Plasmonic nanohole electrodes for active color tunable liquid crystal transmissive pixels.

Plasmonic pixels have been shown to offer numerous advantages over pigment-based color filters used in modern commercial liquid crystal (LC) displays. However, wideband dynamic tunability across the visible spectrum remains challenging. We experimentally demonstrate transmissive electrically tunable LC-nanohole pixels operating across the visible spectrum with unpolarized input light. An ultrathin Al nanohole electrode is designed to exhibit a polarized spectral response based on surface plasmon resonances. An output analyzer in combination with a nematic LC layer enables pixel color to be electronically controlled through an applied voltage across the device, where LC reorientation leads to tunable mixing of the relative contributions from the plasmonic color input. The nanostructured Al layer, acting as a combined electrode, polarizer, and functional color filter, is highly promising for electro-optic display applications.

Fabrication of nanostructured transmissive optical devices on ITO-glass with UV1116 photoresist using high-energy electron beam lithography.

High-energy electron beam lithography for patterning nanostructures on insulating substrates can be challenging. For high resolution, conventional resists require large exposure doses and for reasonable throughput, using typical beam currents leads to charge dissipation problems. Here, we use UV1116 photoresist (Dow Chemical Company), designed for photolithographic technologies, with a relatively low area dose at a standard operating current (80 kV, 40-50 µC cm-2, 1 nAs-1) to pattern over large areas on commercially coated ITO-glass cover slips. The minimum linewidth fabricated was ∼33 nm with 80 nm spacing; for isolated structures, ∼45 nm structural width with 50 nm separation. Due to the low beam dose, and nA current, throughput is high. This work highlights the use of UV1116 photoresist as an alternative to conventional e-beam resists on insulating substrates. To evaluate suitability, we fabricate a range of transmissive optical devices, that could find application for customized wire-grid polarisers and spectral filters for imaging, which operate based on the excitation of surface plasmon polaritons in nanosized geometries, with arrays encompassing areas ∼0.25 cm2.

Therapeutic vaccination with a trivalent T-cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis.

Therapeutic vaccination using T-cell receptor (TCR) peptides from V genes commonly expressed by potentially pathogenic T cells remains an approach of interest for treatment of multiple sclerosis (MS) and other autoimmune diseases. We developed a trivalent TCR vaccine containing complementarity determining region (CDR) 2 peptides from BV5S2, BV6S5 and BV13S1 emulsified in incomplete Freund's adjuvant that reliably induced high frequencies of TCR-specific T cells. To evaluate induction of regulatory T-cell subtypes, immunological and clinical parameters were followed in 23 treatment-naïve subjects with relapsing-remitting or progressive MS who received 12 monthly injections of the trivalent peptide vaccine over 1 year in an open-label study design. Prior to vaccination, subjects had reduced expression of forkhead box (Fox) P3 message and protein, and reduced recognition of the expressed TCR repertoire by TCR-reactive cells compared with healthy control donors. After three or four injections, most vaccinated MS subjects developed high frequencies of circulating interleukin (IL)-10-secreting T cells specific for the injected TCR peptides and significantly enhanced expression of FoxP3 by regulatory T cells present in both 'native' CD4+ CD25+ and 'inducible' CD4+ CD25- peripheral blood mononuclear cells (PBMC). At the end of the trial, PBMC from vaccinated MS subjects retained or further increased FoxP3 expression levels, exhibited significantly enhanced recognition of the TCR V gene repertoire apparently generated by perturbation of the TCR network, and significantly suppressed neuroantigen but not recall antigen responses. These findings demonstrate that therapeutic vaccination using only three commonly expressed BV gene determinants can induce an expanded immunoregulatory network in vivo that may optimally control complex autoreactive responses that characterize the inflammatory phase of MS.

Enhanced HIV-1 specific immune response by CpG ODN and HIV-1 immunogen-pulsed dendritic cells confers protection in the Trimera murine model of HIV-1 infection.

We have recently developed a novel small animal model for HIV-1 infection (Ayash-Rashkovsky et al., http://www.fasebj.org/cgi/doi/10.1096/fj.04-3184fje; doi:10.1096/fj.04-3184fje). The mice were successfully infected with HIV-1 for 4-6 wk with different clades of either T- or M-tropic isolates. HIV-1 infection was accompanied by rapid loss of human CD4+ T cells, decrease in CD4/CD8 ratio, and increased T cell activation. HIV specific human humoral and cellular immune responses were observed in all HIV-1 infected animals. In the present study, HIV specific human immune responses, both humoral and cellular, were generated in noninfected Trimera mice, after their immunization with gp120-depleted HIV-1 antigen, presented by autologous human dendritic cells. Addition of CpG ODN to the antigen-pulsed DCs significantly enhanced (by 2- to 30-fold) the humoral and cellular HIV-1 specific immune responses. Only mice immunized with the HIV-1 immunogen and CpG were completely protected from infection with HIV-1 after challenge with high infection titers of the virus. This novel small animal model for HIV-1 infection may thus serve as an attractive platform for rapid testing of candidate HIV-1 vaccines and of adjuvants and may shorten the time needed for the development and final assessment of protective HIV-1 vaccines in human trials.

Characterization of a novel metabolic strategy used by drug-resistant tumor cells.

Acquired or inherent drug resistance is the major problem in achieving successful cancer treatment. However, the mechanism(s) of pleiotropic drug resistance remains obscure. We have identified and characterized a cellular metabolic strategy that differentiates drug-resistant cells from drug-sensitive cells. This strategy may serve to protect drug-resistant cells from damage caused by chemotherapeutic agents and radiation. We show that drug-resistant cells have low mitochondrial membrane potential, use nonglucose carbon sources (fatty acids) for mitochondrial oxygen consumption when glucose becomes limited, and are protected from exogenous stress such as radiation. In addition, drug-resistant cells express high levels of mitochondrial uncoupling protein 2 (UCP2). The discovery of this metabolic strategy potentially facilitates the design of novel therapeutic approaches to drug resistance.

Immunization with gp120-depleted whole killed HIV immunogen and a second-generation CpG DNA elicits strong HIV-specific responses in mice.

HIV-1 Immunogen is a gp120-depleted whole killed virus vaccine candidate formulated with Incomplete Freund's Adjuvant (HIV-IFA). We evaluated in a mouse model the immunogenicity of HIV-IFA by itself and when combined with HYB2055, an immunomodulatory oligonucleotide consisting of a novel DNA structure and synthetic CpR immunostimulatory motif, as an adjuvant. C57/BL6 mice were immunized with HIV-IFA alone or combined with HYB2055. Mice treated with HYB2055 or with PBS were used as controls. Compared to HIV-IFA alone, immunization with HIV-IFA and HYB2055 combination elicited strong production of HIV- and p24-specific IFNgamma, RANTES, MIP 1alpha, and MIP 1beta, as well as high titers of HIV- and p24-specific antibodies. Inclusion of HYB2055 also reduced levels of IL-5 produced by HIV-IFA alone. HYB2055 enhances the immunogenicity of HIV-IFA and shifts responses towards a type 1 cytokine profile. The immune enhancing effects of HYB2055 adjuvant were dose-dependent. These findings warrant clinical evaluation of the HIV-1 immunogen/HYB2055 candidate as a therapeutic vaccine for HIV-1 infected patients.

Decreased FOXP3 levels in multiple sclerosis patients.

Autoimmune diseases such as multiple sclerosis (MS) may result from the failure of tolerance mechanisms to prevent expansion of pathogenic T cells. Our study is the first to establish that MS patients have abnormalities in FOXP3 message and protein expression levels in peripheral CD4+ CD25+ T cells (Tregs) that are quantitatively related to a reduction in functional suppression induced during suboptimal T-cell receptor (TCR) ligation. Of importance, this observation links a defect in functional peripheral immunoregulation to an established genetic marker that has been unequivocally shown to be involved in maintaining immune tolerance and preventing autoimmune diseases. Diminished FOXP3 levels thus indicate impaired immunoregulation by Tregs that may contribute to MS. Future studies will evaluate the effects of therapies known to influence Treg cell function and FOXP3 expression, including TCR peptide vaccination and supplemental estrogen.

Specificity of regulatory CD4+CD25+ T cells for self-T cell receptor determinants.

Although the phenotypic and regulatory properties of the CD4(+)CD25(+) T cell lineage (Treg cells) have been well described, the specificities remain largely unknown. We demonstrate here that the CD4(+)CD25(+) Treg population includes the recognition of a broad spectrum of human TCR CDR2 determinants found in the germline V gene repertoire as well as that of a clonotypic nongermline-encoded CDR3beta sequence present in a recombinant soluble T cell receptor (TCR) protein. Regulatory activity was demonstrated in T cell lines responsive to TCR but not in T cell lines responsive to control antigens. Inhibitory activity of TCR-reactive T cells required cell-cell contact and involved CTLA-4, GITR, IL-10, and IL-17. Thus, the T-T regulatory network includes Treg cells with specificity directed toward self-TCR determinants.

Epidemiology and transmission of rotavirus infections and diarrhoea in St. Lucia, West Indies

To determine the epidemiology and risk factors of rotavirus in St. Lucia, 229 children in three valleys with varying levels of sanitation were studied for 2 years. A four-fold rise in complement fixation antibody to rotavirus antigen was used in paired samples as evidence of recent infection. Results showed that forty-eight per cent of infants experienced at least one infection during a two-year period, and 17 percent of children were reinfected. Infections occured within the first months of life and peaked between 6 and 23 months of age. The peak infection coincided with the dry season in each age group. Children breast-feeding had fewer infections. Although crowding within the home was significantly associated with repeated infection, the incidence of infection was not affected by the degree of sanitation. Other studies in the region, using recently developed techniques, concur with these findings which advance our understanding of the epidemiological importance of rotavirus in St. Lucia. Although these studies provide insights into the risk factors for rotavirus infections, other studies are required to determine whether investments should be focused on improved sanitation or immunization or both (AU)

Quality control in laboratory investigations on Schistosoma mansoni in St Lucia, West Indies. Maintenance of artificial prevalence as a laboratory aid

A method is described of maintaining an apparent S mansoni prevalence rate of 10 percent in an area estimated to have a natural rate of below 5 percent following two chemotherapy campaigns. To sustain interest and therefore accuracy among microscopists engaged on screening, known S. mansoni-positive stools were seeded without their knowledge, among those collected in the field. The problems of achieving a desired level of seeding, and of a possible further dimension of the scheme are discussed (AU)

Quality control in laboratory investigations on Schistosoma mansoni on St. Lucia, West Indies: a staff assesment scheme

A method is described for the supervision of technicians engaged in microscopical screening of large numbers of stools for Schistosoma mansoni ova. The scheme presents graphically a regular updated longitudinal evaluation of both individual and group standards of technical competence (AU)

Control of Schistosoma mansoni transmission by chemotherapy in St. Lucia. I. Results in man

Control of Schistosoma mansoni transmission solely by treatment of all infected persons was attempted in Marquis Valley (population about 3,100), St. Lucia. Two-year results are reported. Excluding 26 pregnant patients, 709 of 729 persons who were found to be infected received treatment the first year. Most of these, 677, were given a single injection of hyacanthone (2.5 mg/kg of body weight), and the same treatment was administered to 159 patients the second year. Side effects were not severe; the major side effect, vomiting, occurred in about 22 percent on both occassions. In villages with initially high transmission rates, the incidence of new infections in children 0 to 14 years fell from 20.8 percent before chemotherapy to 7.4 percent after 1 year and to 3.7 percent after 2 years. This pattern was significantly different from that in the comparison area where no control scheme exists. Chemotherapy alone appears to ba a rapid, effective, and comparatively inexpensive method of controlling S. mansoni transmission in St. Lucia (AU)

Reduction in transmission of Schistosoma mansoni by a four-year focal mollusciciding programme against Biomphalaria glabrata in St. Lucia

The effect on transmission of Schistosoma mansoni of a focal snail control programme was investigatsd over four years amongst approximately 1250 people living in 5 communities in the steep-sided Soufriere river valley, St. Lucia, West Indies. Bayer 6076 was applied from constant flow drip cans to 12 stream sections at a target dose of 8mg/litre clonitralide every four weeks. Only proven and potential transmission sites were treated (AU)

Routine focal mollusciciding after chemotherapy to control Schistosoma mansoni in Cul de Sac valley, St. Lucia

Concluding results of a ten year schistosomiasis control programme in Cul de Sac valley, St. Lucia, are described. After an area wide mollusciciding campaign (1970-1975), and a surveillance/treatment programme supplemented with selective population chemotherapy in 1975 and 1976, prevelence rates of Schistosoma mansoni were reduced to low levels. To prevent a resurgence of transmission a cost effective routine focal mollusciciding programme, suitable for public health implementation was evaluated from 1977 to 1981. Streams and main collector drains in banana fields, considered to be potential S. mansoni transmission sites, were treated every four weeks with Bayluscide 6076 emulsifiable concentrate (Clonitralide). Snail populations were effectively controlled in the treated areas but large numbers were present where no treatment was given. Only 0.06 percent of sentinel snails became infected. Prevalence of infection in the human population remained low (over-all 5 percent) and intensity of infection at a level not normally associated with schistosomal disease. Since control started ten years earlier the level of potential contamination has fallen by 92 percent in high transmisssion areas. The four year programme cost US$12,909, of which 54 percent was for molluscicide, 27 percent for labour and 19 percent for transport, equipment and sundries. The average annual cost per head of population was US$0.46

Further observations from St Lucia on control of Schistosoma mansoni transmission by provision of domestic water supplies

Individual households in five settlements were provided with piped water in a pilot scheme to investigate the effect on transmission of S. mansoni in St Lucia. Nearby comparison settlements, in the same valley, were provided with water through a public standpipe system. The incidence of S. mansoni infection among children decreased in the experimental area, leading to lower prevalence rates and lower intensity of infection in all age groups. Over the study period, indices of infection increased in the comparison settlements, but by the end of the period development was making those settlements less suitable for comparison purposes and some reduction in transmission was occurring. The changes in human infection rates were reflected in the results of studies with sentinel snails. In the experimental area, infection rates gradually fell owing to reduced water contact and consequently less contamination of the river and its banks, and possibly to the intensity of infection. It is suggested that a piped water supply be considered as a method of schistosomiasis control, but that the cost should not be debited only to the control of this disease since clean water supply has other medical and social benefits (AU)

Evaluation of an experimental mollusciciding programme to control Schistosoma mansoni transmission in St Lucia

The size and number of colonies of Biomphalaria glabrata were reduced after four years of a surveillance/treatment snail control programme using an emulsifiable concentrate of niclosamide (25 percent active ingredient). Surveys among the human population showed that the incidence of new Schistosoma mansoni infections in 0-10 year-old children fell from 22 percent to 4.3 percent, while in a comparison area the incidence remained at 20 percent. With the reduced transmission over four years, the prevalence of infection in a cohort of children examined in 1971 and 1975 fell from 34 percent to 23 percent. The fall in prevalence and intensity of infection led to a reduction of 66 percent in the index of potential contamination, which was reflected in a reduced rate of infection among sentinel snails and representative samples of B. glabrata collected during surveillance searchs. The overall annual cost of the programme was US $3.24 per capita (AU)

Immune responses during human schistosomiasis mansoni. III. Regulatory effect of patient sera on human lymphocyte blastogenic responses to schistosome antigen preparations

The in vitro lymphocyte blastogenesis capabilities of patients with schistosomiasis mansoni were tested against phytohemagglutinin (PHA), Candida albicans extract,and soluble preparations of schistosome eggs (SEA), adult worms (SWAP), or cercariae (CAP). When patients lymphocytes were cultured un medium which contained 5 percent human (homologous) normal (uninfected) serum, they responded well to PHA and Candida extract. The responses induced by SEA were maximal in patients with early Schistosma mansoni infections, while reactivity against SWAP and CAP increased during chronic infection. These responses, induced by the Schistosome-derived antigenic preparations,were suppressed if the homologous normal serum supplement of the culture medium was replaced with either the patient's own (autologous) serum, or that of another S. mansoni patient. All sera were heat-inactivated (56 degree C/ 30 min) prior to use. In contrast, responses against the non-specific mitogen (PHA) and the unrelated antigen (Candida extract), were not altered by these changes of the serum supplementation of the media. The degree of suppression by patient serum was not changedby increasing the serum percentage in the medium from 5 percent to 25 percent. The suppressive effects of patient sera on responses induced by SEA and SWAP were increased in relationship to the duration of the serum donor's S. mansoni infection. Preincubation of lymphocytes in suppressive patient sera for 30 min at 37 degree C did not reduce the expected level of responsiveness if the cells were subsequently cultured in homologous-normal serum supplemented medium. The data indicate that during S. mansoni infection patients develop serum component(s) which specifically interfere with the responsiveness of their lymphocytes in regard to certain schistosome-derived antigenic preparations. The immunoregulatory events described could participate in the modulation of immunopathology, the maintenance of chronic worm survival and the prevention of full expression of protective immune responses. (AU)

Schistosoma mansoni control in Cul de Sac Valley Saint Lucia. II Chemotherapy as a supplement to a focal mollusciciding programme

After an intensive area-wide mollusciciding campaign, over four and a half years, transmission of Schistosoma mansoni was reduced. A cheaper scheme suitable for the follow-up or consolidation stage of control was evaluated and two selective population chemotherapy campaigns using hycanthone (2 mg/kg b.w.) and oxamniquine (15mg/kg b.w.) were mounted. Prevalence dropped to 6 percent and 3 percent in areas with previously high and low levels of transmission respectively. Calculations suggested that these figures were falsely low and that perhaps 20 percent of the population were still excreting S. mansoni ova in small numbers. The unco-operative groups in the population are probably more important in maintaining a reservoir of infection in the community than persons with light infections undetected by the sedimentation concentration stool examination technique used. The benefit of more sensitive but more costly examination techniques is not clear since the importance of very light infections in transmission is uncertain. Case detection absorbs an increasing proportion of the total cost of chemotherapy programmes with fewer cases being found amongst the same number screened. Using hycanthone (649 treated) the cost per person protected was $0.74 and using oxamniquine (264 treated) $0.94. The need to develop low cost consolidation or follow-up procedures for preventing a resurgence of transmission after successful control, when the infection is no longer of public health importance, is stressed. (AU)