Clinical and immunohistochemical assessment of vulval intraepithelial neoplasia following photodynamic therapy using a novel bioadhesive patch-type system loaded with 5-aminolevulinic acid

Background: The work in this study appraised photodynamic treatment (PDT) as a treatment method for vulval intraepithelial neoplasia (VIN) using a novel bioadhesive patch to deliver aminolevulinic acid. An analysis of changes in expression of apoptotic and cell cycle proteins (p53, p21, Mdm2, Blc-2, Bax, Ki-67) in response to PDT was evaluated. Methods: PDT was performed using non-laser light, either as a one or two-cycle treatment, with clinical and pathological assessment following after 6 weeks. Twenty-three patients with 25 VIN lesions underwent 49 cycles of PDT Patches were designed to conform to uneven vulval skin and contained 38 mg cm(-2) aminolevulinic acid. Assessment was carried out at 6 weeks post-treatment. Patient-based treatment assessment, along with clinical and pathological changes, were monitored. Immunohistochemical staining was used to elucidate a possible biomolecular basis for induced cellular changes. Results: Most patients (52%) reported a symptomatic response, with normal pathology restored in 38% of lesions. The patch was easy to apply and remove, causing minimal discomfort. Fluorescence inspection confirmed protoporphyrin accumulation. Pain during implementation of PDT was problematic, necessitating some form of local analgesia. Changes in expression of cell cycle and apoptotic-related proteins suggested involvement of apoptotic pathways. Down regulation of p21 and inverse changes in Bcl-2 and Bax were key findings. Conclusion: Treatment of VIN lesions using a novel bioadhesive patch induced changes in cell cycle and apoptotic proteins in response to PDT with possible utilisation of apoptotic pathways. The efficacy of PDT in treating VIN could be improved by a better understanding of these apoptotic mechanisms, the influence of factors, such as HPV status, and of the need for effective pain management.

A role of cellular prion protein in programming T-cell cytokine responses in disease.

The cellular prion protein (PrPC) is widely expressed in neural and non-neural tissues, but its function is unknown. Elucidation of the part played by PrPC in adaptive immunity has been a particular conundrum: increased expression of cell surface PrPC has been documented during T-cell activation, yet the functional significance of this activation remains unclear, with conflicting data on the effects of Prnp gene knockout on various parameters of T-cell immunity. We show here that Prnp mRNA is highly inducible within 8–24 h of T-cell activation, with surface protein levels rising from 24 h. When measured in parallel with CD69 and CD25, PrPC is a late activation antigen. Consistent with its up-regulation being a late activation event, PrP deletion did not alter T-cell-antigen presenting cell conjugate formation. Most important, activated PrP0/0 T cells demonstrated much reduced induction of several T helper (Th) 1, Th2, and Th17 cytokines, whereas others, such as TNF- and IL-9, were unaffected. These changes were investigated in the context of an autoimmune model and a bacterial challenge model. In experimental autoimmune encephalomyelitis, PrP-knockout mice showed enhanced disease in the face of reduced IL-17 responses. In a streptococcal sepsis model, this constrained cytokine program was associated with poorer local control of infection, although with reduced bacteremia. The findings indicate that PrPC is a potentially important molecule influencing T-cell activation and effector function.

Predictable Pathways? Negotiating Risk in the Context of Marginalisation and Social Exclusion

This article is based on ethnographic research with young people living in an area of multiple deprivation in the North-east of England. The young people in this study experience many risk factors associated with social exclusion and future offending. Through in-depth examination of crime within the context of their lives, it will be argued that recent theorisations of youth crime and criminal careers do not fully capture the nature of their offending, the contextual circumstances surrounding it and the differential impact of similar risk factors on their lives. The article concludes by suggesting that not only do such theories detract from the situations of poverty and social exclusion in which young people live but that youth policies informed by them potentially add to their experiences of exclusion and marginalisation.

PKB binding proteins: Getting in on the akt

Protein kinase B (PKB) has emerged as the focal point for many signal transduction pathways, regulating multiple cellular processes such as glucose metabolism, transcription, apoptosis, cell proliferation, angiogenesis, and cell motility. In addition to acting as a kinase toward many substrates involved in these processes, PKB forms complexes with other proteins that are not substrates, but rather act as modulators of PKB activity and function. In this review, we discuss the implications of these data in understanding the multitude of functions predicted for PKB in cells.

Pathways to state-selective control of vibrational wavepackets in the deuterium molecular ion

The capability of intense ultrashort laser pulses to initiate, control and image vibrational wavepacket dynamics in the deuterium molecular ion has been simulated with a view to inform and direct future femtosecond pump-control-probe experiments. The intense-field coherent control of the vibrational superposition has been studied as a function of pulse intensity and delay time, to provide an indication of key constraints for experimental studies. For selected cases of the control mechanism, probing of the subsequent vibrational wavepacket dynamics has been simulated via the photodissociation (PD) channel. Such PD probing is shown to elucidate the modified wavepacket dynamics where the position of the quantum revival is sensitive to the control process. Through Fourier transform analysis the PD yield is also shown to provide a characterisation of the vibrational distribution. It has been shown that a simple 'critical R cut-off' approximation can be used to reproduce the effect of a probe pulse interaction, providing a convenient and efficient alternative to intensive computer simulations of the PD mechanism in the deuterium molecular ion.