Role of subnetworks mediated by [Formula: see text], IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis.

Psoriasis is a chronic inflammatory skin disease clinically characterized by the appearance of red colored, well-demarcated plaques with thickened skin and with silvery scales. Recent studies have established the involvement of a complex signalling network of interactions between cytokines, immune cells and skin cells called keratinocytes. Keratinocytes form the cells of the outermost layer of the skin (epidermis). Visible plaques in psoriasis are developed due to the fast proliferation and unusual differentiation of keratinocyte cells. Despite that, the exact mechanism of the appearance of these plaques in the cytokine-immune cell network is not clear. A mathematical model embodying interactions between key immune cells believed to be involved in psoriasis, keratinocytes and relevant cytokines has been developed. The complex network formed of these interactions poses several challenges. Here, we choose to study subnetworks of this complex network and initially focus on interactions involving [Formula: see text], IL-23/IL-17, and IL-15. These are chosen based on known evidence of their therapeutic efficacy. In addition, we explore the role of IL-15 in the pathogenesis of psoriasis and its potential as a future drug target for a novel treatment option. We perform steady state analyses for these subnetworks and demonstrate that the interactions between cells, driven by cytokines could cause the emergence of a psoriasis state (hyper-proliferation of keratinocytes) when levels of [Formula: see text], IL-23/IL-17 or IL-15 are increased. The model results explain and support the clinical potentiality of anti-cytokine treatments. Interestingly, our results suggest different dynamic scenarios underpin the pathogenesis of psoriasis, depending upon the dominant cytokines of subnetworks. We observed that the increase in the level of IL-23/IL-17 and IL-15 could lead to psoriasis via a bistable route, whereas an increase in the level of [Formula: see text] would lead to a monotonic and gradual disease progression. Further, we demonstrate how this insight, bistability, could be exploited to improve the current therapies and develop novel treatment strategies for psoriasis.

The peripheral clock regulates human pigmentation.

Although the regulation of pigmentation is well characterized, it remains unclear whether cell-autonomous controls regulate the cyclic on-off switching of pigmentation in the hair follicle (HF). As human HFs and epidermal melanocytes express clock genes and proteins, and given that core clock genes (PER1, BMAL1) modulate human HF cycling, we investigated whether peripheral clock activity influences human HF pigmentation. We found that silencing BMAL1 or PER1 in human HFs increased HF melanin content. Furthermore, tyrosinase expression and activity, as well as TYRP1 and TYRP2 mRNA levels, gp100 protein expression, melanocyte dendricity, and the number gp100+ HF melanocytes, were all significantly increased in BMAL1 and/or PER1-silenced HFs. BMAL1 or PER1 silencing also increased epidermal melanin content, gp100 protein expression, and tyrosinase activity in human skin. These effects reflect direct modulation of melanocytes, as BMAL1 and/or PER1 silencing in isolated melanocytes increased tyrosinase activity and TYRP1/2 expression. Mechanistically, BMAL1 knockdown reduces PER1 transcription, and PER1 silencing induces phosphorylation of the master regulator of melanogenesis, microphthalmia-associated transcription factor, thus stimulating human melanogenesis and melanocyte activity in situ and in vitro. Therefore, the molecular clock operates as a cell-autonomous modulator of human pigmentation and may be targeted for future therapeutic strategies.

Skin health in older age.

As people age, their skin undergoes changes which result in reduced elasticity, increased fragility and an altered immune response; in essence it becomes frail. As life expectancy is increasing the health of older skin is becoming a progressively more important facet of overall care. In addition to the consequences of ageing for otherwise healthy skin, the relative incidence of some dermatological conditions is age-dependent. In particular, xerosis (dry skin), cutaneous malignancies and skin injuries are more common in older people. In this review we describe the functional consequences of skin ageing and discuss the current evidence on how skin health may be maintained and dermatological conditions prevented in an ageing population. The future of dermatological health-care provision in the older population relies on the development of coordinated pathways of care, which start from a young age. Better quality research coordinated by the establishment of institutions dealing with skin health and ageing would be a method of addressing these needs.

The influence of bolus to infusion delays on plasma Tissue Plasminogen Activator levels.

BACKGROUND: Estimates of neuronal loss in acute ischemic stroke show that the typical patient may lose 1·9 million neurons each minute that treatment is delayed. Consequently, significant emphasis has been placed on early evaluation and thrombolysis with tissue plasminogen activator (TPA), the only approved thrombolytic therapy. TPA should be administered as a bolus followed by an immediate infusion because of its short half life. However, in the real life clinical situation, delays in starting the infusion after the bolus can occur. Similarly, once infusion has started, interruptions in the infusion of TPA can also occur. These scenarios may result in lower serum concentrations which could decrease the effectiveness of thrombolysis. We sought to simulate, the influence of bolus infusion delays and also the influence of different intervals of interruptions in the infusion of TPA on serum TPA concentrations. METHODS: We simulated the effect of multiple intervals of delay after the bolus on serum TPA concentrations using known pharmacokinetics parameters of TPA. The effect of different intervals of interruptions in the infusion of TPA was also determined. The effect of rebolusing with TPA on serum concentrations in the event of significant bolus to infusion delays or significant infusion interruption was also simulated. RESULTS: Our data show that delays in starting the infusion may have significant effects on serum TPA concentrations. After the initial bolus, there is a rapid decrease in serum TPA concentrations unless the infusion is started immediately. Greater than 5 min delays in starting the infusion results in a slow gradual increase in serum TPA levels and levels stay well below the target concentrations for significant periods of time. Similarly, interruptions in the infusion of TPA lasting longer than 5 min can also significantly influence TPA levels. Rebolusing with TPA in these scenarios rapidly restores TPA levels to target concentrations. CONCLUSION: Because of its short half life, TPA should be administered as a bolus followed by an immediate infusion. Bolus to infusion delays or interruptions in the infusion of TPA after the bolus may significantly impact serum TPA levels and may reduce the efficacy of thrombolysis. Protocols or administration regimens should be employed to prevent delays or interruptions in the infusion. When delays do occur, rebolusing of TPA may be needed to rapidly restore TPA to target levels.

A meeting of two chronobiological systems: circadian proteins Period1 and BMAL1 modulate the human hair cycle clock.

The hair follicle (HF) is a continuously remodeled mini organ that cycles between growth (anagen), regression (catagen), and relative quiescence (telogen). As the anagen-to-catagen transformation of microdissected human scalp HFs can be observed in organ culture, it permits the study of the unknown controls of autonomous, rhythmic tissue remodeling of the HF, which intersects developmental, chronobiological, and growth-regulatory mechanisms. The hypothesis that the peripheral clock system is involved in hair cycle control, i.e., the anagen-to-catagen transformation, was tested. Here we show that in the absence of central clock influences, isolated, organ-cultured human HFs show circadian changes in the gene and protein expression of core clock genes (CLOCK, BMAL1, and Period1) and clock-controlled genes (c-Myc, NR1D1, and CDKN1A), with Period1 expression being hair cycle dependent. Knockdown of either BMAL1 or Period1 in human anagen HFs significantly prolonged anagen. This provides evidence that peripheral core clock genes modulate human HF cycling and are an integral component of the human hair cycle clock. Specifically, our study identifies BMAL1 and Period1 as potential therapeutic targets for modulating human hair growth.

A prototypic mathematical model of the human hair cycle.

The human hair cycle is a complex, dynamic organ-transformation process during which the hair follicle repetitively progresses from a growth phase (anagen) to a rapid apoptosis-driven involution (catagen) and finally a relative quiescent phase (telogen) before returning to anagen. At present no theory satisfactorily explains the origin of the hair cycle rhythm. Based on experimental evidence we propose a prototypic model that focuses on the dynamics of hair matrix keratinocytes. We argue that a plausible feedback-control structure between two key compartments (matrix keratinocytes and dermal papilla) leads to dynamic instabilities in the population dynamics resulting in rhythmic hair growth. The underlying oscillation consists of an autonomous switching between two quasi-steady states. Additional features of the model, namely bistability and excitability, lead to new hypotheses about the impact of interventions on hair growth. We show how in silico testing may facilitate testing of candidate hair growth modulatory agents in human HF organ culture or in clinical trials.

The cycling hair follicle as an ideal systems biology research model.

In the postgenomic era, systems biology has rapidly emerged as an exciting field predicted to enhance the molecular understanding of complex biological systems by the use of quantitative experimental and mathematical approaches. Systems biology studies how the components of a biological system (e.g. genes, transcripts, proteins, metabolites) interact to bring about defined biological function or dysfunction. Living systems may be divided into five dimensions of complexity: (i) molecular; (ii) structural; (iii) temporal; (iv) abstraction and emergence; and (v) algorithmic. Understanding the details of these dimensions in living systems is the challenge that systems biology aims to address. Here, we argue that the hair follicle (HF), one of the signature features of mammals, is a perfect and clinically relevant model for systems biology research. The HF represents a stem cell-rich, essentially autonomous mini-organ, whose cyclic transformations follow a hypothetical intrafollicular "hair cycle clock" (HCC). This prototypic neuroectodermal-mesodermal interaction system, at the cross-roads of systems and chronobiology, encompasses various levels of complexity as it is subject to both intrafollicular and extrafollicular inputs (e.g. intracutaneous timing mechanisms with neural and systemic stimuli). Exploring how the cycling HF addresses the five dimensions of living systems, we argue that a systems biology approach to the study of hair growth and cycling, in man and mice, has great translational medicine potential. Namely, the easily accessible human HF invites preclinical and clinical testing of novel hypotheses generated with this approach.

Methods in hair research: how to objectively distinguish between anagen and catagen in human hair follicle organ culture.

The organ culture of human scalp hair follicles (HFs) is the best currently available assay for hair research in the human system. In order to determine the hair growth-modulatory effects of agents in this assay, one critical read-out parameter is the assessment of whether the test agent has prolonged anagen duration or induced catagen in vitro. However, objective criteria to distinguish between anagen VI HFs and early catagen in human HF organ culture, two hair cycle stages with a deceptively similar morphology, remain to be established. Here, we develop, document and test an objective classification system that allows to distinguish between anagen VI and early catagen in organ-cultured human HFs, using both qualitative and quantitative parameters that can be generated by light microscopy or immunofluorescence. Seven qualitative classification criteria are defined that are based on assessing the morphology of the hair matrix, the dermal papilla and the distribution of pigmentary markers (melanin, gp100). These are complemented by ten quantitative parameters. We have tested this classification system by employing the clinically used topical hair growth inhibitor, eflornithine, and show that eflornithine indeed produces the expected premature catagen induction, as identified by the novel classification criteria reported here. Therefore, this classification system offers a standardized, objective and reproducible new experimental method to reliably distinguish between human anagen VI and early catagen HFs in organ culture.

Modernising medical careers and factors influencing career choices of medical students.

This article details medical students' views towards future career choices and factors that may influence this choice. The role of gender in career choice and the importance of structured career advice and management is highlighted and discussed.