Immunological studies in multiple low dose streptozotocin induced diabetes in mice

1. Multiple low doses of streptozotocin (MSZ) treatment successfully induced diabetes in male TO, MFI and HO lean mice. In contrast however, BALB/c mice failed to develop persistent hyperglycaemia. Single streptozotocin (SSZ) treatment also produced diabetes in TO mice. SSZ treatment however, produced severe weight loss and atrophy of the lymphoid organs. MSZ treatment on the other hand, was not cytotoxic towards lymphoid organs and, whilst there was no loss of body weight, growth rates were reduced in MSZ treated mice. 2. Following sheep red blood cell (SRBC) immunisation of MSZ-treated mice, haemagglutination titres, and numbers of antigen reactive cells and plaque forming cells were all significantly lower than control values. 3. In vitro proliferation of spleen cells in response to phytohaemagglutinin (PHA) and conconavalin A (ConA) was found to be significantly depressed in MSZ treated mice. However, T-lymphocyte responses were intact when the mice were not overtly hyperglycaemic. In contrast, however, T cell independent responses to lipopolysaccharide (LPS) were generally intact throughout the study period. 4. Cell mediated immunity, as assessed by measurements of delayed (Type IV) hypersensitivity, was also depressed in MSZ treated mice. This suppression could be reversed by insulin therapy. 5. Both natural killer cell activity and antibody dependent cell mediated cytotoxicity were found to be significantly increased in MSZ treated mice. 6. Histological examination of the pancreas showed the presence of insulitis, in MSZ treated mice, and cytotoxic effector cells against obese mice islet cells (as assessed by 51Cr release) and HIT-T15 cells (as assessed by insulin secretion) were found to be significantly increased. Furthermore, these effector cells were also found to show increased proliferation in the presence of homogenates prepared from HIT-T15 cells. Examination of the Sera from MSZ treated mice showed that islet cell surface antibodies were present.

Particulate carriers as immunological adjuvants

In recent years, much interest has focused on the significance of inducing not only systemic immunity but also good local immunity at susceptible mucosal surfaces. A new field of mucosal immunity has been established as information accumulates on gut-associated lymphoid tissue, bronchus-associated lymphoid tissue and nasal-associated lymphoid tissue (GALT, BALT and NALT, respectively) and on their role in both local and systemic immune responses. This project, following the line of investigation started by other workers, was designed to study the use of microspheres to deliver antigens by the mucosal routes (oral and nasal). Antigen-containing microspheres were prepared with PLA and PLGA, by either entrapment within the particles or adsorption onto the surface. The model protein antigens used in this work were mainly tetanus toxoid (TT), bovine serum albumin (BSA) and γ-globulins.In vitro investigations included the study of physicochemical properties of the particulate carriers as well as the assessment of stability of the antigen molecules throughout the formulation procedures. Good loading efficiencies were obtained with both formulation techniques, which did not affect the immunogenicity of the antigens studied. The influence of the surfactant employed on the microspheres' surface properties was demonstrated as well as its implications on the adsorption of proteins. Preparations containing protein adsorbed were shown to be slightly more hydrophobic than empty PLA microspheres, which can enhance the uptake of particles by the antigen presenting cells that prefer to associate with hydrophobic surfaces. Systemic and mucosal immune responses induced upon nasal, oral and intramuscular administration have been assessed and, when appropriate, compared with the most widely used vaccine adjuvant, aluminium hydroxide. The results indicate that association of TT with PLA microspheres through microencapsulation or adsorption procedures led to an enhancement of specific mucosal IgA and IgG and systemic IgG responses to the mucosal delivered antigens. Particularly, nasal administration of TT produced significantly higher serum levels of specific IgG in test animals, as compared to control groups, suggesting that this is a potential route for vaccination. This implies the uptake and transfer of particles through the nasal mucosa, which was further demonstrated by the presence in the blood stream of latex particles as early as 10 min after nasal administration.

Abnormal retinal vascular reactivity in individuals with impaired glucose tolerance:a preliminary study

To investigate the relationship between vascular function parameters measured at the retinal and systemic level and known markers for cardiovascular risk in patients with impaired glucose tolerance (IGT). Sixty age- and gender- matched White-European adults (30 IGT and 30 normal glucose tolerance -NGT) were recruited for the study. Fasting plasma glucose, lipids and 24-hour blood pressure (BP) was measured in all subjects. Systemic vascular and endothelial function was assessed using carotid-artery intimal media thickness (cIMT) and flow mediated dilation (FMD). Retinal vascular reactivity was assessed by the Dynamic Retinal Vessel Analyser (DVA). Additionally, blood glutathione (GSH, GSSG and tGSH) and plasma von-Willebrand (vWF) factor levels were also measured. Individuals with IGT demonstrated higher BP values (p<0.001), fasting TG and TG:HDL ratios (p<0.001) than NGT subjects. Furthermore, Total:HDL-C ratios and Framingham scores were raised (p=0.010 and p<0.001 respectively). Blood glutathione levels (GSH, GSSG and tGSH) were lower (p<0.001, p=0.039 and p<0.001 respectively) while plasma vWF was increased (p=0.014) in IGT subjects compared to controls. IGT individuals also demonstrated higher IMT in right and left carotid arteries (p=0.017 and p=0.005, respectively) alongside larger brachial artery diameter (p=0.015), lower FMD% (p=0.026) and GTN induced dilation (GID) (p=0.012) than healthy controls. At the retinal arterial level, the IGT subjects showed higher baseline fluctuations (BDF) (p=0.026), longer reaction time (RT) (p=0.032) and reduced baseline-corrected flicker response (bFR) (p=0.045). In IGT subjects retinal BDF correlated with and Total:HDL (p= 0.003) and HDL-C (p= 0.004). Arterial RT also correlated with FMD (p=0.017) in IGT but not NGT subjects. In IGT individuals there is a relationship between macro- and microvascular function, as well as a direct correlation between the observed retinal microcirculatory changes and established plasma markers for CVD. Multifactorial preventive interventions to decrease vascular risk in these individuals should be considered.

Size dependent enhancement of helium ion irradiation tolerance in sputtered Cu/V nanolaminates

We have investigated the evolution of radiation damage and changes in hardness of sputter-deposited Cu/V nanolaminates upon room temperature helium ion irradiation. As the individual layer thickness decreases from 200 to 5 nm, helium bubble density and radiation hardening both decrease. The magnitude of radiation hardening becomes negligible for individual layer thickness of 2.5 nm or less. These observations indicate that nearly immiscible Cu/V interface can effectively absorb radiation-induced point defects and reduce their concentrations.

PMD tolerance of 288 Gbit/s Coherent WDM and transmission over unrepeatered 124 km of field-installed single mode optical fiber

Low-cost, high-capacity optical transmission systems are required for metropolitan area networks. Direct-detected multi-carrier systems are attractive candidates, but polarization mode dispersion (PMD) is one of the major impairments that limits their performance. In this paper, we report the first experimental analysis of the PMD tolerance of a 288Gbit/s NRZ-OOK Coherent Wavelength Division Multiplexing system. The results show that this impairment is determined primarily by the subcarrier baud rate. We confirm the robustness of the system to PMD by demonstrating error-free performance over an unrepeatered 124km field-installed single-mode fiber with a negligible penalty of 0.3dB compared to the back-to-back measurements. (C) 2010 Optical Society of America

An RZ DPSK receiver design with significantly improved dispersion tolerance

We show an improved DPSK receiver design which can increase useful dispersion tolerance by up to a factor of two. The increased dispersion tolerance is achieved through optimization of the optical filter at the receiver and the delay of the Mach-Zehnder interferometer. In this paper we fully explain the concept, quantify the gain and provide an explanation for the operation of the receiver. © 2007 Optical Society of America.

Experimental verification of the dispersion tolerance improvement of partial DPSK with optimised filtering

We experimentally confirm the optimum combination of modulator delay and filter bandwidth to maximize the dispersion tolerance of partial DPSK.

Size-dependent radiation tolerance in ion irradiated TiN/AlN nanolayer films

Interface effects on ion-irradiation tolerance properties are investigated in nanolayered TiN/AlN films with individual layer thickness varied from 5 nm to 50 nm, prepared by pulsed laser deposition. Evolution of the microstructure and hardness of the multilayer films are examined on the specimens before and after He ion-implantation to a fluence of 4 × 10 m at 50 keV. The suppression of amorphization in AlN layers and the reduction of radiation-induced softening are observed in all nanolayer films. A clear size-dependent radiation tolerance characteristic is observed in the nanolayer films, i.e., the samples with the optimum layer thickness from 10 nm to 20 nm show the best ion irradiation tolerance properties, and a critical layer thickness of more than 5 nm is necessary to prevent severe intermixing. This study suggests that both the interface characteristics and the critical length scale (layer thickness) contribute to the reduction of the radiation-induced damages in nitride-based ceramic materials. © 2013 Elsevier B.V. All rights reserved.

Evaluating the effect of splitting cylindrical power on improving patient tolerance to toric lens misalignment

Purpose: Evaluating the impact of splitting toric power on patient tolerance to misorientation such as with intraocular lens rotation. Setting: University vision clinic. Methods: Healthy, non astigmats had +1.50D astigmatism induced with spectacle lenses at 90°, 135°, 180° and +3.00D at 90°. Two correcting cylindrical lenses of the opposite sign and half the power each were subsequently added to the trial frame misaligned by 0°, 5° or 10° in a random order and misorientated from the initial axis in a clockwise direction by up to 15° in 5° steps. A second group of adapted astigmats with between 1.00 and 3.00DC had their astigmatism corrected with two toric spectacle lenses of half the power separated by 0°, 5° or 10° and misorientated from the initial axis in both directions by up to 15° in 5° steps. Distance, high contrast visual acuity was measured using a computerised test chart at each lens misalignment and misorientation. Results: Misorientation of the split toric lenses caused a statistically significant drop in visual acuity (F= 70.341; p< 0.001). Comparatively better acuities were observed around 180°, as anticipated (F= 3.775; p= 0.035). Misaligning the split toric power produced no benefit in visual acuity retention with axis misorientation when subjects had astigmatism induced with a low (F= 2.190, p= 0.129) or high cylinder (F= 0.491, p= 0.617) or in the adapted astigmats (F= 0.120, p= 0.887). Conclusion: Misalignment of toric lens power split across the front and back lens surfaces had no beneficial effect on distance visual acuity, but also no negative effect. © 2013 British Contact Lens Association.

Close contact fluctuations:the seeding of signalling domains in the immunological synapse

We analyse the size and density of thermally induced regions of close contact in cell : cell contact interfaces within a harmonic potential approximation, estimating these regions to be below one-tenth of a micron across. Our calculations indicate that as the distance between the close contact threshold depth and the mean membrane-membrane separation increases, the density of close contact patches decreases exponentially while there is only a minimal variation in their mean size. The technique developed can be used to calculate the probability of first crossing in reflection symmetry violating systems. © Europhysics Letters Association.

Enhanced dispersion tolerance of coherent offset-QAM OFDM over conventional OFDM

We experimentally demonstrate 38-Gbit/s offset-16QAM OFDM over 840km without guard interval, and numerically show that 112-Gbit/s PDM offset-QPSK OFDM achieves 23% increase in net capacity over conventional OFDM under the same transmission reach. © 2014 Optical Society of America.

Contact time periods in immunological synapse

This paper resolves the long standing debate as to the proper time scale τ of the onset of the immunological synapse bond, the noncovalent chemical bond defining the immune pathways involving T cells and antigen presenting cells. Results from our model calculations show τ to be of the order of seconds instead of minutes. Close to the linearly stable regime, we show that in between the two critical spatial thresholds defined by the integrin:ligand pair (Δ2∼ 40-45 nm) and the T-cell receptor TCR:peptide-major-histocompatibility-complex pMHC bond (Δ1∼ 14-15 nm), τ grows monotonically with increasing coreceptor bond length separation δ (= Δ2-Δ1∼ 26-30 nm) while τ decays with Δ1 for fixed Δ2. The nonuniversal δ-dependent power-law structure of the probability density function further explains why only the TCR:pMHC bond is a likely candidate to form a stable synapse.

Novel glucagon-like peptide-1 (GLP-1) analog (Val8)GLP-1 results in significant improvements of glucose tolerance and pancreatic β-cell function after 3-week daily administration in obese diabetic (ob/ob) mice

This study evaluates the antidiabetic potential of an enzyme-resistant analog, (Val8)GLP-1. The effects of daily administration of a novel dipeptidyl peptidase IV-resistant glucagon-like peptide-1 (GLP-1) analog, (Val8)GLP-1, on glucose tolerance and pancreatic β-cell function were examined in obese-diabetic (ob/ob) mice. Acute intraperitoneal administration of (Val8)GLP-1 (6.25-25 nmol/kg) with glucose increased the insulin response and reduced the glycemic excursion in a dose-dependent manner. The effects of (Val8)GLP-1 were greater and longer lasting than native GLP-1. Once-daily subcutaneous administration of (Val8)GLP-1 (25 nmol/kg) for 21 days reduced plasma glucose concentrations, increased plasma insulin, and reduced body weight more than native GLP-1 without a significant change in daily food intake. Furthermore, (Val8)GLP-1 improved glucose tolerance, reduced the glycemic excursion after feeding, increased the plasma insulin response to glucose and feeding, and improved insulin sensitivity. These effects were consistently greater with (Val8)GLP-1 than with native GLP-1, and both peptides retained or increased their acute efficacy compared with initial administration. (Val8)GLP-1 treatment increased average islet area 1.2-fold without changing the number of islets, resulting in an increased number of larger islets. These data demonstrate that (Val8)GLP-1 is more effective and longer acting than native GLP-1 in obese-diabetic ob/ob mice.