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Nanocarriers can be translocated to the peripheral region of tumor tissues through the well-known enhanced permeability and retention effects. However, a high dose of nanocarriers need to be injected due to the low delivery efficiency of nanocarriers, which can also increase the side effects of off-targeted nanocarriers in normal tissues. It was demonstrated that on-demand drug release from tumor-targeted nanocarriers can reduce the effective dosage of anti-cancer drugs by rapidly increasing the local drug concentration in the tumor tissue. Here we report a near-infrared (NIR) photodynamic method to trigger drug release from tumor-targeted polymer nanoparticles via reactive oxygen species (ROS)-mediated polymer degradation. Paclitaxel and silicon 2,3-naphthalocyanine bis(trihexylsilyloxide) were co-encapsulated as an anti-cancer drug and photosensitizer, respectively, within biotin-decorated poly(ethylene glycol)-polythioketal micelles. Upon NIR light illumination under the maximum permissible exposure level, the photoexcited naphthalocyanine generated ROS cleaved the thioketal groups in the micelles to release the encapsulated paclitaxel. The photodynamically-induced release of paclitaxel dramatically reduced the half maximal inhibitory concentration of paclitaxel by 39.9-fold and eliminated lung adenocarcinoma at a concentration an order of magnitude smaller than its maximum tolerated dosage. Even under a simulated deep tissue condition with a tissue-like phantom, the NIR light-illuminated micelles exhibited a high level of cytotoxicity against the tumor cells and efficiently suppressed tumor growth. Our study demonstrates that photodynamic polymer degradation is an effective means to improve the anticancer drug efficacy of tumor-targeted micelles. [ABSTRACT FROM AUTHOR]

Zoonotic trematode infections are an area of the neglected tropical diseases that have become of major interest to global and public health due to their associated morbidity. Human fascioliasis is a trematode zoonosis of interest in public health. It affects approximately 50 million people worldwide and over 180 million are at risk of infection in both developed and underdeveloped countries. The one health paradigm is an area that seeks to address the problem of zoonotic infections through a comprehensive and sustainable approach. This review attempts to address the major challenges in managing human and animal fascioliasis with valuable insights gained from the one health paradigm to global health and multidisciplinary integration. [ABSTRACT FROM AUTHOR]

The rapid and robust identification of viral infections has broad implications for a number of fields, including medicine, biotechnology and biodefense. Most detection systems rely on specific molecules, such as nucleic acids or proteins, to identify the target(s) of interest. These molecules afford great specificity, but are often expensive, labor-intensive, labile and limited in scope. Label free detection methods seek to overcome these limitations by instead using detection methods that rely on intrinsic properties as a basis for identifying and separating species of interest and thus do not rely on specific prior knowledge of the target. Optical chromatography, one such technique, uses the balance between optical and fluidic drag forces within a microfluidic channel to determine the optical force on cells or particles. Here we present the application of individual optical force measurements as a means of investigating pseudorabies virus infection in Vero cells. Optical force differences are seen between cells from uninfected and infected populations at a multiplicity of infection as low as 0.001 and as soon as 2 hours post infection, demonstrating the potential of this technique as a means of detecting viral infection. Through the application of a pattern recognition neural network, individual cell size data are combined with optical force as a means of classifying cell populations. Potential applications include the early detection of bloodborne pathogens for the prevention of sepsis and other diseases as well as the detection of biological threat agents. [ABSTRACT FROM AUTHOR]

We describe the clinical course of two cases of neuroinvasive West Nile Virus (WNV) infection in the critical care unit. The first case is a 70-year-old man who presented during summer with mental status changes. Cerebrospinal fluid (CSF) analysis revealed pleocytosis with lymphocyte predominance. WNV serology was positive in the CSF. His condition worsened with development of left-sided weakness and deterioration of mental status requiring intensive care. The patient gradually improved and was discharged with residual left-sided weakness and near-complete improvement in his mental status. The second case is an 81- year-old man who presented with mental status changes, fever, lower extremity weakness, and difficulty in walking. CSF analysis showed pleocytosis with neutrophil predominance. WNV serology was also positive in CSF. During the hospital stay his mentation worsened, eventually requiring intubation for airway protection and critical care support. The patient gradually improved and was discharged with residual upper and lower extremity paresis. Neuroinvasive WNV infection can lead to significant morbidity, especially in the elderly. These cases should be suspected in patients with antecedent outdoor activities during summer. It is important for critical care providers to be aware of and maintain a high clinical suspicion of this disease process. [ABSTRACT FROM AUTHOR]

The protective efficacy and immunogenicity of a chimeric peptide against West Nile virus (WNV) was evaluated. This virus is the aetiological agent of West Nile fever, which has recently emerged in the western hemisphere. The rapid spread of WNV throughout North America, as well as the constantly changing epidemiology and transmission of the virus by blood transfusion and transplantation, have raised major public-health concerns. Currently, there are no effective treatments for WNV or vaccine for human use. We previously identified a novel, continuous B-cell epitope from domain III of the WNV envelope protein, termed Ep15. To test whether this epitope can protect against WNV infection, we synthesized a linear chimeric peptide composed of Ep15 and the heat-shock protein 60 peptide, p458. The p458 peptide is an effective carrier peptide for subunit vaccines against other infectious agents. We now report that mice immunized with the chimeric peptide, p458-Ep15, were resistant to lethal challenges with three different WNV strains. Moreover, their brains were free of viral genome and infectious virus. Mice immunized with Ep15 alone or with p431-Ep15, a control conjugate, were not protected. The chimeric p458-Ep15 peptide induced WNV-specific immunoglobulin G antibodies that neutralized the virus and induced the secretion of interferon-γ in vitro. Challenge of chimeric peptide-immunized mice considerably enhanced WNV-specific neutralizing antibodies. We conclude that this chimeric peptide can be used for formulation of a human vaccine against WNV. [ABSTRACT FROM AUTHOR]

Israel has a long history of concern with chemical and biological threats, since several hostile states in the Middle East are likely to possess such weapons. The Twin-Tower terrorist attacks and Anthrax envelope scares of 2001 were a watershed for public perceptions of the threat of unconventional terror in general and of biological terror in particular. New advances in biotechnology will only increase the ability of terrorists to exploit the burgeoning availability of related information to develop ever-more destructive bioweapons. Many areas of modern biological research are unavoidably dual-use by nature. They thus have a great potential for both help and harm; and facilitating the former while preventing the latter remains a serious challenge to researchers and governments alike. This article addresses how Israel might best (1) prevent hostile elements from obtaining, from Israel’s biological research system, materials, information and technologies that might facilitate their carrying out a biological attack, while (2) continuing to promote academic openness, excellence and other hallmarks of that system. This important and sensitive issue was assessed by a special national committee, and their recommendations are presented and discussed. One particularly innovative element is the restructuring and use of Israel’s extensive biosafety system to also address biosecurity goals, with minimal disruption or delay. [ABSTRACT FROM AUTHOR]

γδ T cells are unique, and their localization at sites of infection is considered critical in immune defence. We demonstrate the accumulation of γδ T cells in rat regional popliteal lymph nodes (PLNi) starting 2 days after inoculation of cytomegalovirus (CMV) into the footpad. Earlyappearance PLNi γδ T cells significantly inhibited plaque development and the spread of CMV infection. These γδ T cells were negative for CD4 and CD8beta receptors, proliferated in response to interleukin-2 (IL-2) and contained high levels of interferon-γ (IFN-γ), the appearance of which correlated with the curing of fibroblasts from virus infection. The addition of anti-IFN-γ abolished the ability of fibroblast monolayers to be cured from CMV infection. In contrast, this protection was not abolished by the addition of anti-rat IL-2 or anti-rat TNF-α, or by the depletion of NKR-P1bearing cells within γδ T cells. In addition, the present study shows that while γδ T cells derived from naive and CMV-infected rats are able to kill both YAC-1 targets and CMV-infected syngeneic fibroblasts in vitro, only the latter are able to clear CMV-infected fibroblast monolayers. Finally, our data suggest that the expression of NKR-P1 by γδ T cells is critical for cytotoxicity, but its contribution to the curing from CMV infection was limited. [ABSTRACT FROM AUTHOR]

The severe disease atypical measles occurred when individuals immunized with a poorly protective inactivated vaccine contracted measles, and was postulated to be due to a lack of fusion-inhibiting antibodies. Here, rhesus macaques immunized with formalin-inactivated measles vaccine developed transient neutralizing and fusion-inhibiting antibodies, but no cytotoxic Tcell response. Subsequent infection with measles virus caused an atypical rash and pneumonitis, accompanied by immune complex deposition and an increase in eosinophils. Fusion-inhibiting antibody appeared earlier in these monkeys than in non-immunized monkeys. These data indicate that atypical measles results from previous priming for a nonprotective type 2 CD4 T-cell response rather than from lack of functional antibody against the fusion protein. [ABSTRACT FROM AUTHOR]

Retinoids exhibit a wide spectrum of activities, including antiinflammatory properties. We have investigated the effect of retinoic acid (RA) and retinyl acetate (RAc) on the production of reactive oxygen metabolites and the release of lysosomal enzymes by human polymorphonuclear leukocytes (PMN). Incubation of PMN with RAc or RA (1-100 μ M) caused a dose-dependent inhibition (upto 90%) in O production and chemiluminescence induced by phorbol myristate acetate (PMA), N-formyl-methionylleucyl-phenylanaline (fMLP), opsonized zymosan or ionophore A23187. Both retinoids (1-100 μ M) also inhibited, in a dose-dependent way, degranulation induced by fMLP (upto 85% at the highest concentration of RA). These inhibitory effects appear irreversible, since they persist after the drugs are removed and the cells washed before stimulation. Inhibitors of cyclo-oxygenase activity such as acetylsalicylic acid and indomethacin did not influence the effects of RAc. In contrast, BW755, an inhibitor of both cyclooxygenase and lipoxygenase, reversed the inhibitory action of RAc, suggesting that the effect of retinoids occurs possibly through the mediation of lipoxygenase products. The modulation of PMN oxidative metabolism and degranulation might help explain the antiinflammatory properties of retinoids. [ABSTRACT FROM AUTHOR]

The effect of persistent measles virus infection on the expression of major histocompatibility complex (MHC) class I antigens was studied. Mouse neuroblastoma cells C1300, clone NS20Y, were persistently infected with the Edmonston strain of measles virus. The persistently infected cell line, NS20Y/MS, expressed augmented levels of both H-2K and H-2D MHC class I glycoproteins. Activation of two interferon(IFN)-induced enzymes, known to be part of the IFN system: (2′-5′)oligoadenylate synthetase and double-stranded-RNA-activated protein kinase, was detected. Measles-virus-infected cells elicited cytotoxic T lymphocytes that recognized and lysed virus-infected and uninfected neuroblastoma cells in an H-2-restricted fashion. Furthermore, immunization of mice with persistently infected cells conferred resistance to tumor growth after challenge with the highly malignant NS20Y cells. The rationale for using measles virus for immunotherapy is that most patients develop lifelong immunity after recovery or vaccination from this infection. Patients developing cancer are likely to have memory cells. A secondary response induced by measles-virus-infected cells may therefore induce an efficient immune response against non-infected tumour cells. [ABSTRACT FROM AUTHOR]

Infection of mice with murine cytomegalovirus (CMV) presents a model for the study of the role of the immune system in the pathogenesis of human CMV. We performed adoptive transfer experiments to evaluate the prospects for enhancing the anti-viral potential of murine CMV immune spleen cells by THF-γ2. Adult BALB/e mice resistant to murine CMV become highly susceptible following immunosuppression by cyclophosphamide. Recipient mice were injected with murine CMV and cyclophosphamide concomitantly, and 24 h later adoptive transfers of syngeneic immune spleen cells were performed. We showed that passive transfers of murine CM V immune spleen cells prevented the development of a fatal disease in 38%, of the recipient mice. Daily injections of murine CMV immune donor mice with THF-γ2 enhanced considerably (93%) the therapeutic potential of virus-specific immune cells. These experiments provide direct evidence for the antiviral capacity of THF-γ2 through its immunomodulatory effect on immune T cells. [ABSTRACT FROM AUTHOR]

Infants suffering from bronchopulmonary dysplasia (BPD) are known to have low levels of vitamin A, a factor which may be implicated in the pathogenesis of the condition. The ability of retinoic acid (RA) (one of the active forms of vitamin A) to influence the production of superoxide anion (02-) and hydrogen peroxide (H2O2) by stimulated human adult or cord blood neutrophils and macrophages has been studied, RA was found to inhibit the O2- and H2O2 production in a dose-dependent manner. The time required for maximal inhibition was 30 min for neutrophils and 24 h for macrophages. Although cord blood neutrophils produced larger quantities of O2- and H2O2 both with and without RA, the degree of inhibition was similar in both adult and neonatal cells (40-60%). The results suggest that retinoic acid may prevent neutrophil and macrophage mediated lung damage by inhibiting the production of toxic oxygen compounds, especially in BPD conditions. [ABSTRACT FROM AUTHOR]

Cytomegalovirus causes T cell immune impairment in infected mice, reflected by a decreased response to the T cell mitogens PHA and Con A. and reduction of Con A-induced IL-2 secretion. Concomitantly, a marked increase in the spleen weight of infected mice was found. Histological examination of the liver revealed focal hepatitis. These signs of infection lasted from day 5 today 14 after infection when mice slowly started to recover. Systemic treatment of MCMV-infected mice with thymic humoral factor (THF) resulted in a reconstitution of the mitogenic responses, lL-2 secretion, normalization of spleen weight and recovery of liver inflammation. Unlike other thymic hormones, THF did not affect interferon synthesis and NK cytotoxicity in infected mice. It is concluded that THF restores immune competence of mice immunosuppressed as a result of MCMV infection, through modulation of the T cell compartment. [ABSTRACT FROM AUTHOR]

Adult mice infected with coxsackieviruses A-15, B-1, B-2, B-4 and B-6 showed depressed antibody responses to unrelated antigens; mice infected with coxsackievirus B-3 developed reduced humoral and cell-mediated immune responses. These findings might have clinical and epidemiological implications. [ABSTRACT FROM AUTHOR]

Antisera against purified monoclonal IgM from patients with Waldenström's macroglobulinemia were raised in guinea-pigs. Absorption with normal human serum and heterologous macroglobulinemic serum resulted in an antiserum to a subgroup present in 5 of 54 sera. [ABSTRACT FROM AUTHOR]