Evaluation of early and late presentation of patients with ocular mucous membrane pemphigoid to two major tertiary referral hospitals in the United Kingdom

PURPOSE: Ocular mucous membrane pemphigoid (OcMMP) is a sight-threatening autoimmune disease in which referral to specialists units for further management is a common practise. This study aims to describe referral patterns, disease phenotype and management strategies in patients who present with either early or established disease to two large tertiary care hospitals in the United Kingdom.\ud \ud PATIENTS AND METHODS: In all, 54 consecutive patients with a documented history of OcMMP were followed for 24 months. Two groups were defined: (i) early-onset disease (EOD:<3 years, n=26, 51 eyes) and (ii) established disease (EstD:>5 years, n=24, 48 eyes). Data were captured at first clinic visit, and at 12 and 24 months follow-up. Information regarding duration, activity and stage of disease, visual acuity (VA), therapeutic strategies and clinical outcome were analysed.\ud \ud RESULTS: Patients with EOD were younger and had more severe conjunctival inflammation (76% of inflamed eyes) than the EstD group, who had poorer VA (26.7%=VA<3/60, P<0.01) and more advanced disease. Although 40% of patients were on existing immunosuppression, 48% required initiation or switch to more potent immunotherapy. In all, 28% (14) were referred back to the originating hospitals for continued care. Although inflammation had resolved in 78% (60/77) at 12 months, persistence of inflammation and progression did not differ between the two phenotypes. Importantly, 42% demonstrated disease progression in the absence of clinically detectable inflammation.\ud \ud CONCLUSIONS: These data highlight that irrespective of OcMMP phenotype, initiation or escalation of potent immunosuppression is required at tertiary hospitals. Moreover, the conjunctival scarring progresses even when the eye remains clinically quiescent. Early referral to tertiary centres is recommended to optimise immunosuppression and limit long-term ocular damage.\ud \u

Massless D-strings and moduli stabilization in type I cosmology

We consider the cosmological evolution induced by the free energy F of a gas of maximally supersymmetric heterotic strings at finite temperature and weak coupling in dimension D>=4. We show that F, which plays the role of an effective potential, has minima associated to enhanced gauge symmetries, where all internal moduli can be attracted and dynamically stabilized. Using the fact that the heterotic/type I S-duality remains valid at finite temperature and can be applied at each instant of a quasi-static evolution, we find in the dual type I cosmology that all internal NS-NS and RR moduli in the closed string sector and the Wilson lines in the open string sector can be stabilized. For the special case of D=6, the internal volume modulus remains a flat direction, while the dilaton is stabilized. An essential role is played by light D-string modes wrapping the internal manifold and whose contribution to the free energy cannot be omitted, even when the type I string is at weak coupling. As a result, the order of magnitude of the internal radii expectation values on the type I side is (lambda_I alpha')^{1/2}, where lambda_I is the ten-dimensional string coupling. The non-perturbative corrections to the type I free energy can alternatively be described as effects of "thermal E1-instantons", whose worldsheets wrap the compact Euclidean time cycle.Comment: 39 pages, 1 figur

Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner

The blood vessels of cancerous tumours are leaky and poorly organized. This can increase the interstitial fluid pressure inside tumours and reduce blood supply to them, which impairs drug delivery. Anti-angiogenic therapies—which ‘normalize’ the abnormal blood vessels in tumours by making them less leaky—have been shown to improve the delivery and effectiveness of chemotherapeutics with low molecular weights, but it remains unclear whether normalizing tumour vessels can improve the delivery of nanomedicines. Here, we show that repairing the abnormal vessels in mammary tumours, by blocking vascular endothelial growth factor receptor-2, improves the delivery of smaller nanoparticles (diameter, 12 nm) while hindering the delivery of larger nanoparticles (diameter, 125 nm). Using a mathematical model, we show that reducing the sizes of pores in the walls of vessels through normalization decreases the interstitial fluid pressure in tumours, thus allowing small nanoparticles to enter them more rapidly. However, increased steric and hydrodynamic hindrances, also associated with smaller pores, make it more difficult for large nanoparticles to enter tumours. Our results further suggest that smaller (~12 nm) nanomedicines are ideal for cancer therapy due to their superior tumour penetration.ImClone Systems IncorporatedNational Institutes of Health (U.S.) (P01-CA080124)National Institutes of Health (U.S.) (R01-CA126642)National Institutes of Health (U.S.) (R01-CA115767)National Institutes of Health (U.S.) (R01-CA096915)National Institutes of Health (U.S.) (R01-CA085140)National Institutes of Health (U.S.) (R01-CA098706)National Institutes of Health (U.S.) (T32-CA073479)United States. Dept. of Defense (Breast Cancer Research Innovator Award W81XWH-10-1-0016

Conformational landscapes of bimesogenic compounds and their implications for the formation of modulated nematic phases

The twist-bend phase (NTB) is most commonly observed in materials with a gross-bent shape: dimers; bent-cores; bent-oligomers. We had suggested previously that the bend-angle of such systems effectively dictates the relative thermal stability of the NTB phase. However, our earlier paper relied on the use of a single energy-minimum conformer and so failed to capture any information about flexibility and conformational distribution. In the present work, we revisit our hypothesis and examine a second set of dimers with varying linking groups and spacer composition. We have improved on our earlier work by studying the conformational landscape of each material, allowing average bend-angles to be determined as well as the conformer distribution. We observe that the stability of the NTB phase exhibits a strong dependence not only on the Boltzmann-weighted average bend-angle (rather than just a static conformer), but also on the distribution of conformers. To a lesser extent, the flexibility of the spacer appears important. Ultimately, this work satisfies both theoretical treatments and our initial experimental study and demonstrates the importance of molecular bend to the NTB phase

DNA Vaccine-Generated Duck Polyclonal Antibodies as a Postexposure Prophylactic to Prevent Hantavirus Pulmonary Syndrome (HPS)

Andes virus (ANDV) is the predominant cause of hantavirus pulmonary syndrome (HPS) in South America and the only hantavirus known to be transmitted person-to-person. There are no vaccines, prophylactics, or therapeutics to prevent or treat this highly pathogenic disease (case-fatality 35–40%). Infection of Syrian hamsters with ANDV results in a disease that closely mimics human HPS in incubation time, symptoms of respiratory distress, and disease pathology. Here, we evaluated the feasibility of two postexposure prophylaxis strategies in the ANDV/hamster lethal disease model. First, we evaluated a natural product, human polyclonal antibody, obtained as fresh frozen plasma (FFP) from a HPS survivor. Second, we used DNA vaccine technology to manufacture a polyclonal immunoglobulin-based product that could be purified from the eggs of vaccinated ducks (Anas platyrhynchos). The natural “despeciation" of the duck IgY (i.e., Fc removed) results in an immunoglobulin predicted to be minimally reactogenic in humans. Administration of ≥5,000 neutralizing antibody units (NAU)/kg of FFP-protected hamsters from lethal disease when given up to 8 days after intranasal ANDV challenge. IgY/IgYΔFc antibodies purified from the eggs of DNA-vaccinated ducks effectively neutralized ANDV in vitro as measured by plaque reduction neutralization tests (PRNT). Administration of 12,000 NAU/kg of duck egg-derived IgY/IgYΔFc protected hamsters when administered up to 8 days after intranasal challenge and 5 days after intramuscular challenge. These experiments demonstrate that convalescent FFP shows promise as a postexposure HPS prophylactic. Moreover, these data demonstrate the feasibility of using DNA vaccine technology coupled with the duck/egg system to manufacture a product that could supplement or replace FFP. The DNA vaccine-duck/egg system can be scaled as needed and obviates the necessity of using limited blood products obtained from a small number of HPS survivors. This is the first report demonstrating the in vivo efficacy of any antiviral product produced using DNA vaccine-duck/egg system

Hunting for Dynamical Supersymmetry Breaking in Theories That S-confine

The s-confining theories are a class of supersymmetric gauge theories with infrared dynamics which are well-understood. Perturbing such theories can give rise to dynamical supersymmetry breaking. We realize simple models of dynamical supersymmetry breaking by perturbing two of the 10 SU(N) s-confining gauge theories by a single trilinear operator. These examples have locally stable vacua with spontaneous supersymmetry breaking. The first is SU(5) with two generations (consisting of an antisymmetric tensor and an antifundamental) plus two flavors. The second is SU(5) with three generations. The properties of the former vacuum are calculable while those of the latter vacuum are not. We briefly discuss the other SU(N) models.Comment: 21 pages, 1 figur

Quality of sleep in patients with schizophrenia is associated with quality of life and coping

BACKGROUND: While sleep disturbance is widespread in schizophrenia it is less clear whether sleep disturbance is uniquely related to impaired coping and perceived quality of life. METHODS: We simultaneously assessed sleep quality, symptoms, and coping in 29 persons with schizophrenia or schizoaffective disorder in a post acute phase of illness. Assessment instruments included the Pittsburgh Sleep Quality Index; the Positive and Negative Symptom Scale; the Heinrichs Quality of Life Scale; and the Ways of Coping Scale. Multiple regressions were performed predicting quality of life and coping from sleep quality controlling for age and symptom severity. On a subset of seven subjects non-dominant wrist actigraphy was used as an objective check of their self-reported poor sleep. RESULTS: Analyses revealed that poor sleep quality predicted low quality of life (r = -0.493; p = .022) and reduced preference for employing positive reappraisal when facing a stressor (r = -0.0594; p = 0.0012). Actigraphy confirmed poor sleep quality in a subset of subjects. They had shorter sleep duration (p < .0005), shorter average sleep episodes (p < .005) and more episodes of long awakening (p < 0.05) than community norms. CONCLUSION: The results are consistent with the hypotheses that poor sleep may play a unique role in sustaining poor quality of life and impaired coping in patients with schizophrenia. These associations may hold for community controls as well

Identification of a Cryptic Prokaryotic Promoter within the cDNA Encoding the 5′ End of Dengue Virus RNA Genome

Infectious cDNA clones of RNA viruses are important research tools, but flavivirus cDNA clones have proven difficult to assemble and propagate in bacteria. This has been attributed to genetic instability and/or host cell toxicity, however the mechanism leading to these difficulties has not been fully elucidated. Here we identify and characterize an efficient cryptic bacterial promoter in the cDNA encoding the dengue virus (DENV) 5′ UTR. Following cryptic transcription in E. coli, protein expression initiated at a conserved in-frame AUG that is downstream from the authentic DENV initiation codon, yielding a DENV polyprotein fragment that was truncated at the N-terminus. A more complete understanding of constitutive viral protein expression in E. coli might help explain the cloning and propagation difficulties generally observed with flavivirus cDNA