1, 4, 10 and 15 days but Hg concentration measured in the experimental water was much lower than the nominal concentration. Hg was also measured in both gill and liver tissues and displays a significant increase of its concentration in gills after 1 day of exposure followed by a decrease throughout the experiment. In the liver, Hg burden reaches its maximum at day 4 followed also by a decrease. Partial-length cDNA of mt1, mt2, gpx, cat, mnsod and cuznsod was characterized. Results from mRNA expression levels displayed an up-regulation of mt1, gpx and mnsod while a downregulation of cat was observed. Several biomarker activities were determined in gills and liver and exposure to Hg affected all antioxidant enzymes in gills. EROD, GST and GPx significantly decreased, while CAT levels increased from 4 days of Hg exposure. No lipid peroxidation (LPO) induction was observed in gills of exposed fish. Regarding the liver, the activity of all enzymes increased significantly from the beginning of the experiment. LPO induction was, however, induced after 4 days only. The histological analysis also performed indicated that fish exhibited several damages in gills and liver, mainly in relation to circulatory disturbances in the gills and regressive changes in the liver. All biomarkers assessed showed that peacock blennies are able to detoxify Hg from gill and liver tissues by developing various defense mechanisms.

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Study of silver, selenium and arsenic concentration in wild edible mushroom Macrolepiota procera , health benefit and risk

Abstract

The content and bioaccumulation of trace (Ag, Se, As) and major elements (Ca, Mg, Na and K) in wild edible mushroom Macrolepiota procera and its corresponding soil substrates, collected from five sites in the Rasina region in central Serbia, were investigated. The content of Ag, As and Se was determined by inductively coupled plasma mass spectrometer (ICP-MS) while the amount of Ca, Mg, Na and K was determined by inductively coupled plasma optical emission spectrometer (ICP-OES). The concentrations of major elements in the mushrooms were at typical levels. As far as trace elements are concerned, M. procera bioaccumulates silver although all samples were collected from unpolluted sites. It was found that the content of Ag depended on the geographical origin and the density of fruiting body on the certain site. Principal component analysis distinguished the mushroom samples from different geographical areas and revealed the influence of soil composition on metal content in fruiting bodies. Also, a linear regression correlation test was performed to investigate correlations between Ag, Cd, Se, Pb and As in caps and stipes at different geographic sites separately. In addition, our results indicated that M. procera could serve as a good dietary source of Mg, K and Se. The content of Ag and As was low, so it could not pose a health risk for consumers.

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Transdermal delivery of vaccines – Recent progress and critical issues

Publication date: October 2016
Source:Biomedicine & Pharmacotherapy, Volume 83
Author(s): Kevin Ita
In 2010, the number of deaths from infectious diseases globally was approximately 15 million. It has been reported that two-thirds of deaths from infections are caused by around 20 species, mainly bacteria and viruses. Transnational migration caused by war and the development of transportation facilities have led to the global spread of infectious diseases. Subcutaneous vaccination, though widespread, has a number of problems: the need for trained healthcare personnel, pain, needle-related injuries as well as storage difficulties. Two layers of the human skin- epidermis and dermis- are populated by dendritic cells (DCs), which are potent antigen-presenting cells (APCs). Transcutaneous immunization has therefore become an attractive and alternative route for vaccination. In this review, the various techniques for enhancing vaccine delivery are discussed. These techniques include iontophoresis, elastic liposomes as well as microneedles. Progress made so far with these techniques and the critical issues facing scientists will be highlighted.



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A family-based study of gene variants and maternal folate and choline in neuroblastoma: a report from the Children’s Oncology Group

Abstract

Purpose

Neuroblastoma is a childhood cancer of the sympathetic nervous system with embryonic origins. Previous epidemiologic studies suggest maternal vitamin supplementation during pregnancy reduces the risk of neuroblastoma. We hypothesized offspring and maternal genetic variants in folate-related and choline-related genes are associated with neuroblastoma and modify the effects of maternal intake of folate, choline, and folic acid.

Methods

The Neuroblastoma Epidemiology in North America (NENA) study recruited 563 affected children and their parents through the Children's Oncology Group's Childhood Cancer Research Network. We used questionnaires to ascertain pre-pregnancy supplementation and estimate usual maternal dietary intake of folate, choline, and folic acid. We genotyped 955 genetic variants related to folate or choline using DNA extracted from saliva samples and used a log-linear model to estimate both child and maternal risk ratios and stratum-specific risk ratios for gene–environment interactions.

Results

Overall, no maternal or offspring genotypic results met criteria for a false discovery rate (FDR) Q-value <0.2. Associations were also null for gene–environment interaction with pre-pregnancy vitamin supplementation, dietary folic acid, and folate. FDR-significant gene–choline interactions were found for offspring SNPs rs10489810 and rs9966612 located in MTHFD1L and TYMS, respectively, with maternal choline dietary intake dichotomized at the first quartile.

Conclusion

These results suggest that variants related to one-carbon metabolism are not strongly associated with neuroblastoma. Choline-related variants may play a role; however, the functional consequences of the interacting variants are unknown and require independent replication.

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Variability of high risk HPV genotypes among HIV infected women in Mwanza, Tanzania- the need for evaluation of current vaccine effectiveness in developing countries

Abstract

Background

High risk (HR) human papilloma Virus (HPV) genotypes have been associated with cervical cancer. In Tanzania there is a limited data on the epidemiology of HPV and genotypes distribution among HIV infected women. Here we document varieties of HPV genotypes associated with cervical squamous intraepithelial lesions (SIL) among HIV- infected women at Bugando Medical Centre, Mwanza-Tanzania.

Methods

A cross sectional hospital based study involving HIV infected women was conducted between August and October, 2014. Exfoliated cells from ectocervix and endocervix were collected using cytobrush. HPV genotypes were detected using polymerase chain reaction (PCR) followed by sequencing using specific primers targeting broad range of HPV types. Cytology was done to establish squamous intraepithelial lesions. Log binomial regression analysis was done to establish risk ratios (RR) associated with HPV infection using STATA version 11.

Results

A total of 255 HIV infected women with mean age 39.2 ± 9.1 years were enrolled in the study. HPV DNA was detected in 138/255 (54.1 %, 95 % CI: 47-60) of HIV infected women. Twenty six genotypes were detected in various combinations; of these 17(65.3 %) were of HR genotypes. HR genotypes were detected in 124(48.6 %) of HIV infected women. Common HR genotypes detected were HPV-52(26), HPV-58(21), HPV-35(20) and HPV-16(14). The risk of being HPV positive was significantly higher among women with CD4 counts <100 (RR: 1.20, 95 % CI: 1.05-1.35, P = 0.006) and women with SIL (RR: 1.37, 95 % CI: 1.11-1.68, P = 0.005)

Conclusion

Significant proportion of HIV infected women with low CD4 counts have various grades of cervical SIL associated with varieties of uncommon HR genotypes. There is a need to evaluate the effectiveness of the current vaccine in preventing cervical cancer in developing countries where HIV is endemic.

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A Novel Regenerative Bandage for Hastening Healing of Diabetic Wounds

Chronic diabetic foot ulcers, which can be notoriously difficult to treat, affect 15% of diabetic patients, causing severe pain and a reduction in quality of life.  The complications of diabetic foot ulcers can be severe, necessitating amputation and in some circumstances causing death. A research team of biomedical engineers from Northwestern University has devised a novel therapeutic regenerative bandage, which has antioxidant properties and delivers a protein that hastens the body's own ability to heal itself.

The regenerative bandage is composed of a thermo-responsive, biocompatible material, which when applied to the wound as a liquid, solidifies into a gel at body temperature. The researchers incorporated a protein, called stromal cell derived factor-1, into the gel. The human body innately uses this protein to elicit the homing of repair cells (stem or progenitor cells) to the site of injury, where they produce new blood vessels, thus increasing blood flow and promoting wound healing.  The slow release of this protein from the biocompatible material mimics the body's innate healing response.  The thermo-responsivity of the material enables safe wound dressing changes by rinsing with cool saline, thereby preventing re-injury of the healing tissue during bandage replacement.

Published in the Journal of Controlled Release, the study shows that the regenerative bandage promotes diabetic wound healing four times quicker than a conventional bandage, without side effects.  The researchers showed increased blood flow to the wound with the use of the regenerative bandage, suggesting that the biological wound repair process, which is impaired in diabetic patients, is partially restored by the regenerative bandage.

Study in Journal of Controlled Release: Sustained release of stromal cell derived factor-1 from an antioxidant thermoresponsive hydrogel enhances d ermal wound healing in diabetes

Via: Northwestern Engineering

This post A Novel Regenerative Bandage for Hastening Healing of Diabetic Wounds appeared first on Medgadget.

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Investigators Map Genomes of Three Historically Important Zika Strains

Washington, DC - August 18, 2016 - A team of researchers from Utah State University, Logan, has characterized the consensus genome sequences of three historically important Zika virus strains. This work is an important step towards developing antiviral therapeutic and preventive strategies again...

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Fungus Causing Fatal Infections in Hospitalized Patients Has Unique Growth Patterns

Washington, DC – August 17, 2016 – The multidrug-resistant yeast Candida auris, which has caused fatal infections in some hospitalized patients, has at least two different growth patterns and some of its strains are as capable of causing disease as the most invasive type of yeast called Candida ...

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Psychosocial development of 5-year-old children with hearing loss: Risks and protective factors

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Contributions of p38 and ERK to the antinociceptive effects of TGF-β1 in chronic constriction injury-induced neuropathic rats

Transforming growth factor-βs (TGF-βs) are a group of multifunctional proteins that have neuroprotective roles in various experimental models. We previously reported that intrathecal (i.t.) injections of TGF-β...

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Oxacillin for Injection, USP, 10g by Sagent: Recall - Iron Oxide Particulate Matter

Audience: Pharmacy [Posted 08/19/2016] ISSUE: Sagent Pharmaceuticals, Inc. announced the voluntary nationwide recall of one lot of Oxacillin for Injection, USP, 10 g (NDC 25021-163-99) Lot OXT512 (Exp. Date March 2017) manufactured by Astral...

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Predicting Attitudes toward the Masculine Structure of the Military with Turkish Identification and Ambivalent Sexism

Abstract

Why do people support the masculine structure of the Turkish military? Why do women hold inferior positions in the military? How are sexism and Turkish identification relevant to attitudes toward the masculine structure of the military? Focusing on these questions, the current study explored the associations among Turkish identification, ambivalent sexism (including hostile and benevolent sexism), and attitudes toward the masculine structure of the military in Turkey after controlling for gender, political views, and military affiliation. University students (316 women; 262 men; M _age = 22.02, SD = 2.20) completed the Attitude toward The Masculine Structure of the Military, Turkish Identification, Ambivalent Sexism scales and provided information about age, gender, political view, and military affiliation. The results showed that Turkish identification, hostile sexism, and benevolent sexism predicted attitudes toward the masculine structure of the military after controlling for gender, political view, and military affiliation. Participants who scored higher on Turkish identification and hostile and benevolent sexism supported the masculine structure of the military. The findings may be useful for researchers who aim to better understand why Turkish military personnel is primarily male, how some improvement can be provided for the process of recruitment and retention of military personnel, and how to improve the positions of women in the military or women who would like to join military.

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Materialism Predicts Young Chinese Women’s Self-Objectification and Body Surveillance

Abstract

Previous research on antecedents of women's self-objectification mainly focuses on situational factors whereas our study examined whether women's values on materialism would predict their self-objectification and body surveillance in a sample of 218 undergraduate women in south China. Specifically, we proposed that materialism would increase women's tendency to regard sexual attractiveness as capital for them to gain positive life outcomes (i.e., capitalization of sexual attractiveness, CSA), and the tendency to have appearance-contingent self-worth (i.e., appearance CSW), which would in turn predict their self-objectification and body surveillance. Results provided support for the proposed theoretical model. Specifically, CSA and appearance CSW mediated the relationship between materialism and women's self-objectification, whereas appearance CSW mediated the relationship between materialism and women's body surveillance. These results expand the scope of investigation by incorporating Chinese samples and suggest that in addition to socio-cultural and interpersonal predictors, women's values can contribute to the development of an objectifying perspective on themselves. Therefore, interventions on women's values combined with attempts to change sexually-objectifying environments are both critical in reducing self-objectification and body surveillance in women.

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Increased activity of TRPV3 in keratinocytes in hypertrophic burn scars with post burn pruritus

ABSTRACT

Post burn pruritus is a common distressing sequela of burn wounds. Empirical antipruritic treatment often fails to have a satisfactory outcome, as the mechanism of it has not been fully elucidated. The aim of this study was to evaluate the manifestation of transient receptor potential vanilloid 3 (TRPV3), transient receptor potential ankyrin 1 (TRPA1) and other related receptors in post burn pruritus. Sixty-five burn patients with (n = 40) or without (n = 25) pruritus were investigated, including skin biopsies. Keratinocytes and fibroblasts from skin biopsy samples were separated. Real time-PCR showed that mRNA of TRPV3 was significantly increased in keratinocytes from pruritic burn scars than in keratinocytes from non-pruritic burn scars. With TRPV3 activation, intracellular Ca²⁺ concentrations were more significantly increased in keratinocytes from pruritic burn scars than in those from non-pruritic ones. Additionally, mRNA and protein levels of protease-activated receptor 2 (PAR2) and neurokinin-1 receptor (NK1R) were also significantly increased in pruritic burn scars. In conclusion, we confirmed that TRPV3, PAR2, and NK1R were highly expressed in pruritic burn scars. These results may help determine a novel mechanism for post burn pruritus. This article is protected by copyright. All rights reserved.

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