Sulfur Mustard Induces Markers of Terminal Differentiation and Apoptosis in Keratinocytes Via a Ca2+-Calmodulin and Caspase-Dependent Pathway

Sulfur mustard (SM) induces vesication via poorly understood pathways. The blisters that are formed result primarily from the detachment of the epidermis from the dermis at the level of the basement membrane. In addition, there is toxicity to the basal cells, although no careful study has been performed to determine the precise mode of cell death biochemically. We describe here two potential mechanisms by which SM causes basal cell death and detachment: namely, induction of terminal differentiation and apoptosis. In the presence of 100 μM SM, terminal differentiation was rapidly induced in primary human keratinocytes that included the expression of the differentiation-specific markers K1 and K10 and the cross-linking of the cornified envelope precursor protein involucrin. The expression of the attachment protein, fibronectin, was also reduced in a time- and dose-dependent fashion. Features common to both differentiation and apoptosis were also induced in 100 μM SM, including the rapid induction of p53 and the reduction of Bcl-2. At higher concentrations of SM (i.e., 300 μM), formation of the characteristic nucleosome-sized DNA ladders, TUNEL-positive staining of cells, activation of the cysteine protease caspase-3/apopain, and cleavage of the death substrate poly(ADP-ribose) polymerase, were observed both in vivo and in vitro. Both the differentiation and the apoptotic processes appeared to be calmodulin dependent, because the calmodulin inhibitor W-7 blocked the expression of the differentiation-specific markers, as well as the apoptotic response, in a concentration-dependent fashion. In addition, the intracellular Ca2+ chelator, BAPTA-AM, blocked the differentiation response and attenuated the apoptotic response. These results suggest a strategy for designing inhibitors of SM vesication via the Ca2+-calmodulin or caspase-3/PARP pathway

Inorganic Polyphosphates Are Important for Cell Survival and Motility of Human Skin Keratinocytes and Play a Role in Wound Healing

Inorganic polyphosphate (polyP) is a simple ancient polymer of linear chains of orthophosphate residues linked by high energy phospho-anhydride bonds ubiquitously found in all organisms. Despite its structural simplicity, it plays diverse functional roles. polyP is involved in myriad of processes including serving as microbial phosphagens, buffer against alkalis, Ca2+ storage, metal-chelating agents, pathogen virulence, cell viability and proliferation, structural component and chemical chaperones, and in the microbial stress response. In mammalian cells, polyP has been implicated in blood coagulation, inflammation, bone differentiation, cell bioenergetics, signal transduction, Ca2+-signaling, neuronal excitability, as a protein-stabilizing scaffold, and in wound healing, among others. This chapter will discuss (1) polyP metabolism and roles of polyP in prokaryotic and eukaryotic cells, (2) the contribution of polyP to survival, cell proliferation, and motility involved in wound healing in human skin keratinocytes, (3) the use of polyP-containing platelet-rich plasma (PRP) to promote wound healing in acute and chronic wounds, including burns, and (4) the use of polyP-containing PRP in excisional wound models to promote faster healing. While polyP shows promise as a therapeutic agent to accelerate healing for acute and chronic wounds, the molecular mechanisms as a potent modulator of the wound healing process remain to be elucidated

Co-construction of chronic illness narratives by older stroke survivors and their spouses

Illness narratives have mainly focused on individual patients' accounts, and particularly those of people experiencing the onset of chronic illness in mid-life. However, a growing number of older people are spending their later life with their partner, with both experiencing complex morbidities. We examine the shared creation of meanings among older stroke survivors and their spouses and the implications for individual and couple identity. Joint biographical narrative interviews were held with 13 stroke survivors aged 75-85 and their spouses. The analysis examined both narrative content and narrative style. Three main types of co-presentation of identity were identified. The 'united couple' described couples who pulled together and emphasised their accommodation of the stroke and normality as a couple, despite often considerable disability, and was strongly underpinned by collaborative interaction in interviews. Caring relationships were distinguished as 'positive', involving self-reliant couples who took pride in how they managed and 'frustrated' in couples who emphasised the difficulties of caring and hardships experienced and were characterised by a conflictual style of narrative. We argue that joint interviews provide new forms of data that extend notions of how illness is lived and demonstrates how the marital relationship can mediate the experience of chronic illness and disability and its impact on identity. © 2013 The Authors. Sociology of Health & Illness © 2013 Foundation for the Sociology of Health & Illness/JohnWiley & Sons Ltd

Outcomes of Recurrent Head and Neck Cutaneous Squamous Cell Carcinoma

Recurrent, advanced stage cutaneous squamous cell carcinoma (cSCC) is uncommon with limited publications on patient outcomes. A retrospective study including patients who underwent surgical resection for recurrent, advanced stage cSCC of the head and neck was performed (n = 72). Data regarding tumor site, stage, treatment, parotid involvement, perineural invasion, positive margins, metastasis, and disease-free survival was analyzed. The majority of patients were male (85%) and presented with recurrent stage III (89%) cSCC. Two-year disease-free survival was 62% and decreased to 47% at 5 years. Parotid involvement, positive margins, nodal metastasis, or the presence of perineural invasion did not correlate with decreased survival (P > .05). Distant metastasis was a strong indicator of poor overall survival (P < .001). Adjuvant postoperative radiotherapy did not improve overall survival (P = .42). Overall survival was poor for patients with advanced recurrent cSCC despite the combined treatment with surgery and radiotherapy

Come to Daddy? Claiming Chris Cunningham for British Art Cinema

Twenty years after he came to prominence via a series of provocative, ground-breaking music videos, Chris Cunningham remains a troubling, elusive figure within British visual culture. His output – which includes short films, advertisements, art gallery commissions, installations, music production and a touring multi-screen live performance – is relatively slim, and his seemingly slow work rate (and tendency to leave projects uncompleted or unreleased) has been a frustration for fans and commentators, particularly those who hoped he would channel his interests and talents into a full-length ‘feature’ film project. There has been a diverse critical response to his musical sensitivity, his associations with UK electronica culture – and the Warp label in particular – his working relationship with Aphex Twin, his importance within the history of the pop video and his deployment of transgressive, suggestive imagery involving mutated, traumatised or robotic bodies. However, this article makes a claim for placing Cunningham within discourses of British art cinema. It proposes that the many contradictions that define and animate Cunningham's work – narrative versus abstraction, political engagement versus surrealism, sincerity versus provocation, commerce versus experimentation, art versus craft, a ‘British’ sensibility versus a transnational one – are also those that typify a particular terrain of British film culture that falls awkwardly between populism and experimentalism

Fiscal Centralization, Limited Government, and Public Revenues in Europe, 1650-1913

Old Regime polities typically suffered from fiscal fragmentation and absolutist rule. By the start of World War I, however, many such countries had centralized institutions and limited government. This article uses a new panel data set to perform a statistical analysis of political regimes and public revenues in Europe from 1650 to 1913. Panel regressions indicate that centralized and limited regimes were associated with significantly higher revenues than fragmented and absolutist ones. Structural break tests also suggest close relationships between major turning points in revenue series and political transformations

Short-Term Retinoic Acid Treatment Increases In Vivo, but Decreases In Vitro, Epidermal Transglutaminase-K Enzyme Activity and Immunoreactivity

Epidermal transglutaminase-K is believed to catalyze the covalent linking of loricrin and involucrin to form cross-linked (CE) envelopes. In normal skin, transglutaminase-K is expressed as a band immediately below the stratum corneum, whereas in psoriasis and healing skin its expression is considerably expanded throughout the suprabasal layers. We have investigated whether the hyperproliferative state induced by short-term application of topical retinoic acid is similarly characterized by an increase in transglutaminase-K enzyme activity and immunoreactivity.Retinoic acid (0.1% cream) or vehicle were applied to human skin and occluded for 4 d. Skin biopsies were obtained for measurement of transglutaminase-K and transglutaminase-C activity and immunoreactivity. For comparison, cultured normal human keratinocytes were incubated for 4 d in the presence of 1 μM retinoic acid and the subsequent transglutaminase-K activity and immunoreactivity measured. Transglutaminase-K activity was increased 2.8 times in retinoic acid compared to vehicle-treated skin (p < 0.005, n = 12) whereas there was no significant difference in transglutaminase-C activity. However, transglutaminase-K mRNA levels were not significantly different between retinoic acid- and vehicle-treated skin. In vehicle-treated skin, transglutaminase-K immunoreactivity was limited to a narrow, substratum corneal band, but was considerably expanded in a diffuse suprabasal pattern in retinoic acid-treated epidermis. In contrast, transglutaminase-K immunostaining was decreased and its enzymatic activity reduced sixfold in retinoic acid-treated keratinocytes (p < 0.01, n = 4).These results demonstrate that retinoic acid treatment in vivo, in contrast to in vitro, leads to not only increased transglutaminase-K protein expression but also increased enzymatic activity in the absence of detectable increases in mRNA levels.These data, taken with the previously reported lack of in vivo modulation of the differentiation markers keratins 1 and 10 by retinoic acid, indicate that certain aspects of keratinocyte terminal differentiation that are altered in vitro by retinoic acid do not occur in vivo in human skin

Are mixed diets beneficial for the welfare of captive axolotls (Ambystoma mexicanum)? Effects of feeding regimes on growth and behavior

Good nutritional husbandry is crucial to maintain high welfare standards in captive animals. Both direct effects of diet on growth, development, and maintenance and indirect effects of feeding regimes on behavior may be important. Despite this, many questions remain as to how we should best feed many of the species that are commonly kept in captivity. There is a great deal of speculation among animal keepers as to issues such as whether a mixed diet is better than an invariant one, but little research is available to inform this question. In this study, we investigate the impact of mixed versus invariant diets on growth and behavior in the axolotl (. Ambystoma mexicanum), an aquatic amphibian of severe conservation concern that is frequently maintained in captive collections. We then use our results to provide advice on feeding management in the context of improved welfare. We maintained juvenile axolotls under 1 of 3 "diets" (feeding regimes): bloodworm (invariant), Daphnia (invariant), and alternating these 2 prey items between feeds (mixed). Morphologic and behavioral data were collected over a period of 15weeks and analyzed using generalized linear mixed models to determine whether our feeding treatments influenced growth and behavior. We find that axolotls grew fastest on our bloodworm diet and slowest on our Daphnia diet, with a mixed feeding regime leading to intermediate growth rates. Diet treatment did not significantly influence our measured behaviors, but feeding and locomotion events were more frequent (and resting less frequent) on feeding days than nonfeeding days. These data suggest that providing a mixed diet is not necessarily beneficial to either growth or welfare of captive animals. In the case of axolotls, an invariant diet of bloodworm should increase growth rates, but the diet (mixed vs. invariant) does not influence behavior. Overall, our results suggest that mixed diets in themselves may not be beneficial to the growth or welfare of axolotls as compared with a high-quality invariant diet