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Volume 1, Issue 1 â&#x20AC;&#x201C; the 16th of March, 2017

Contents Article

Open letter

The pharmacological targeting potential of the body clocks

How do wounds heal?

Statistical analysis of trypophobic reactions suggests fear of disease as the underlying mechanism

Is there a scientific argument for the decriminalisation of class A drugs in the UK?

Colour changes due to interference at the wings of blue Rhopalocera

The split-brain studies and what they unveiled about the brain and the mind

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Manchester Undergraduate Journal of Biological Sciences | vol. 1 issue 1, March 2017

Opening letter Alexandru Ioan Vodă & Alexandru Băciţa

Open communication has been key in the development of modern science. This journal attempts to bring a middle-ground for students and researchers to interact outside of the academic courses. Of course, students – at the beginning of their journey as scientists – have yet to achieve their full potential in many ways. However, we consider that young aspiring scientists can have valuable ideas as well and definitely deserve guidance in their journey to good practice. This is why we aim to provide feedback for every article that is submitted to us, through professors in the adequate field. We also aim to promote – by publishing – every such student-written article that brings an interesting view on a topic within biological sciences. We therefore ask for your help: read their ideas, write a critical or encouraging remark in the comment sections and share with others the interesting ideas if there are any.

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Helping future generations of scientists develop might have never been as essential as it is now.

Manchester Undergraduate Journal of Biological Sciences | vol. 1 issue 1, March 2017

The pharmacological targeting potential of the body clocks George Thompson (george.thompson-2@student.manchester.ac.uk) Faculty of Biology, Medicine and Health, The University of Manchester, U.K.

Introduction The body clocks dictate the circadian rhythms that control daily cycles of

Circadian Rhythms Circadian rhythms are circadian clock controlled, oscillating events with around 24 hours in period length and are possessed by nearly every type of organism (Edgar et al., 2012). The term circadian is derived from the Latin words ‘circa’ meaning around and ‘diem’ meaning day. First described in 1729 by Jean Jacques d'Ortous de Mairan who noticed the closing of Mimosa pudica leaves at night and their subsequent opening in the day, even in total darkness (Sweeney, 1969). These findings were mirrored when human subjects living in complete absence of natural light in an underground bunker continued to act according to a roughly 24 hour cycle (Aschoff et al., 1967). This is one of the criteria for determining a circadian rhythm; it must be autonomous and not reliant on environmental inputs. Circadian rhythms can be entrained to

Manchester Undergraduate Journal of Biological Sciences | vol. 1 issue 1, March 2017

The body clocks and the circadian rhythms they dictate are present in nearly every organism and vital for healthy cellular functions. The body clocks are made up of a transcriptiontranslation feedback loop of clock proteins, regulated by nuclear receptors and post translational modifications. This review aims to discuss the mechanisms and roles of the clocks in health and disease, identify compounds targeting the body clocks and assess their potential as therapies for human disease. Circadian disruption predisposes an individual to cancer, diabetes, obesity and cardiovascular disease; understanding the role of the clocks in disease may provide targets for therapeutic modification of the clocks. Novel compounds targeting clock components have shown therapeutic efficacy in cellular models of cancer and in vivo models of diabetes, obesity, anxiety, addiction, cardiovascular disease, sleep disorders, rheumatoid arthritis and multiple sclerosis. Compounds targeting the body clocks show huge potential in the treatment of a wide range of diseases, this potential will only increase as knowledge of the clocks grows.

activity, metabolism, gene expression and growth. Circadian clocks are present in nearly all known organisms and almost every cell in the human body. Normal function of the circadian clocks is vital for the health of single cells and whole organisms. The aims of this literature review are to describe the circadian clocks and their role in health and disease, identify compounds targeting clock components and discuss their potential as therapies for human disease.

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Abstract

In humans the circadian rhythm is controlled hierarchically by a system of body clocks, with the suprachiasmatic nucleus (SCN) of the hypothalamus at the top (Ko, 2006). Neurons of the SCN act as the master clock and synchronise the peripheral circadian clocks found in almost all cells in the body (Mohawk et al., 2012). The SCN is projected into by intrinsically photosensitive retinal ganglion cells (ipRGCs) which serve to entrain the SCN master clock to ambient light levels (Baver et al., 2008). The master clock of the SCN acts as the conductor to synchronise an orchestra of peripheral clocks. Loss of synchronisation between the master and peripheral clocks gives rise to a number of adverse effects discussed in this review. In this review the terms clock, circadian clock, body clock, refer to the transcription translation feedback loop (TTFL) described in the next paragraph.

Molecular Mechanism of the Body Clocks The body clocks are comprised of a complex transcription translation feedback loop (TTFL) shown diagrammatically in Fig 1. In daytime the basic helix-loop-helix (bHLH) transcription factors; Neuronal Per-ArntPost translational modification of clock proteins is vital for regulation and fine tuning of the body clocks. Phosphorylation of PER and CRY

The primary TTFL is modified and stabilised by a secondary regulatory TTFL. The CLOCK/BMAL1 dimer binds to enhancer box (E-box) elements in the promoter for REV-ERBα, inducing its transcription. REV-ERBα inhibits BMAL1 transcription by competing with retinoic-acid receptor related orphan receptors (RORs), activators of BMAL1 transcription, for binding to ROR response elements (ROREs) (Forman et al., 1994). It is this balance of stimulation and inhibition of BMAL1 transcription that serves to regulate the primary TTFL. proteins by casein kinases 1δ and 1ε (CK1δ/1ε) determines their ability to

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Circadian Control in Humans

Single Minded domain-containing protein 2 (NPAS2) or Circadian Locomotor Output Cycles Kaput (CLOCK) form a dimer with brain and muscle Arnt like protein 1 (BMAL1) (Johnson, 2010, Lee et al., 2001). CLOCK and NPAS2 have similar roles in the molecular clock, henceforth only CLOCK will be referred to for simplicity (DeBruyne, et al. 2007). The active dimer of CLOCK and BMAL1 diffuses into the nucleus and binds to enhancer box elements on period 1/2 (PER1/2) and cryptochrome 1/2 (CRY1/2) genes (Gekakis et al., 1998, Takahashi et al., 2008). In the primary feedback loop PER and CRY proteins are synthesised and their cytoplasmic concentrations increase for around 12 hours. Once concentrations are high enough, PER/CRY heterodimers form which are able to move into the nucleus to bind and inhibit the BMAL1/CLOCK complex, in doing so inhibiting transcription of more PER/CRY genes (Etchegaray et al., 2009). This self repression is dependent on acetylation of BMAL1 by CLOCK (Hirayama et al., 2007).

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external stimuli known as zeitgebers, meaning time givers in German. The second criterion of a true circadian rhythm is that its period compensates for temperature (Eckardt, 2006). Unlike other biochemical processes a circadian rhythm will not speed up or slow down with an increase or decrease in temperature (Kidd et al., 2015).

Figure 1: Transcription Translation Feedback Loops that compose the mammalian body clock. CLOCK and BMAL1 dimerise and bind E box regions for PER1/2 and CRY1/2 genes to induce their transcription. PER and CRY proteins accumulate and dimerise. The PER-CRY dimer inhibits CLOCK/BMAL1 and represses PER/CRY transcription. PER and CRY proteins are tagged for degradation by β-TCRP1 and FBXL3 E3 ubiquitin ligases. CLOCK/BMAL1 stimulate transcription of clock controlled genes (CCGs) until the cycle repeats. The primary TTFL is regulated by the BMAL1/CLOCK induced transcription of REV-ERBα. REV-ERBα inhibits BMAL1 transcription by competing with retinoic-acid receptor related orphan receptors (RORs) for binding to retinoid response elements (RREs), thus inhibiting its own transcription. Figure taken from Takahashi et al., (2008) with permission from the author.

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compensating if CK1δ is not expressed (Walton et al., 2009). Phosphorylation or association of phosphorylated proteins may also activate transcription factors CLOCK and BMAL1, suggested by PER/CRY transcription being initiated when CLOCK and BMAL1 concentration is at its least (Lee et al., 2001).

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dimerise and translocate into the nucleus (Lee et al., 2001). Further phosphorylation of PER1, PER2 and BMAL1 by CK1δ/1ε, targets the proteins for ubiquitination and degradation by βTCRP1 for PER proteins and E3 ubiquitin ligase UBE3A for BMAL1 (Gossan et al., 2014). CK1δ is the principle mediator of PER/CRY phosphorylation, with CK1ε

Clocks in Disease and Therapeutic Applications of Clock Targeting Compounds Having evolved independently multiple times, body clocks give a survival advantage, this is true for plants, cyanobacteria and humans (Young and Kay, 2001, Dodd et al., 2005, Ouyang et al., 1998). Circadian disruption is linked to a whole host of diseases from diabetes

Shift Work Circadian disruption is seen chronically among shift workers. With this circadian disruption comes increased susceptibility to diabetes, cardiovascular disease and various forms of cancer (Schernhammer et al., 2003, Lund et al., 2001, Davis et al., 2001, Pan et al., 2011). CK1δ/1ε are known to have different roles in regulating the body clocks, with CK1δ determining the period length and entrainment to zeitgebers (Meng et al., 2010). The pharmacological inhibitor of CK1δ, PF-670462 restored circadian rhythms to arrhythmic mice, with the timing of drug administration affecting the timing of the cycle (Meng et al., 2010). CK1ε knockout mice entrain their circadian rhythms to changes in light schedule faster than wild type animals (Pilorz et al., 2014). Selective inhibition of CK1ε in mice by PF-4800567 induced more rapid entrainment of the animals to changed light dark cycles (Pilorz et al., 2014). These studies demonstrate the importance of CK1δ/1ε in regulating the period and entrainment of circadian rhythms. CK1ε inhibitors could help a shift worker adjust to a new rotation and timed administration of a CK1δ inhibitor could keep their body clocks synchronised, potentially reducing some of the serious medical effects of shift work. Inhibition of CK1ε could also be a method of reducing the duration of jet lag symptoms.

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Clock controlled gene expression is mediated in part by changes in the arrangement of chromatin. It was known that histone acetylation changed in a rhythm similar to that of clock controlled gene (CCG) expression (Etchegaray et al., 2002). The mechanism for these changes was unknown until CLOCK was demonstrated to be a histone acetyltransferase (HAT) which promotes transcription of CCGs by inducing decondensation of chromatin (Doi et al., 2006). The actions of CLOCK are antagonised by the histone deacetylase (HDAC) silent information regulator 1 (SIRT1). SIRT1 is activated by NAD+ and triggers chromatin to condense, stopping transcription of CCGs (Nakahata et al., 2008). CLOCK and SIRT1 also directly acetylate and deacetylate BMAL1 respectively (Asher et al., 2008). The NAD+ dependent nature of SIRT1 is thought to provide the link between metabolism and the core clock proteins (Asher et al., 2008). SIRT1 also acts to modulate PER2 stability by mediating deacetylation leading to degradation of PER2 (Asher et al., 2008). SIRT1 dysfunction appears to play a role in many metabolic diseases, highlighting it as a potential therapeutic target (Rodgers et al., 2007).

to dementia (Zelinski et al., 2014). This section of the review will examine the epidemiological and experimental links between circadian disorder and disease and evaluate novel pharmacological methods for modifying the clock and treating disease.

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How Does the Molecular Clock Influence Gene Expression?

Ageing Ageing has been linked to a weakening in the strength of circadian rhythms and reduced ability to adjust to phase changes in rodent models (Weinert, 2000). In humans age is linked to a reduction in the concentrations of PER2 following exposure to blue light (Jud et al., 2009). Circadian rhythms of testosterone release, prevalent in younger men were almost lost in older men (Bremner et al., 1983). Age is linked to a reduction in sleep quality with a reduced ability to sleep unbroken through the night (Van Cauter et al., 1998). Ageing is accompanied by a reduced amount of slow wave or deep sleep with increased amounts of non REM sleep (Edward et al., 2011). In older people the magnitude of circadian

The widely accepted Free Radical Theory of ageing hypothesises that ageing and the pathologies associated with it are caused by increased accumulation of reactive oxygen species (ROS) in the cells of the body (Harman, 1992, Balaban et al., 2005). ROS homeostasis is mediated by the clock protein BMAL1 and BMAL1 knockout mice age prematurely (Kondratov et al., 2006). Antioxidant therapy was found to reduce some of the symptoms of premature ageing in BMAL1 knockout mice (Kondratov et al., 2009). Pharmacological methods of strengthening the body clocks and increasing BMAL1 concentrations inside the cell may provide a method of reducing the negative effects of ageing.

Cancer The link between circadian disruption and increased susceptibility to cancer has been repeatedly demonstrated; with epidemiological studies of night shift workers revealing increased rates of breast, colorectal, endometrial and prostate cancer (Davis et al., 2001, Schernhammer et al., 2003, Viswanathan et al., 2007, Conlon et al., 2007). Polymorphisms in clock genes have also been associated with altered risk of prostate cancer (Chu et al., 2007). Loss of circadian rhythms of cortisol was associated with poorer prognosis in breast cancer patients (Sephton et al., 2000). These links have also been demonstrated experimentally, shown by complete ablation of the SCN increasing

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Uniquely among disorders of circadian dysfunction, FASPS has been linked to one single mutation (Jones et al., 1999). FASPS is characterised by a phenotype of early sleeping and waking, around 4 hours before that of healthy individuals. Rhythms of melatonin and body temperature are similarly advanced by about 4 hours. Genetic analysis of FASPS sufferers revealed a mutation at position 662 of the PER2 protein, with a glycine replacing a serine residue at that position. Further investigation revealed this mutation was within the CKIÉ&#x203A; binding region of PER2 leading to the hypothesis that a difference in PER2 phosphorylation caused FASPS (Toh et al., 2001). A subsequent study demonstrated that the FASPS mutation inhibits PER2 phosphorylation by CKIÉ&#x203A; which causes more rapid removal of PER2 from the nucleus leading to increased rates of PER2 degradation in the cytoplasm (Vanselow et al., 2006).

rhythms of body temperature, melatonin, and cortisol are around one third smaller than those of younger people (Dijk et al., 2000). This change in rhythm contributes to the sleep changes seen in older people. Improving the strength of circadian rhythms and therefore sleep quality in older people may provide one mechanism to reduce the negative effects of ageing on the body.

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Familial Advanced Sleep Phase Syndrome (FASPS)

tumour growth rates and decreasing survival times for mice implanted with Glasgow osteosarcoma or pancreatic adenocarcinoma cells (Filipski et al., 2002).

demonstrated the same in humans (Colles et al., 2007). Exposure to light at night caused increased body mass in mice when compared to mice on normal light dark cycles (Fonken et al., 2010).

The probable mechanism of the circadian-cancer connection may lie in circadian regulation of the cell cycle. The oncogene c-myc, involved in mediation of apoptosis, contains E box elements in its promoter and cellular concentrations display circadian oscillations (Battey et al., 1983, Fu et al., 2002). Clock protein mediated control of other cell cycle regulating proteins has also been demonstrated. Mice with mutated or knocked out Per2 genes display increased rates of cancer and decreased survival when exposed to gamma radiation, this is thought to be caused by reduced rates of p53 mediated apoptosis in response to DNA damage (Fu et al., 2002). This and other studies have demonstrated the role of Per2 as tumour suppressor (Fu et al., 2002, Xiang et al., 2008). The ROR agonist SR1078 increased P53 stability and P53 mediated apoptosis in HepG2, hepatocellular carcinoma cells (Wang et al., 2012).

The Rev-erbα agonists SR9009 and SR9011 decreased fat mass in diet induced obese mice, without affecting food intake or activity levels (Solt et al., 2012). The weight loss is thought to be mediated by an increase in energy expenditure due to changes in metabolic enzyme gene expression (Solt et al., 2012). This may provide a solution to the global obesity epidemic, reducing reliance on patients to make lifestyle changes or undergo surgical procedures.

Genetic knockdown of Rev-erbα in mice led to increased rates of atherosclerotic plaque formation without altering blood lipid concentrations (Ma et al., 2013). The authors demonstrated that knockdown of Rev-erbα led to more infiltration of inflammatory M1 macrophages, leading to greater plaque formation. Interestingly treatment of M1 macrophages with the endogenous Reverbα ligand haem induced differentiation into the anti-inflammatory M2 subtype

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Obesity has reached epidemic levels globally and is one of the largest causes of death that could be prevented (Barness et al., 2007). Circadian disruption and obesity seem to be linked, with poor sleep predisposing an individual to obesity (Spiegel et al., 2009). Many studies have also demonstrated the circadian disruption caused by high fat diets, lengthening the period of circadian rhythms and altering the expression of core clock genes (Kohsaka et al., 2007). Further studies have shown eating during rest periods causes more weight gain than eating the same amount during the active period in mice (Arble et al., 2009). Epidemiological studies have

A circadian variation in the timing of myocardial infarction (MI) has been known for many years, with MI 3 times more likely to take place at 9 am than 11 pm (Muller et al., 1985). Similar variation has been found in the timings of stroke and sudden cardiac death (Elliott, 1998, Muller et al., 1987). Circadian misalignment is thought to be the cause of increased rates of metabolic and cardiovascular disease among shift workers (Scheer et al., 2009). It could be speculated that using compounds to restore order to the clocks of disrupted individuals would reduce the occurrence of these diseases.

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Obesity

Cardiovascular Disease

As previously mentioned, circadian disruption predisposes an individual to many problems, including diabetes. Mice with mutated pancreatic CLOCK and BMAL1 proteins show decreased β cell insulin production and reduced glucose tolerance (Marcheva et al., 2010). This circadian diabetic link has been demonstrated experimentally in humans, kept on a 28 hour cycle. After eating during normal rest periods subjects had elevated blood glucose and insulin levels, indicating increased insulin resistance (Scheer et al., 2009). Clock regulator Rev-erbα regulates gluconeogenesis by controlling glucose-6phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PCK) expression (Yin et al., 2007). GSK4112, the first synthetic agonist for Rev-erbα, reduced gluconeogenesis in mouse hepatocytes, highlighting Reverbα agonists for potential use in the treatment of diabetes (Grant et al., 2010). Another synthetic Rev-erbα agonist SR9009 was found to decrease plasma glucose and insulin concentrations in mice (Solt et al., 2012). The SIRT1 agonist SRT1720 was found to reduce blood glucose concentrations and improved insulin sensitivity in mouse models of type 2 diabetes (Milne et al., 2007). A small molecule modulator of CRY, KL001 inhibited gluconeogenesis in mouse primary hepatocytes, revealing CRY modulation as a possible treatment strategy for diabetes (Hirota et al., 2012).

Mental Disorders The association between circadian disruption and mood disorders was known long before the biology was fully understood (Wehr et al., 1979). More recently CLOCK mutant mice (ClockΔ19) have been noted to display mania like symptoms of decreased anxiety, sleep, depression and increased cocaine reward value (Roybal et al., 2007). In humans, polymorphisms in clock genes have been linked to bipolar disorder (Shi et al., 2008, Etain et al., 2011). Interestingly existing treatments for depression have been shown to modulate the body clock, Fluoxetine (prozac) caused advanced the firing of rat SCN neurons (Sprouse et al., 2006). The body clocks certainly appear to play a role in mental disorders, although it is still not well understood.

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Diabetes

A structurally similar molecule to KL001, Compound 41 was also found to act on CRY. Diet induced obese mice showed faster glucose clearance in an oral glucose tolerance test when dosed with compound 41 for 7 days previously (Humphries et al., 2016). SR3335 a selective inverse agonist of RORα reduced hepatic gluconeogenesis in diet induced obese mice, indicating that it and similar compounds may prove relevant in treatment of type 2 diabetes (Kumar et al., 2011). SR1078 an agonist of RORα and RORγ, increases the expression of Fibroblast Growth Factor-21 (FGF-21) (Wang et al., 2010). FGF-21 was shown to reduce fasting plasma glucose, insulin and glucagon levels, in addition to improving blood lipid ratios in both mice and monkeys (Kharitonenkov et al., 2005, Kharitonenkov et al., 2007). SR1078 may provide one method of treating diabetes by raising FGF-21 concentrations whilst avoiding the problems of injecting the protein directly as a route of administration.

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(Ma et al., 2013). The synthetic Rev-erbα agonist SR9009 was shown to reduce atherosclerotic plaque size in mice through the previously mentioned mechanism (Sitaula et al., 2015) This action highlights the importance of further development of Rev-erbα ligands.

The body clocks also play a role in modulating immune response, with immune cell numbers and inflammatory cytokine concentrations in the blood varying in a circadian manner (Haus and Smolensky, 1999). Certain autoimmune diseases such as multiple sclerosis, type 1 diabetes and arthritis occur at higher rates at more northern latitudes (Cantorna, 2008). Ultraviolet light and vitamin d may play a role in preventing autoimmunity (Ponsonby et al., 2002). Given the circadian gating of the immune system and the effects of vitamin D on clock protein expression, the role of the body clocks in autoimmunity should not be ignored (Scheiermann et al., 2013, Gutierrez-Monreal et al., 2014). SR1001, an inverse agonist of RORα and RORγ, inhibited the differentiation of

Conclusions Circadian rhythms and body clocks are present in all organisms and are vital to the normal function of single cells and complex organisms. These rhythms are seen clearly in daily cycles of waking and sleeping, but are also present in regulation of gene expression, metabolism and the cell cycle. With modern life comes clock disruption, seen chronically in shift workers with less regularity in patterns of sleeping and eating. The damaging effects of circadian disruption are serious and varied, increasing an individual's susceptibility to many diseases. As the mechanisms behind the body clocks and their disruption in disease becomes increasingly well understood, so too do pharmacological methods to modify clocks and treat the disruption. This review has given a brief summary of some pathologies associated with circadian disruption, many were left unmentioned due to space constraints. New compounds to modulate targets within the body clocks and their potential applications in disease have been described. Important drug targets in the body clock include the nuclear receptors Rev-erb, ROR and enzymes CK1δ/1ε,

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Autoimmune Disorders

key autoimmune mediators: T helper 17 cells, and reduced inflammatory cytokine production in splenocytes (Solt et al., 2011). SR1001 slowed the development of multiple sclerosis and reduced the severity of symptoms in a mouse model of the disease (Kojetin and Burris, 2014). A structurally similar RORγ inverse agonist: SR2211 reduced joint inflammation in mice with collageninduced arthritis, a model for rheumatoid arthritis (Chang et al., 2014). The success of these compounds in animal models undoubtedly warrants further study of clock modulators as therapies for autoimmune disorders.

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Pharmacological targeting of the body clocks provides a relatively unexplored avenue for treatment of mental disorders. CK01, a casein kinase inhibitor was found to restore normal behaviour to the manic ClockΔ19 mutant mice, highlighting a potential for treatment of bipolar disorder (Arey and McClung, 2012). The synthetic Rev-erb agonists S9011 and SR9009 reduced anxious behaviours in mice, in multiple assays of anxiety (Banerjee et al., 2014). The anxiolytic effect was dose dependent and comparable to the benzodiazepine chlordiazepoxide. In the same study the authors demonstrated that S9011 administered with cocaine, reduced its reward value (Banerjee et al., 2014). SR10067, a more potent Rev-erb agonist had similar anxiolytic effects, at a dose around 5 times lower than that of S9011 and SR9009 (Banerjee et al., 2014). This study demonstrates the potential of pharmacological clock modulators in two of the most common mental conditions; anxiety and addiction.

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How do wounds heal? Robyn Wood (woodrobyn95@yahoo.co.uk) Faculty of Biology, Medicine and Health, The University of Manchester, U.K.

Introduction The skin is the largest organ of the body, and has a variety of associated structures, including hair and glands, which together form the integumentary system. It plays a number of critical roles in the survival of an organism. These can be condensed into four main functions: the regulation of body temperature, the regulation of fluid balance to prevent dehydration, the collection of sensory information to provide sensation and the protection of the body from the environment to prevent infections (Cohen and Wood, 2000). When the skin is wounded, this diminishes the barrier against the external environment, permitting the entrance of toxins, chemicals and pathogens into the body (Chen et al., 2009). Thus, it is of great importance that the wound healing process occurs effectively to minimise this risk. There are many factors that can affect the rate at which wounds heal, such as age, health of the individual and the severity of the wound (McDaniel and Browning, 2014). Due to the complexity and the need of intense regulation of the wound healing mechanism, errors in this mechanism can result in serious

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Wound healing is a complex and highly ordered process which is essential for the prevention of pathogenic infection. Inefficient healing of cutaneous wounds can result in the formation of chronic wounds- a problem that is dramatically increasing in prevalence worldwide. This literature review aims to outline the mechanism of healing and the factors affecting this process in order to gain an understanding on the causation of chronic wounds. In addition to this, it investigates how knowledge of the latter can be of great importance in the development of potential clinical treatments to assist in healing. There are three main phases in healing: the inflammatory phase, the proliferative phase and the remodelling phase. Upon injury, a haemostatic plug is formed, and an inflammatory response is initiated. Platelets within the plug secrete proinflammatory cytokines and growth factors, stimulating the migration of leukocytes and fibroblasts to the wound site. In the proliferative phase, reepithelialisation and formation of granulation tissue occurs. In addition, fibroblasts synthesise extracellular matrix (ECM), and new capillaries are formed through angiogenesis. In the final stage, the ECM undergoes remodelling, a process that is highly regulated, to produce a mature scar. Factors such as age, oxygen, diabetes mellitus and

smoking have all been shown to affect the wound healing process. Understanding the influence of these factors on healing allows the development of treatments to reduce chronic wound incidence and improve healing.

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Abstract

The skin is composed of three layers: the epidermis, the dermis and the hypodermis (Han, 2016). The epidermis is the stratified and keratinised outermost layer of the skin that provides the first barrier against the invasion by foreign molecules (Pocock and Richards, 1999). The thickness of the epidermis is dependent upon its location in the body. For example, it is 0.05mm in thickness on the eyelids and it is 1.5mm thick on the soles of the feet (Han, 2016). The epidermis can be subdivided into five layers: the stratum basale, the stratum spinosum, the stratum granulosum, the stratum lucidum and the stratum corneum, shown in Figure 1 (Vohr, 2016). There is very little ECM found within the epidermis (Chen et al., 2009). There are no blood vessels within the epidermis, therefore the living cells can only be found in the stratum basale, the innermost layer, where there is a supply of nutrients provided by the underlying dermis. Furthermore, the stratum basale contains pigment producing melanocytes and keratinocytes (Cohen and Wood, 2000). These keratinocytes are able to migrate from the basal layer to the outermost layer, simultaneously maturing and differentiating as they progress, to form the outer keratinised layer of dead cells known as the stratum corneum (Chen et al., 2009). The epidermis undergoes constant renewal and is replaced every 3 to 4 weeks (Harvey, 2005). The loss of cells from the stratum corneum is balanced by the proliferation and cell growth of the cells in the stratum basale to ensure this state of constant renewal (Bouwstra and Ponec, 2006). The synthesis of lipids

The dermis is the second layer of the skin, and can be further divided into two layers; the papillary and the reticular dermis (Han, 2016). The papillary layer consists of extensions into the epidermis, forming a distinct pattern of ridges on the skin surface unique to each individual, known as a fingerprint (Cohen and Wood, 2000). The dermis consists of many cell types that are integral to the bodyâ&#x20AC;&#x2122;s defence mechanism against infection, such as fibroblasts and macrophages (Han, 2016). The fibroblasts also provide collagen and elastin which forms part of the elastic connective tissue framework of the dermis, providing the skin with strength and enabling the skin to stretch with minimal damage (Cohen and Wood, 2000; Chen et al., 2009). The dermis also has an important role in the regulation of body heat, as arrector pili muscle can be located in the dermis, enabling the erection of hair follicles (Watt and Fujiwara, 2011). This structure is depicted in Figure 1. The hypodermis, often also referred to as the subcutaneous layer, lies below the dermis and is composed mainly of adipose tissue (Figure 1) (Smeltzer et al., 2010). This layer provides insulation and hence contributes to the role of the skin in regulating temperature (Han, 2016).

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The Structure of the Skin

within the stratus corneum forms a relatively impermeable barrier, enabling the skin to carry out its function of protection from infections and regulation of water loss (Smeltzer et al., 2010).

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consequences, such as the formation of chronic wounds.

the underlying tissue. Hence, regeneration is an insufficient method of healing and a more complex mechanism known as second-intention healing, or healing by secondary union, takes place (Kumar et al., 2007).

Cutaneous Wounds A cutaneous wound is the term given to an injury of the skin. For cutaneous wound healing to be efficient, it requires extensive regulation and the integration of a multitude of biological events, such as the deposition and remodelling of connective tissue, cell migration and angiogenesis (Wu et al., 2007) The mechanism of wound healing can be divided into 3 main stages: the inflammatory phase, the proliferative phase and the remodelling phase (Kirsner and Eaglstein, 1993). The complexity of the wound healing mechanism is dependent on the size and damage inflicted by the wound. In a small clean wound involving discontinuity of the basement membrane and death of epithelial and connective tissues localised to the site of injury, a relatively simple mechanism of wound healing is necessary. This mechanism is known as healing by first intention or primary union and relies greatly on the regeneration of cells (Kumar et al., 2007). In more severe wounds, damage can occur to the connective tissue surrounding the wound site in addition to

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Figure 1. A schematic showing a cross-section of the skin (Redrawn and adapted from Malmivuo and Plonsey, 1995; Betts et al., 2013).

Damage to the vascular endothelium as a result of an injury initiates vasoconstriction localised to the site of injury as a preliminary method to prevent too much blood loss (Pocock and Richards, 1999). This vasoconstriction is extremely minimal in first intention healing in comparison to secondintention healing. The clotting cascade is activated to ensure haemostasis occurs to stop the flow of blood and an immediate inflammatory response is initiated at the site of injury (Gurtner et al., 2008). Figure 2 demonstrates the key steps involved in the inflammatory phase of wound healing. Vascular injury results in the exposure of constituents of the ECM such as collagen and other protein (Kumar et al., 2007). Within the first 4 hours post injury, platelets accumulate at the site of the wound and bind to the exposed collagen (Spaet and Zucker, 1964; Kumar et al., 2007; Rubin and Reisner, 2009). The accumulation of platelets at the site of injury is known as a primary platelet plug (Pocock and Richards, 1999). The platelets secrete adenosine diphosphate (ADP) and thromboxane A2 (TXA2), initiating the activation and cohesion of more platelets resulting in the formation of a mass of platelets, known as a secondary haemostatic platelet plug (Pocock and Richards, 1999; Kumar et al., 2007). This is a temporary blockage and must be stabilised to ensure efficient haemostasis. In the clotting cascade, factor Xa converts prothrombin into

The Inflammatory Phase

The Proliferative Phase It is in the proliferative phase of wound healing that re-epithelialisation of the wound occurs, along with angiogenesis,

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Neutrophils are a type of granulated immune cell known as a polymorphonuclear leukocyte (PMN). They are recruited to the fibrin clot within the first 24 hours after injury and are essential in the prevention of infection through the secretion of proteases and antimicrobial peptides (Eming et al., 2007; Wilgus et al., 2013). These antimicrobial substances include reactive oxygen species (ROS), cationic peptides, and proteases such as proteinase 3 which possess the ability to degrade and kill potential pathogens (Eming et al., 2007). The platelets within the haemostatic plug and the wound tissue also secrete a variety of growth factors such as: platelet-derived growth factor (PDGF), transforming growth factor (TGF)-Î˛, fibroblast growth factor (FGF) and epidermal growth factors (EGF), along with pro-inflammatory cytokines (Guo and DiPietro, 2010). Secretion of these factors initiates the migration of more inflammatory cells such as monocytes and fibroblasts to the site of injury by the process of chemotaxis, activating them (Epstein et al., 1999). The migration of leukocytes is a result of actin rich protrusions known

as lamellipodia at the leading edge of the cell. The polymerisation of this actin pushes on the plasma membrane, driving the cell forwards (Ridley, 2003). Similarly, the migration of fibroblasts is also a result of actin polymerisation in protrusions at the leading edge of the cell. However, in slow moving cells such as fibroblasts there are filopodia rather than lamellipodia projections (Rubin and Reisner, 2009). Monocytes differentiate into macrophages at the wound site and secrete cytokines to recruit additional leukocytes. In this manner, the inflammatory response is intensified. (Guo and DiPietro, 2010). Macrophages are involved in the phagocytosis of debris in the wound site, including ECM fragments and pathogens (Epstein et al., 1999). Furthermore, macrophages also secrete PDGF and vascular endothelial growth factor (VEGF). These growth factors have an important role in the formation of granulation tissue in the later stages of the wound healing process (Epstein et al., 1999). The formation of a fibrin matrix entraps these growth factors and becomes the scaffold for infiltrating cells (Gurtner et al., 2008). An increase in vascular permeability is initiated by inflammatory agents such as histamine and components of the complement system, resulting in the extravasation of plasma (Chen et al., 2009). The inflammatory response has a greater intensity during the healing of wounds by second intention rather than by first intention (Kumar et al., 2007). A symptom of the inflammatory phase is localised reddening and swelling around the site of injury.

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active thrombin, which is a key enzyme in haemostasis (Smith et al., 2015). Thrombin converts plasma fibrinogen into a fibrin clot which anchors the platelets into position, stabilised by transglutaminase factor XIII (Xi et al., 2002; Di Cera, 2008). This provides tensile strength to ensure a reduction in blood loss (Kumar et al., 2007). This clot is essential in protecting the body from the infection of pathogens and toxins through the wound entry site, in addition to preventing excess fluid loss (Chen et al., 2009).

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endothelial cells (Hinsbergh et al., 2006). This is proceeded by lumen and basement membrane formation and hence new blood vessels are formed. This mechanism is positively regulated by several growth factors, such as vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 2 (FGF2) (Gurtner et al., 2008). This was exemplified by Galiano and colleagues (2004), who demonstrated that wounds of diabetic patients treated with VEGF showed normalised healing, with increased epithelisation, matrix deposition and enhanced cellular proliferation. Angiogenesis can also occur using endothelial progenitor cells derived from the bone marrow, but the contribution of this method of angiogenesis in the healing of incisional wounds has been found to be insignificant (Bluff et al., 2007). Another important stage in the proliferative phase that is essential for efficient wound healing is re-epithelialisation. This involves the restoration of the epidermal barrier through the directed migration of keratinocytes from the wound edges and over the granulation tissue (Raja et al., 2007). Fibroblasts can differentiate into myofibroblasts with the ability to contract due to expression of Îą-smooth muscle actin (Chen et al., 2009). In a clean, moist wound this contraction will cause the wound to decrease in size. However, if there is a lack of blood flow or moisture an eschar may form (Harvey, 2005). The colour of the eschar crust is indicative of the cause of its formation; a white eschar is an indication of total loss of perfusion, known as ischemia, and a red eschar indicates the destruction of red blood cells (Han, 2016). Wound contraction can be observed in healing by second intention but is observed

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tissue regeneration and repair of connective tissue. The cells that are unharmed by the injury maintain the capacity to proliferate. The vascular endothelial cells, fibroblasts and remnants of the injured tissue proliferate during tissue repair (Kumar et al., 2014). Cells can be classified by their intrinsic proliferative capacity. The cell types that possess the ability to constantly undergo renewal can be referred to as labile cells and include epithelial cells such as keratinocytes (Rubin and Reisner, 2009). On the other hand, endothelial cells and fibroblasts cannot be described as labile cells as under normal conditions their proliferative activity is minimal and they present limited capacity for regeneration (Kumar et al., 2014). However, upon injury, they are able to increase the speed of proliferation, and hence are described as stable cells (Rubin and Reisner, 2009). A third proliferative class of cells exist known as permanent cells. Being incapable of regeneration, they are described as terminally differentiated (Rubin and Reisner, 2009). The main processes involved within the proliferative phase are outlined in Figure 2. In order to progress in the wound healing process, granulation tissue must form on the surface of the wound. Granulation tissue is new connective tissue formed to replace the lost dermal layer as a result of injury (Ganten and Ruckpaul, 2006). Considerably greater quantities of granulation tissue are produced through the healing by second intention rather than by first intention. A process of angiogenesis occurs whereby new blood vessels are formed from capillary sprouts of pre-existing vessels (Kumar et al., 2007). In angiogenesis, the basement membrane of endothelial cells is degraded, thus allowing the migration and subsequent proliferation of these

The Remodelling Phase The remodelling phase usually occurs 2/3 weeks post injury and is the final stage in the wound healing process and the longest in duration. It is in this phase that the granulation tissue formed in the proliferative phase is remodelled to form a scar which can then undergo maturation, as shown in Figure 2 (Harvey, 2005). Fibroblasts play an important role in scar formation. Fibroblasts begin synthesising collagen within the first 2 weeks of injury, however they can continue this synthesis for many weeks, even years in some circumstances (Han, 2016). Collagen synthesis is shown to progressively increase throughout the process of wound healing, and therefore deposition of the ECM increases (Cotran et al., 1999). Once sufficient levels of collagen have been synthesised, the collagen can undergo remodelling and the scar can mature (Han, 2016). The remodelling of the collagen occurs as a result of the simultaneous synthesis and degradation of collagen by a number of different

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Fibroblasts in the wound synthesise and secrete collagen and connective tissue for the formation of ECM (Harvey, 2005). The ECM is a dynamic structure that has many important functions within tissues thus its formation is essential. It is a reservoir of growth factors, and hence is a mediator of cell proliferation and differentiation, a substrate for cell growth and it also provides the tissue with mechanical support. The deposition of collagen results in an increase in tensile strength of the wound (Kumar et al., 2007).

factors and enzymes (Epstein et al., 1999). Growth factors such as PDGF, FGF and TGF- Î˛ that stimulate the proliferation of fibroblasts have been shown to have a similar effect on the synthesis of the ECM (Cotran et al., 1999). The activity of enzymes called matrix metalloproteinases (MMPs) secreted by leukocytes has shown to degrade collagen (Rubin and Reisner, 2009; Han, 2016). Their secretion can be stimulated by factors such as EGF, PDGF and FGF, as well as cytokines and physical stress (Cotran et al., 1999; Pakyari et al., 2013). It is extremely important that the action of these enzymes is under tight regulation. TGFÎ˛ type 1 has been shown to inhibit the synthesis of MMPs, as has the use of steroids (Cotran et al., 1999; Pakyari et al., 2013). Tissue inhibitors of metalloproteinases (TIMPs) are produced by mesenchymal stem cells of the bone marrow and are shown to inhibit active MMPs (Kumar et al., 2007). Despite the remodelling of the ECM and the increase in tensile strength observed, the structure of the tissue will never regain the strength of an uninfected tissue (Epstein et al., 1999). A study conducted on rat wounds demonstrated this, showing that at a year post-injury, the wounds had 80% of the strength of unwounded skin (Levenson et al., 1965).

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considerably less in healing by first intention (Rubin and Reisner, 2009).

affecting

Wound

When the efficiency and order of the wound healing process is lost, the wound

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Factors Healing

Systemic factors, such as age, lifestyle and overall health of an individual can have great effects on the efficiency of the healing process (Guo and DiPietro, 2010). Studies have shown that wound healing is delayed with increasing age. In a study conducted on aged mice, it was found that re-epithelialisation, collagen synthesis and angiogenesis were all delayed when compared with young mice. Moreover, the wounds of aged mice contained significantly less FGF type 2 and VEGF, which are known mediators of angiogenesis (Swift et al., 1999). In addition, it has been demonstrated that all phases of the wound healing process undergo age-related alterations that vary from an increase in platelet aggregation in haemostasis to a decrease in wound strength in the final phase of wound healing (Gosain and DiPietro, 2004). The sex-hormone oestrogen has been shown to affect the expression of particular genes associated with healing, such as those involved in inflammation, matrix production and protease inhibition

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Figure 2: The mechanism of normal, effective healing of a cutaneous wound. Wound healing can be divided into three main phases; the inflammatory phase, the proliferative phase and the remodelling phase. The inflammatory phase involves the activation of the clotting cascade for the prevention of excessive blood loss, and the recruitment of white blood cells (leukocytes) to the wound site to prevent infection. In the proliferative phase, the extracellular matrix (ECM) is synthesised and granulation tissue is formed. New capillaries are produced by the process of angiogenesis. The final phase of wound healing is the remodelling phase, in which the ECM is remodelled and the formation of a mature scar occurs. This phase is tightly regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPS). (Redrawn and adapted from Enoch and Harding, 2003).

is referred to as a chronic wound. Often, chronic wounds remain in the inflammatory phase for a prolonged period of time, unable to progress to the proliferative phase due to a lack of regulation (Diegelmann and Evans, 2004). There are three main categories of chronic wounds: venous leg ulcers, diabetic foot ulcers and pressure ulcers. There are a number of known risk factors for chronic wound formation, such as age, diabetes mellitus, and smoking. As a result of this, chronic wounds are becoming increasingly common, approaching epidemic proportions and thus creating profound socioeconomic burdens on healthcare systems and patients (McDaniel and Browning, 2014).

Systemic factors within an individual can significantly alter the level of oxygenation of a tissue and affect the healing of a wound. In tissues, a deficient supply of oxygen is referred to as hypoxia, and is often a result of a lack of perfusion, known as ischemia (Sen, 2009). In ischaemic wounds, there are a number of factors that can result in damage to the microvasculature causing hypoxic conditions such as smoking and diabetes. Smoking can be detrimental to oxygen delivery due to the production of toxic constituents in cigarette smoke, including carbon monoxide, hydrogen cyanide and nicotine (Rodriguez et al., 2008). It was found that nicotine is a vasoconstrictor, and hence reduces blood flow to tissues, thus implying the role of nicotine in tissue ischemia (Silverstein, 1992). Furthermore, cigarette smoke

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Local factors can affect how wounds heal by directly influencing the wound characteristics (Guo and DiPietro, 2010). Oxygen is an essential local factor that has been shown to have many roles in wound healing. For example, oxygen has been shown to assist in the production of reactive oxygen species (ROS) and hydrogen peroxide (Rodriguez et al., 2008). The production of ROS enables oxidative killing to occur, which is a highly important mediator of neutrophil bactericidal activity (Greif et al., 2000). Superoxide ions are a type of ROS produced and function by breaking down the bacterial membranes (Bishop, 2008). These findings therefore suggests that oxygen has an important role in the prevention of infection. Furthermore, exposure to oxygen was found to have decreased the amount of necrosis experienced in guinea pig wounds inoculated with Escherichia coli (Knighton et al., 1984). This implies that oxygen has a role in promoting wound healing. Oxygen was shown to be of great use during mechanisms imposed in the proliferative phase of the wound healing. In a study on the effect of topical oxygen therapy (TOT) on rat ischemic wounds, a faster decrease in wound size was observed with TOT treatment, and the complete closure and healing of the wound was achieved significantly faster than in the absence of treatment (Rao et al., 2016). This implies that oxygen is involved in angiogenesis and the re-

epithelialisation of wounds and hence accentuates its importance in wound healing. In a study conducted on the effect of an oxygen supply on the tensile strength of healing rat wounds, a significantly increased tensile strength was observed in the rats who were using an oxygen supply (Bishop, 2008). This indicates that oxygen also has a positive effect on collagen synthesis. The balance between the rate of oxygen consumption and oxygen perfusion in a particular tissue at a specific time can be referred to as tissue oxygen tension (Ragheb, 2004). Reading and colleagues (2013) found that the skin can absorb oxygen from water, as when immersed in oxygen-enriched water, the skin oxygen tension is improved. This could be of great benefit in devising a potential method of treatment for chronic wounds resulting from hypoxic ischaemia (Reading et al., 2013).

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(Hardman and Ashcroft, 2008). Therefore, due to the decrease in oestrogen levels with increasing age, it can be suggested that this change in hormone levels is a potential cause for the impairment of wound healing with age (Emmerson and Hardman, 2011).

Discussion Wound healing is a complex, extensively regulated and ordered process that is essential for our health and survival. All three phases of the wound healing process are necessary for the complete closure and healing of a wound. A multitude of cell types, such as leukocytes, keratinocytes and fibroblasts are involved in each phase of healing. Each type of cell performs a specific function that ensures that the wound is healed successfully. Haemostasis, prevention of infection, reepithelialisation, wound contraction and the synthesis and remodelling of the ECM are all vital for efficient wound healing. Failure to progress through all phases of the wound healing mechanism can have detrimental consequences, such as the formation of chronic wounds.

Conclusion Chronic wounds are a worldwide health problem, and are increasing in prevalence in epidemic proportion, and hence creating overwhelming burdens on healthcare systems and the patients affected. There are many local and systemic factors associated with the

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In patients with diabetes mellitus, diabetic ulcers often form due to the hypoxic environment created as a result of the vasculopathies associated with the disease (Rubin and Reisner, 2009). Type 2 diabetes is substantially prevalent worldwide, with 6.4% of the worldâ&#x20AC;&#x2122;s population diagnosed with the disease, and this figure is intended to increase to 8% in 2030 (Eming et al., 2007). A complication of diabetes mellitus is diabetic peripheral neuropathy (DPN) in which there is a loss of both motor and sensory function, particularly in the lower extremities (Kumar et al., 2007; Wu et al., 2016). It is in the areas that are devoid of sensation that diabetic ulcers are likely to form (Rubin and Reisner, 2009). Diabetes is usually accompanied by peripheral arterial disease (PAD), in which atherosclerotic plaques can occur in the femoral, popliteal and posterior tibial arteries (Puri et al., 2012). This results in occlusion of blood vessels and

the subsequent development of an ischemic, hypoxic wound environment. Furthermore, due to the bodyâ&#x20AC;&#x2122;s inability to control glucose levels in diabetes, high intracellular concentrations of glucose, and high levels of glycolysis result in the formation of excess ROS, resulting in oxidative stress (Vincent et al., 2004). In addition, MMP levels have been shown to be almost 60 times higher in chronic wound fluid than in acute wound fluid (Sibbald and Woo, 2008). This suggests an increase in degradation of collagen occurs in chronic wounds in the remodelling phase.

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suppresses the immune response as it impairs the function of cells, such as neutrophils and macrophages that play a key role in the inflammatory response (McDaniel and Browning, 2014). Carbon monoxide found in the smoke prevents the transport of oxygen to the tissues, hence contributing to hypoxia (Silverstein, 1992). Additionally, hydrogen cyanide in cigarette smoke inhibits the enzyme required in oxidative metabolism and oxygen transport, further contributing to the hypoxic and toxic effect of smoking (Silverstein, 1992). These findings suggest the need to provide increased smoking cessation advice by healthcare systems to globally reduce the number of individuals who smoke, and hence assist in reducing the incidence of chronic wound formation.

efficiency with which a wound heals. For example, studies have shown the beneficial effects of oxygen in many of the phases of wound healing, and the effect of topical oxygen therapy on healing. With this knowledge, and the evidence of the skin’s ability to absorb oxygen from water, the possibility of using oxygen therapies in wound healing is promising. Furthermore, increasing education of the lifestyle risk factors associated with impaired wound healing such as smoking, and providing support such as smoking cessation strategies, the prevalence of chronic wound formation could be decreased even further. To conclude, the combination of current knowledge into the mechanism of wound healing and emerging studies of the affecting factors will provide a strong foundation for the development of potential treatments to assist the healing process and reduce the incidence of chronic wound formation.

Cohen, B. and Wood, D. (2000). Memmler's the structure & function of the human body. Philadelphia: Lippincott Williams & Wilkins.

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Diegelmann, R. and Evans, M.C. (2004). Wound healing: an overview of acute, fibrotic and delayed healing. Frontiers in Bioscience, 9, pp.283-9 Eming, S., Krieg, T. and Davidson, J. (2007). Inflammation in Wound Repair: Molecular and Cellular Mechanisms. Journal of Investigative Dermatology, 127(3), pp.514525. Emmerson, E. and Hardman, M. (2011). The role of estrogen deficiency in skin ageing and wound healing. Biogerontology, 13(1), pp.320. Enoch, S. and Harding, K. (2003). Wound Bed Preparation: The Science Behind the Removal of Barriers to Healing. Wounds. 15(7). Epstein, F., Singer, A. and Clark, R. (1999). Cutaneous Wound Healing. New England Journal of Medicine, 341(10), pp.738-746.

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Han, S. (2016). Innovations and advances in wound healing. 2nd ed. Springer-Verlag Berlin Heidelberg, pp.1-287. Hardman, M. and Ashcroft, G. (2008). Estrogen, not intrinsic aging, is the major regulator of delayed human wound healing in the elderly. Genome Biol, 9(5) Harvey, C. (2005). Wound Healing. Orthopaedic Nursing, 24(2), pp.143-157. Hinsbergh, V., Collen, A. and Koolwijk, P. (2006). Role of Fibrin Matrix in Angiogenesis. Annals of the New York Academy of Sciences, 936(1), pp.426-437. Kirsner, R. and Eaglstein, W. (1993). The wound healing process. Dermatologic Clinics, 11(4), pp.629-640. Knighton, D., Halliday, B. and Hunt, T. (1984). Oxygen as an Antibiotic: The Effect of Inspired Oxygen on Infection. Arch Surg, 119(2), p.199-204 Kumar, V., Abbas, A. and Aster, J. (2014). Robbins pathologic basis of disease. 9th ed. Philadelphia: Saunders. Kumar, V., Abbas, A., Fausto, N. and Mitchell, R. (2007). Robbins basic pathology. 8th ed. Philadelphia, PA: Saunders/Elsevier. Levenson, S., Geever, E., Chowley, L., Oates, J., Berard, C. and Rosen, H. (1965). The Healing of Rat Skin Wounds. Annals of Surgery, 161(2), pp.293-308. Malmivuo, J. and Plonsey, R. Bioelectromagnetism. New York: University Press.

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Statistical analysis of trypophobic reactions suggests fear of disease as the underlying mechanism Kali Ravel (kalis.ravel@student.manchester.ac.uk) Faculty of Biology, Medicine and Health, The University of Manchester, U.K.

Introduction ‘Trypophobia’ refers to feelings of discomfort, shock and disgust resulting from the sight of clusters of small holes or irregularly pitted structures. Images of small circles or bumps can also induce similar symptoms. The term is not formally defined in a dictionary and is not used in the Diagnostic and Statistical Manual of Mental Disorders. The term itself appears to have been coined on internet message boards circa 2005. The symptoms appear to range from inducing anxiety attacks and vomiting to feelings of disquiet. These reactions appear to exist as a varying spectrum rather than a simple binary. Phobias can result from

Within this study, ‘trypophobic symptoms’ will be used to describe selfreported feelings of disgust and discomfort. ‘Trypophobic images’ are those believed to induce such symptoms.

Methods & statistical analysis A survey was created containing nine images, split into three categories. Those surveyed were asked to rank each image on a scale of 1-10, with 10 indicating strong feelings of disgust and discomfort, while 0 indicated no reaction. Images are included on MUJBSc.ML. Kruskal-Wallis with Dunn’s multiple comparison was conducted (GraphPad Prism v7), which found significant differences between the mean votes for each image set (Figure 2).

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Trypophobia is a self-reported condition in which the affected person has an extreme fear of small holes and bumps. The purpose of this study is to examine the prevalence of trypophobic symptoms and to explore whether these symptoms might be connected to the sight of deadly diseases or dangerous animals. One hundred participants rated their levels of discomfort after viewing a variety of images. The results show that the images of human diseases induced significantly more trypophobic symptoms in comparison to innocuous images or images of dangerous animals.

a number of causes; they can be learned from others, they can be the result of a traumatic experience, or they can be biological in origin. Although Trypophobia is not formally recognised or defined, it is widely self-reported. A study conducted by Arnold Wilkins and Geoff Cole from the University of Essex (Cole and Wilkins 2013) examined the hypothesis that Trypophobia is biological in origin, and that these symptoms result from a similarity to the markings of potentially dangerous animals, such as the blue-ringed octopus and the blue poison frog.

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Abstract

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Figure 2: Ratings for each set of images. The human set of images received significantly higher ratings.

Figure 1: Average ratings for all images.

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Table 1: Categories and Details of Specific Images Used Innocuous – Set I Images which included small holes but which were harmless to the majority of human beings.

Human – Set H Images of small holes on human flesh, including the smallpox rash.

Animal – Set A Images of animals with circular markings reported to induce trypophobic symptoms.

Image 1

A lotus seed pod; an image commonly reported to induce trypophobic symptoms, but which is objectively harmless.

A lotus seed pod edited to be shown as part of a human hand.

Blue-Ringed Octopus – have a bite capable of causing fatalities.

Image 2

Plastic pipes, seen from above. The pipes are slightly different lengths, resulting in an impression of slightly differing diameters. Again, objectively harmless.

An image of a human leg covered in a typical smallpox rash. As above, smallpox is contagious from close-contact and fatal in 30% of cases.

Male Giant Water Bug – Family Belostomatidae – carrying eggs on its back. The insect is capable of delivering a very painful bite but is not fatal.

Image 3

An image of honeycomb within a bee hive. The percentage of people with fatal reactions to bee stings is reported to be between 1-7% of the general population (World Allergy Organization, 2016).

An image of a Blue Poison Frog – human hand which can induce appears to be fatalities. covered in small irregular pits; created using makeup. The image was originally intended to induce feelings of discomfort but not specifically to resemble any known disease or fungal infection.

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Category Description

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Table 2: Mean Ratings from All Surveyed Animal Set BlueRinged Octopus (A1)

Water Bug (A2)

Blue Poison Frog (A3)

Category Mean

1.4

4.5

0.8

2.2

Human Set Lotus Pod Smallpox Hand (H3) Hand (H1) (H2)

Category Mean

5.5

6.3

6.2

7.1

Control (Innocuous) Lotus Pod Tubes (I1) (I2)

Honeycomb Category (I3) Mean

2.6

0.6

0.5

1.2

Table 3: Mean Ratings from Trypophobic Outliers Animal Set BlueRinged Octopus (A1)

Water Bug (A2)

Blue Poison Frog (A3)

Category Mean

Human Set Lotus Pod Smallpox Hand (H3) Hand (H1) (H2)

Category Mean

Control (Innocuous) Lotus Pod Tubes (I1) (I2)

Honeycomb Category (I3) Mean

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Table 4: Mean Ratings from Null Outliers Animal Set BlueRinged Octopus (A1)

Water Bug (A2)

Blue Poison Frog (A3)

Category Mean

Human Set Lotus Pod Smallpox Hand (H3) Hand (H1) (H2)

Category Mean

Control (Innocuous) Lotus Pod Tubes (I1) (I2)

Honeycomb Category (I3) Mean

Results have shown that resemblance to disease may be a factor in trypophobic symptoms. Across all groups, Set H was rated highest with a mean of 6.3, Set A was given a mean rating of 2.2, while Set I was given a mean rating of 1.2 (Table 2). This was found to be a significant difference. Interestingly, within all image sets, the least deadly image was rated as producing the greatest degree of symptoms; in Set I this was I1, the lotus pod, with a mean rating of 2.6, in Set H this was H3, the hand decorated with stage make-up and finally, in Set A, the Water Bug was given a mean rating of 4.5, despite being the only creature shown which does not usually induce fatalities. Of the one hundred people surveyed there are two outliers who exhibit the most severe trypophobic symptoms, rating all images a mean of 7 or more

(Table 3). In both cases, all images were rated as 10, except for I2 (tubes) which was rated at 3, and I3 and A1 (honeycomb and the blue ringed octopus respectively) which were both rated 8. This was interesting to observe as both I3 and A1 are more likely to cause fatalities than I1, the lotus pod. Eight individuals rated each image a mean of less than 1.5, and are classified as null outliers (Table 4). This group gave Set 1 a mean rating of 0, although I1 did receive a single score of '4' from one otherwise unaffected individual. A1 and A3 were also ranked as 0, on average, although A2 had a mean ranking of 1. Finally, Set H was given a mean ranking of 2, with H1, the lotus pod hand, being ranked lowest, with a mean of 1.

Discussion This study sought to examine an alternative hypothesis for a biological origin of trypophobia, the idea that trypophobic symptoms result from a

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Results

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Smallpox, which existed for approximately 3000 years and was eradicated in 1977, produced a characteristic rash resembling many images which are reported as producing trypophobic reactions. The condition was spread through person-to-person contact via infected saliva droplets in the infected person’s breath (WHO 2016). If trypophobic symptoms are induced by the resemblance of trypophobic images to illnesses then it is expected that images in Set H would be given consistently higher ratings than those in Set A or I. If both are sources of the condition, then we would expect the human and animal categories to receive similar ratings. If trypophobic symptoms result from neither of these, we would expect all categories to receive similar ratings. If trypophobic symptoms are the cause of the feelings of disgust induced – as opposed to, for example, simply being disquieted by images of abnormal human body parts – then we would expect image I1 and H1 to receive very similar ratings. The results of the survey showed significantly different ratings for each image, indicating that images of human diseases induce the most trypophobic symptoms, followed by images of dangerous animals, with innocuous images producing the least trypophobic symptoms.

regarding the observed effect of the least deadly image in each set producing the most reported discomfort. For example, a comparison of rashes caused by different real illnesses rather than a mixture of real and fake images might produce relevant data. Better information would also be gained with a larger sample size, and via comparison of the images to ensure the size and appearance of the 'holes' in each image were more uniform, to eliminate the possibility that variance is due to changes in the appearance of the holes rather than their context, as was done in the 2013 Cole and Wilkins study. Further tests might involve survey subjects ranking images in pairs, grading each as inducing more or less symptoms than the other. This would allow different types of images to be more directly compared.

Acknowledgements The author would like to acknowledge Dr. Christian Heintzen and Dr. Martin Steward for their insightful feedback.

Declaration of interests The author declares no conflict of interests.

References Cole, G.G. and Wilkins, A.J. (2013) ‘Fear of holes’, Psychological Science, 24(10), pp. 1980–1985. WHO (2016) Frequently asked questions and answers on smallpox. Available at: http://www.who.int/csr/disease/smallpox/faq/ en/ (Accessed: 30 November 2016). Organization, W.A. (2016) World allergy organization. Available at: http://www.worldallergy.org/professional/all ergic_diseases_center/insect_allergy/ (Accessed: 30 November 2016).

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Further study would be needed to examine alternative hypotheses

resemblance of these small holes to the rashes caused by illnesses such as smallpox. This may be in addition to the resemblance of these holes to the markings of potentially dangerous animals, or may be an alternative origin for the phobia.

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Is there a scientific argument for the decriminalisation of class A drugs in the UK? Thomas D. Bradley (thomas.bradley-3@student.manchester.ac.uk) Faculty of Biology, Medicine and Health, The University of Manchester, U.K.

Introduction In the winter of 1995 large bill-boards featuring a photo of dead teen-ager Leah Betts were erected nationwide as part of an anti-drug campaign aiming to deter the nation’s youth from taking the partydrug ecstasy (Murji, 1998). Leah Betts, was an 18-year-old teenager hospitalised just four hours after taking a single pill of ecstasy on her birthday (BBC News, 1995). The death of this young, middleclass, white girl – the daughter of a retired Metropolitan police man, began a media frenzy over drug use in the UK. This was exacerbated by the later death of two other teenagers: Helen Cousins, and Andreas Bouzis; ‘The Sun’ stating “evil ecstasy pushers are cashing in on Leah’s death” (Murji, 1998). Despite the portrayal by the media at the time of ecstasy as an evil and dangerous drug, Professor Nutt, head of an independent drug advisory body to the government famously stated that ecstasy is “no more dangerous than horse-riding” (Hope, 2009). This lead to the dismissal of Nutt from his position by then Home Secretary Jack Straw (Coemgenus, 2010). Yet Nutt has since continued to campaign for a more rational approach towards drug policies (Nutt, 2012).

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The Death of Leah Betts - a middle-class daughter of a retired police-man, on her 18th birthday after taking just one ecstasy pill catapulted the UK drug problem into the headlines in 1995. Twenty-two years on, and the UK drug culture is arguably just as prevalent. Yet many experts and high-profile figures are now calling for the decriminalisation of Class A drugs, such as prominent academic Professor David Nutt. This review will look at the true nature of the drug problem in the UK, and explore arguments both for and against decriminalisation. Criminalisation advocates argue that decriminalisation will lead to increased drug usage in the UK. On the contrary, advocates of decriminalisation argue that drug criminalisation has failed, whereas decriminalisation would be more prudent as it would prevent criminal drug trafficking, and increase the safety of drugs - reducing the harmful effects. Analysis of both arguments, as well as comparative studies for this purpose conducted in Portugal where drugs have been decriminalised since 2001 show that the nature of this issue is complex, with many factors influencing drug abuse and its consequences. Chiefly it was found that for decriminalisation to work, it must be combined with a change

in culture, and increased investment into the treatment of drug addicts.

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Abstract

In the summer of 2015 ‘The Guardian’ published an article describing an ‘ecstasy epidemic’ with levels of ecstasy usage in the UK increasing in the previous two years, exceeding record levels in 2003 due to the revival of the student rave scene. The article poses the question of how the UK is supposed to deal with such an issue, especially alongside a growing number of young people choosing to experiment with new psychoactive substances such as legal highs. As an example, popular Manchester student rave The Warehouse Project is mentioned. One way the managers at The Warehouse Project are ensuring the safety of party goers is by inviting Criminology Professor Measham

The mainstream British media often represents drugs as “evil”, with newspapers such as ‘The Sun’ producing headlines like "Evil Ecstasy Pushers Cash in on Leah’s Death” (Murji, 1998). In ‘The Newsatesman & Society’ Platt explores how this may cause more harm than good. Platt speaks of the ‘media hysteria’ following the death of Leah Betts, when newspapers were filled with clichés of drugs ruining young lives, personal tragedy, and the desire of her parents to use Leah’s death to dissuade others from trying the drug. Yet estimated sales of Ecstasy increased after the death of Leah Betts (Platt, 1995). In addition to this, newspapers such as ‘The Daily Mail’ and ‘The Daily Mirror’ pursued a clubber’s magazine ‘Eternity’ for listing the different types of pills available and their potency, even though this would have allowed users to be more informed, and less likely to take

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The UK and Drugs

to set-up an on-site drug testing facility so that young people are able to know the potency of their pills (Daly, 2015). This reflects a problem almost paradoxical in nature: despite the illegality of drugs their use persists, meaning that some venues are choosing more novel methods to limit the amount of harm to society. However, the use of illicit drugs is still seen as a large and relevant issue, on the 12th of December 2016 ‘Manchester Evening News’ reported the tragic death of a 19-year-old girl, whom had been attending a rave at The Warehouse Project. In 2006 YouGov conducted what is arguably the most comprehensive survey on British attitudes towards drugs (Johnson, 2006). The findings showed that the majority of Britons deplored the use of hard drugs such as heroin, or cocaine - yet most acknowledged that drug use is a persistent part of life, and that the idea of a drug free society is fantasy (Johnson, 2006).

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Professor Nutt is not alone, many academics and high profile members of society have since stated that UK law around drugs needs to change. This includes entrepreneur Richard Branson, who recently claimed that the UN policy on drug legislation is set to change in favour of decriminalisation (Withnall, 2015). The decriminalisation of drugs is not a totally new concept; in-fact many countries including Portugal, the Netherlands, Mexico, and Argentina have begun to take a more liberal approach to the possession and use of drugs. Meanwhile in the UK, drug use is perceived as a big problem. Home Office statistics show that in England and Wales from 2014 to 2015 around 8.8% of 16-59 year olds had taken a Class A drug within the past year. This figure increases to 19.4% in young adults (Office for National Statistics, 2015). In this review, I intend to explore the relationship between the UK and class A drugs, asking what the real cost to society is, if they are harmful, and whether decriminalisation would be an effective, or even plausible solution.

Current UK drug legislation stems from the 1961 UN Single Convention. Most illegal drugs in the UK are prohibited under the 1971 Misuse of Drugs Act. This Act classifies drugs upon their perceived harm to society: Class A being the most harmful, and Class C the least (Bean, 2010). This change in law reflects the tightening approach to drug issues as their use increased, with a change in social attitudes so that drug habits were no longer perceived as a chronic illness

Are Drugs Harmful? Given that drugs are classified by the risk that they impose upon the user, it is necessary to assess how harmful drugs are to the users, and society. Professor Henry, coroner of the inquest into the death of Leah Betts has since found that the cause of death was hyponatraemia (Henry, 2001). Ecstasy causes a rise in levels of anti-diuretic hormone, causing an increase in water retention. This coupled with increased water intake due to feeling hot whilst dancing can lead to fatal levels of water in the body. This highlights limitations in the assessment of the harm that drugs cause: should we assess drugs by what they do to us, or by what they make us do? Many experts are quick to highlight the differences between drug misuse and addiction when discussing this issue. Drug misuse is where a drug which may have originally been intended for medicinal or research purposes is instead used recreationally (National

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Drug use and legislation in the UK has a long history. English physician John Jones recorded possible treatments for opium dependency in 1700, with medical literature on morphine dating back to 1864, and Cocaine 1886 (Pierce, 1969). Yet for the latter part of the of the 19th century the use of narcotics were common place, and seen as harmless. Some estimating up to 4% of the population of North America and Europe had a narcotics addiction (Pierce, 1969). With the drugs issue growing, the UK passed its first drugs law after the 1912 Hague International Opium Convention, The Dangerous Drugs Act (1920) which prohibited the manufacture, importation, sale and possession of nonprescription narcotics. Yet the Act did allow the prescription of narcotics to treat addicts (Pierce, 1969). This was successful, with the number of addicts known to the Home Office falling to under 400 by 1955 (Pierce, 1969). This highlights how drug misuse is not a new problem, demonstrating how a seemingly liberal approach compared to today’s standards managed to successfully reduce drug related harm to society.

but instead a criminal activity (Lart, 2008). On the 6th of April England and Wales began to enforce a new law: The Psychoactive Substances Act, outlawing substances previously considered ‘legalhighs’ (Drug Wise, 2016). This has been surrounded by much controversy with many people claiming that this will cause more harm than good, by criminalising drug addicts and forcing them to seek drugs from dealers rather than manufacturers (Wilson, 2016). In-fact, on the 10th of March 2017 ‘The Mail Online’ published photos of men and women on popular legal-high drug ‘Spice’, which the newspaper claimed turns people into “zombies” (Malone, 2017). Alongside shocking images of a Wrexham busdriver sleeping in a flower-pot, are the claims that the North-west of England is under a “spice epidemic” (Malone, 2017).

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risks (Platt, 1995). Could it be that the illegal nature of drugs is what attracts new users? And would decriminalisation help lead to a more balanced and better informed public when it comes to the issue of drugs?

Cocaine works by blocking sodium ion influx into neurones producing an anaesthetic effect by preventing the propagation of action potentials. Cocaine also then stimulates the CNS by altering synaptic transmission within the noradrenergic, dopaminergic, serotoninergic, and cholinergic systems. Blocking reuptake of noradrenaline and dopamine increases their availability of synapses, stimulating the sympathetic nervous system. Pathophysiologically this can cause an acute rise in arterial pressure, tachycardia, and a predisposition to ventricular arrhythmias, seizures, mydriasis, hyperglycaemia, and hyperthermia (Agarwal, 2015). The potentially harmful effects of cocaine are therefore well known. It is estimated that 2.3% of adults in England and Wales (and 4.8% of young adults) use cocaine each year (Office for National Statistics, 2015). Yet cocaine accounted for only 247 drug related deaths in the England and Wales in 2014 (Office for National Statistics, 2015). Some may argue that although the risk to users of cocaine is indisputable, the dangers of the drug are exaggerated in public perception, given that alcohol related deaths in the UK in 2014 reached 8,697 (Office for National Statistics, 2016). Heroin is an opioid originally derived from poppy seeds. Once in the brain heroin is converted to morphine, binding rapidly to Îź-opioid receptors. These are activated in the dopaminergic system producing a sensation of pleasure. Yet the rush that heroin users experience depends upon the rapidity of heroin delivery (National Institute on Drug Abuse, 2014). This is accompanied by a flushing of the skin, drying of the

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Drug addiction is a complex process caused by underlying neurological changes that occur in the body as an adaptation to exposure to the drug. Cellular and subcellular research has identified specific receptors which are overexpressed upon exposure to certain drugs, causing profound changes to the nervous system associated with dependency (Gupta & Kulhara, 2007). The overexpression of receptors causes the issue of tolerance, where drug users begin to show addict behaviour as they require more of the drug to experience the same level of psychoactive effects. Dependence is then caused as withdrawal is experienced upon drug cessation, with physical and psychological disturbances being experienced by the user (Nestler, 1992). Although many researchers make a point to differentiate between physical and psychological dependence, both are based upon neural mechanisms. It is both the tolerance, and dependence on a drug that produce the phenotype of addictive behaviour in a drug user (Nestler, 1992).

Knowing the mechanisms which form drug addiction allows the possibility of novel therapies.

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Institute on Drug Abuse, 2016). Addiction occurs when some drugs cause the user to develop a dependency, and the user requires the drug else they will experience withdrawal (National Institute on Drug Abuse, 2016). This physical dependence can be produced by many drugs both legal and illegal, such as: heroin, cocaine, and many medically used pain-killers and psychiatric drug therapies. Drug addiction can also occur socially as opposed to biologically, with the user taking the drug to the extent where their family, work, social, and personal lives are compromised (National Institute on Drug Abuse, 2012). It is argued that many of the negative costs to society commonly associated with drug abuse are due to drug addiction, yet not all drug users are addicts.

From this it is obvious to most people that drugs such as heroin and cocaine have the potential to cause harm in our society. Yet on the contrary some academics argue that some of these banned substances also have the potential to benefit our society when used correctly. Morphine derived from opiates has long been used in hospitals as an analgesic effective even in the most severe cases, as well as a local and general anaesthetic. Other opioids are also used relieve severe coughs and diarrhoea (Mandal, 2013). MDMA (used in Ecstasy) has the potential for use in treatment of psychiatric disorders such as treatment-resistant post-traumatic disorder (Sessa & Nutt, 2015). Cocaine in the UK has limited uses, yet is still used

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According to the National Treatment Agency for Substance Misuse, heroin and crack (a form of cocaine) are the most problematic drugs in our society, yet there are only around 300,000 problem-

users (National Treatment Agency for Substance Misuse , 2012). A report from the British Medical Association recently estimated that problem users only form around 10% of the total of drug users. The report also highlighted the alarming increase in drug related deaths in the UK of 67.5% between 1996 and 2010 (BMA Board of Science, 2013). A 2000 Home Office Research Report differentiated between different types of user, including young recreational, older regular, and problem users. Costs are hard to estimate yet include costs related to: crime, policing, GPs, Accident and Emergency, hospital days, mental health services, state benefits, police custody, court appearances and prison. It was estimated that young recreational users cost the economy £6 million with social costs of £28.8 million, older regular users cost the economy around £6.2 million per year. The cost to society of problem users varied in estimates between £2.9 billion and £5.3 billion (Godfrey, et al., 2000). Surprisingly however, a recent analysis published in The Lancet has claimed that alcohol is the costliest drug to UK society (Nutt, et al., 2010).

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mouth, heavy feeling in the extremities, and possibly nausea and vomiting. After these effects of the initial rush comes a period of drowsiness that lasts several hours, this can be accompanied by bradycardia and a decrease in breathing rate as opioids begin to act on the brainstem. These effects can be severe, endangering life and possibly leading to coma or brain damage (National Institute on Drug Abuse, 2014). Long term Heroin usage has been linked to the collapse of blood vessels, infections of the heart lining and valves, abscesses, liver disease, and pulmonary complications such as pneumonia. There is also a significant risk of the contraction of blood-borne infections such as HIV, and Hepatitis B and C in intravenous users (National Institute on Drug Abuse, 2014). Another risk is of overdose following heroin use; an Australian study found that 54% of regular heroin users reporting that they had experienced a non-fatal overdose in their lifetime, with effects such as: slow and shallow breathing, convulsions, pin-point pupils, confusion, and possibly coma and death (Center for Substance Abuse Research , 2013). Heroin is highly addictive, with tolerance developing quickly and easily. This causes many of the social problems linked to heroin, such as users often turning to crime to fund their habit. One police chief claiming that each heroin user costs UK society £850,000 (The Telegraph, 2011). However, recently heroin prices have fallen to a near alltime low, leading to a higher rate of abuse amongst the working classes who may previously have had only a limited access to the drug (Townsend, et al., 2006).

The main argument that drug criminalisation advocates use is that the legalisation, or decriminalisation of drugs would advocate drug use - leading to an increase in abuse rates and social costs associated with drugs. In a 1996 letter to the British Medical Journal Voth argues that decriminalisation decreasing usage is a common misconception - the illegality of cannabis is the reason that it is used less than alcohol and tobacco. Voth gives the example of The Netherlands where more liberal laws lead to an increase in cannabis usage by 277% in 18-24-yearold males between 1984 and 1992, with shootings, car thefts, and robberies increasing by 40%, 62%, and 69% respectively (Voth, 1996). Brett also highlighted that strong drug campaigns which are well supported by the population such as the 1979 Just Say No campaign in the United States do work, with surveys at the time finding that 70% of U.S. teenagers abstained from cannabis usage due to fears of physical or psychological damage, 60% because of parental disapproval, and 40% because of the law (Brett, 2007). Yet how successful has criminalisation been in the first place? It is obvious that

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Drug Criminalisation: Has it worked?

there are still drug issues in the UK A 2007 analysis of UK drug policy (Reuter & Stevens, 2007) showed that drug use in the UK increased sharply in the late 20th century, giving the UK the highest rates of drug abuse and dependency in Europe -25% of people born between 1976 and 1980 had tried a Class A drug by 2005. The levels of drug abuse then stabilised into the beginning of the 21st century. Since the late 1990s when drug abuse rates were at their highest, UK legislation has focussed on severe sentences for drug dealers, as well as programs aimed at reducing the harmful effect of drugs. Between 1994 and 2005 the annual number of persons imprisoned for drug trafficking increased by 111%, and the average sentence length increased by 29%. The 2007 report summarised that the majority of government funds are spent on the enforcing of drug laws as opposed to the treatment of addicts, but argued that drug legislation most likely has little effect on the rates of use. Yet the report did show how improved treatment strategies such as rehabilitation clinics, and needle exchange programs had proved successful in integrating drug addicts back into society, and reducing rates of blood-borne infections. The UK now has one of the lowest HIV rates amongst heroin addicts in Europe. The number of criminal offences associated with drugs also showed a decline (Reuter & Stevens, 2007). From this, one could instead argue that it is not the criminalisation of drugs that has been effective, but rather programs aimed at rehabilitating and treating offenders. Similarly, another study claimed that there were no benefits to the increasingly severe punishments given to drug dealers, many prison terms match those given for offences such as rape and homicide. But the paper also stated that the decriminalisation of drugs would be

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medically in mouthwash to treat ulcers and sores in chemotherapy patients, as well as limited surgical uses such as in nose or eye surgery. But usually cocaine derivatives with less side-effects are preferred (Drug Science: Independent Scientific Committee on Drugs, 2013). This shows how some illegal drugs do have the potential to benefit society when used correctly. This poses a strong argument for governments to re-evaluate their assessment of drugs previously thought to only cause harm.

Contrasting to these views, political scientist Keating wrote in a 1997 edition of ‘The World Today’ that although more liberal drug laws run the risk of increasing use, they would most likely reduce the amount of harm that drug abuse inflicts upon our society. Keating discusses how the true effect of drugs in our society is hard to measure, yet the drug trade is inevitably a large part of the economy; legalising the drugs trade would enable for tighter regulation in the

The Decriminalisation Drugs

When talking of subsequent changes to drug law it is important to differentiate between the decriminalisation, and legalisation. Decriminalisation is when users may possess small amounts of substance without facing punishment. In many countries that have decriminalised drugs their use is still illegal (although not often enforced), and suppliers still face custodial sentences. Recently, ‘The Economist’ has argued that only the legalisation of drugs could fully benefit society (The Economist, 2014). In countries that have already decriminalised drugs, such as Portugal, the drugs are still supplied by the same criminals who carry out atrocities in Columbia – legalisation would allow better regulation and control to prevent this (The Economist, 2014). Further to this, a 1978 study of American legal professionals found that many legal professionals, especially those involved in drug related cases such as prosecutors, took the view that drug laws at the time were too strict - posing un-necessary strain on the legal system (Miller, et al., 1978). In 2009 both Argentinian and Columbian Supreme Courts voted to

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This view is not just from experts, a 1998 study on 245 regular opiate users found that the majority felt that the decriminalisation of drugs would have no effect upon their drug habits (Ahmed & Salib, 1998). Studies such as this warn us that the decriminalisation of drugs may not be effective at reducing the harm caused to society from drug use. On the 19th of June, 2001, Channel 4 broadcast a program entitled ‘Drug Laws Don’t Work: The Phoney War’. This program looked at the horrifying human cost of the so-called war on drugs, mainly those who have suffered ill effects due to drugs such as heroin cut with dangerous substances such as drain cleaner. This program was reviewed in ‘The British Medical Journal’, with psychiatrist Drummond stating that this was not a good enough reason to legalise drugs. Drummond acknowledged that a drug strategy focussed upon treatment would be better, yet stated that legalisation would increase the amount of drugs that are available in the UK (Drummond, 2001).

quality of drugs and prevent the exploitation of workers. Keating also criticised how ‘the war on drugs’ focuses on developing countries such as Afghanistan with aggressive foreign policy. It is hypocritical that nations such as the UK sanction other nations for producing drugs such as cannabis that is traditional in their culture, whilst selling these nations drugs traditional in our culture yet arguably just as harmful, such as alcohol (Keating, 1997). This highlights the question of whether our drug policy should aim to reduce drug use, or the harm done by drugs.

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paradoxical as drug dealers would still be prosecuted even when the drug that they are selling is legal. The paper concluded by stating that there was no binding argument in favour of decriminalisation, yet did recommend that sentence lengths for offenders should be reduced (Bagaric, et al., 2015).

One reason that critics are so tentative about drug decriminalisation is the unpredictability of the consequences â&#x20AC;&#x201C; no one wants to accidentally worsen the UK drug situation. Yet many countries in Europe and South America have already begun to decriminalise drugs, allowing us to use them as a model to predict what decriminalisation would look like in the UK. Portugal became one of the first countries to reform its drug laws in 2001 after historically high levels of heroin abuse in the late 1990s (Hawkes, 2011). A 2010 review of 13 studies which took place between 2007 and 2009 found that there were reductions in the problematic use of drugs, drug-related harms, and criminal over-crowding of the justice system (Hughes & Stevens, 2010). Furthermore, a 2011 study found that decriminalisation did not lead to a mass of drug tourism as was originally feared,

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Some medical experts also argue that the decriminalisation of drugs would be the best way to reduce the harm they do to society. In a 2007 article to The British Medical Journal Chand makes the argument that the decriminalisation of drugs would help Britain move to a more treatment based approach for drug addicts. It is also argued that criminalisation has not worked as Britain clearly still has a drug problem, and that criminalisation is problematic as it means that addicts turn to criminals for supply; the decriminalisation of drugs would allow them to be produced cheaply and safely limiting the financial burden on addicts, taxation could also then help cover the cost of education and treatment programs, and money would be saved due less prosecution of drug offenders (Chand, 2007). Califano disputed this by stating that decriminalisation would increase the available supply of drugs, leading to increased use of substances we know are harmful. The example is used of the change to UK pub licencing laws in 2005, which led to a surge in violent crime between 3am and 6am. This contrasts with Sweden, where increased enforcement of existing drug laws has led to drug usage rates falling to a third of the European average (Califano, 2007). However, Califano has since been criticised for omitting certain facts, such as the Swedish use of clinics where drugs can be safely administered: a novel yet successful approach now being introduced in Canada, Australia, and other parts of Europe (Rolles, 2007).

One argument that has already been raised is the possible economic benefits of drug decriminalisation, yet what would these benefits look like in the UK? A 2001 Economic Affairs article analysed economic policies. It found that the cost of narcotics criminalisation far exceeds public perception; whereas estimates for the economic effects of decriminalisation found that even when the spread of drug addiction and possible increases in crime are accounted for, there would be many economic benefits for the UK (Mishan, 2001). In addition to this, a 2014 Canadian report stated that using public health instead of criminal justice to address the drug problem would cause a decrease in the spread of disease, and argued that addressing the issues that cause drug abuse would be a better way of tackling the issue (Vogel, 2014). These findings were confirmed by an American report which called for a better partnership between medical and legal professionals (Strathdee, et al., 2014).

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allow the possession of small amounts of drugs for personal use, reflecting a growing backlash in South America on the U.S. led â&#x20AC;&#x2DC;war on drugsâ&#x20AC;&#x2122; (Cozac, 2009). This highlights some of the issues that many legal professionals have with criminalisation.

However, one criticism of the Portuguese reform from Pinto is that addicts are more compelled to not give up drugs such as heroin as they are already so freely available. Following this, decriminalisation has not reduced drug harm or abuse levels in every country. In 2009 Mexico reformed its drug laws allowing the possession of a small amount of narcotics for personal use, and created a drugs treatment program for repeat offenders. This movement toward an empirical evidence-based treatment based approach was praised at the time (Mackey, et al., 2014). Yet one year later a study into the effectiveness of this scheme found that it was failing due to a lack of investment and resources. Participants had a mixed view on the effectiveness of the program, and 21.6% reported abuse from staff, mainly physical (Syvertsen, et al., 2010). Therefore, drug treatment programs must be well resourced and managed before a country such as the UK consider a move such as decriminalisation, else there may be negative consequences. In his 2011 review of the effects of Portuguese drug policy Hawkes argued that decriminalisation alone has little or no effect on the levels of drug abuse. Instead, Hawkes argues that other changes in the way the Portugal treats drug addicts were more likely to contribute to the reduced levels of drug abuse and crime. These include a change in social attitudes around drugs so that the user is seen as a person who is ill, not

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The effects of Portuguese drug reform have proved hard to study. One such problem is that there is little literature on the Portuguese drug situation before the changes in law. Many studies also publish conflicting results. A 2012 review highlighted this by looking at two reports: Greenwald who reported that decriminalisation was a resounding success, and Pinto who claimed that decriminalisation was a failure. Greenwald had stated that deaths amongst drug users fell from 76 to 20 between 2001 and 2008; drug use rates were lower than anywhere else in Europe, North America, and Australasia; and that drug use amongst the young had also decreased. Pinto stated that drug use in the young had sky-rocketed, that Portugal had the highest rates of heroin dependency in Europe; and that drug related deaths had increased by 45% between 2006 and 2007. This is because many studies into this area are subject to researcher bias, especially as they are often funded by bodies campaigning either for drug criminalisation, or decriminalisation. For example, Pinto happens to be the president of The Association for a Drug Free Portugal. When measuring deaths, Greenwald classified a drug related death as a person whom had drugs named as a cause of death on their death certificate; whereas Pinto classified a drug related

death as a person who tested positive for drugs post-mortem, (Hughes & Stevens, 2012). It has been said that this could be an artefact due to increased testing for dugs post-mortem (Hawkes, 2011). Despite conflicting reports the majority of peer reviewed literature tends to show an overall reduction in drug use and its associated problems (Hawkes, 2011).

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HIV infections amongst intravenous users also plummeted from 1600 in 1998 to 200 by 2009. Overall heroin use fell sharply, yet this was matched by an increase in cannabis use, and a small increase in cocaine usage. It was also found that lifetime drug use amongst 16 to 18 year olds fell by 8%, and the number of addicts seeking treatment increased. However, the report did point out that some of these effects have been seen in England, so may not be down to Portuguese legislation (Hawkes, 2011).

Drug misuse is a complex issue, it is hard to measure the exact scale or nature of the UKâ&#x20AC;&#x2122;s relationship with drugs. But it is likely that drugs will always be a part of our society. For the past 100-years the western world has seen increasingly tight laws aimed at reducing the harmful effect of drugs. But, given that drugs have only became more prevalent it seems evident that the war on drugs has failed. As many countries move to a more treatment based approach we are now finally beginning to alleviate some of the drug related problems that have been present particularly in the past 50 years. Criminalisation advocates argue that by limiting the availability of drugs, we can then limit their effect. On the contrary more liberal views state that this policy has not succeeded in the past, nor will it do so in the future. Advocates of decriminalisation hope for a more controlled and safe drug market that focuses on the treatment of the user, rather than their punishment. The

So, where has the UK come from the death of Leah Betts in 1995? Arguably not very far, despite the stabilisation of drug abuse levels, drug laws in England and Wales have recently became stricter regardless of opposition. The media portrayal of drugs also continues to lack information and accuracy. Given this, and the fact that the UK is bound by the UN Single Convention, drug decriminalisation in the UK is unlikely. In my opinion the decriminalisation of drugs would be the most rational approach - coupled with a better treatment program for problem users, and regulations on the administration and production of drugs. This would enable the UK to catch-up with many other European countries in its approach to drug abuse. But the question of whether the UK should decriminalise drugs reflects UK society as a whole: do we want to be a society which treats people with a dependency like criminals? A society that ignores evidence and advice from bodies such as medical professionals, scientists, and committees when making our laws? Ultimately the decision over drug legislation lies with politicians and the public whom elect them, but if the public is not yet ready to take a more evidence-based, albeit radical approach to drug abuse, let us atleast open-up the topic to debate.

Bibliography Agarwal, P., 2015. Neurologic Effects of Cocaine. [Online] Available at: http://emedicine.medscape.com/article/11744 08-overview#showall [Accessed 4 February 2016].

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Conclusion

success of decriminalisation in other countries has been hard to measure and is subject to controversy. Aside from this, some experts have now begun to take the view that legislation only has a limited effect on drug use at all.

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a criminal; improved healthcare services, and educational campaigns; and programs such as needle exchanges and heroin clinics (Hawkes, 2011). This complements views from the aforementioned studies, where law was seen to have little impact on drug habits in the community. As well as the findings that in Mexico poorly planned drug schemes were failing. Further to this, McAloon outlined in a letter to â&#x20AC;&#x2DC;The British Medical Journalâ&#x20AC;&#x2122; how according to the National Treatment Agency spending on drug treatment programs have increased in recent years, yet the number of addicts known to the Home Office have stayed at similar levels. McAloon suggests how as a nation the UK must improve services for drug addicts, as legalisation alone is not enough (McAloon, 2007).

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Drug Science: Independent Scientific Committee on Drugs, 2013. Drugs Info: Cocaine. [Online] Available at: http://www.drugscience.org.uk/drugsinfo/cocaine/ [Accessed 28 February 2016]. Drug Wise, 2016. What Are the UK Drug Laws?. [Online] Available at: http://www.drugwise.org.uk/what-are-theuk-drug-laws/ [Accessed 1 March 2016]. Drummond, C., 2001. Reviewed Work: Drug Laws Don't Work: The Phoney War [Tv]. British Medical Journal, 23 June, 332(7301), p. 1551. Godfrey, C., Eaton, G., McDougall, C. & Culyer, A., 2000. The Economic and Social Costs of Class A Drug Use in England and Wales, 2000, London: Home Office. Gupta, S. & Kulhara, P., 2007. Cellular and molecular mechanisms of drug dependence: An overview and update. Indian Journal of Psychiatry, April, 2(49), pp. 85-90. Hawkes, N., 2011. Highs and Lows of Drug Decriminalisation. The British Medical Journal, 26 October.343(6881). Henry, J., 2001. More evidence of Ecstasy risks. [Online] Available at: https://www.imperial.ac.uk/college.asp?P=28 47 [Accessed 26 January 2016]. Hope, C., 2009. Ecstasy 'no more dangerous than horse riding'. [Online] Available at: http://www.telegraph.co.uk/news/uknews/la w-and-order/4537874/Ecstasy-no-moredangerous-than-horse-riding.html [Accessed 30 January 2016]. Hughes, C. E. & Stevens, A., 2010. What Can We Learn From the Portuguese Decriminalisation of Illicit Drugs?. British Journal of Criminology, November, 50(6), pp. 999-1022. Hughes, C. E. & Stevens, A., 2012. A Resounding success or a Disastrous Failure: Re-examining the Interpretation of Evidence

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Bagaric, M., Hepburn, S. J. & Xynas, L., 2015. The Senseless War: The Senseless Drug Offenses Arms Race, Burwood: Oregon Review of International Law.

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Mackey, T. K. et al., 2014. Mexico’s “ley de narcomenudeo” Drug Policy Reform and the International Drug Control Regime. Harm Reduction Journal, 3 November.11(31). Malone, A., 2017. Rise of the zombies: Cheaper and more addictive than crack, Spice is the synthetic drug that turns users into the 'living dead' in minutes and is ruining lives across Britain. [Online] Available at: http://www.dailymail.co.uk/news/article4302806/Spice-synthetic-drug-turns-usersliving-dead.html [Accessed 15 March 2017]. Mandal, A., 2013. Morphine Uses. [Online] Available at: http://www.newsmedical.net/health/Morphine-Uses.aspx [Accessed 17 February 2016]. McAloon, C., 2007. Look Beyond Legalisation. The British Medical Journal, 22 November.335(1061). Miller, E. T., Schmidt, W. & Miller, K. S., 1978. Decriminalizing Drugs: Variations in Endorsement within Professional Roles. Contemporary Drug Problems, 7(2), pp. 181192. Mishan, E. J., 2001. The Staggering Costs of Drug Criminalisation. Economic Affairs, March, 21(1), pp. 37-42. Murji, K., 1998. The Agony and the Ecstasy: Drugs, Media, and Morality. In: R. Coomber, ed. The Control of Drugs and drug Users: Reason or Reaction?. Amsterdam(Holland): Harwood Academic Publishers OPA (Overseas Publisher Association), pp. 69-85. National Institute on Drug Abuse, 2012. Principles of Drug Addiction Treatment: A Research-Based Guide. [Online] Available at: https://www.drugabuse.gov/publications/prin ciples-drug-addiction-treatment-researchbased-guide-third-edition/frequently-asked-

National Institute on Drug Abuse, 2016. The Science of Drug Abuse and Addiction: The Basics. [Online] Available at: https://www.drugabuse.gov/publications/med ia-guide/science-drug-abuse-addiction-basics [Accessed 15 March 2017]. National Treatment Agency for Substance Misuse , 2012. Drug Treatment 2012: The Progress Made, Challenges Ahead, London: The National Treatment Agency for Substance Misuse. Nestler, E. J., 1992. Molecular Mechanisms of Drug Addiction. The Journal of Neuroscience, July, 7(12), pp. 2439-2450. Nutt, D., 2012. Hypothesising an alternative: Applying the scientific process to drug policy. [Online] Available at: https://profdavidnutt.wordpress.com/ [Accessed 30 January 2016]. Nutt, D. J., King, A. L. & Philips, L. D., 2010. Drug harms in the UK: a multicriteria decision analysis. The Lancet, November, 376(9752), pp. 1558-1565. Office for National Statistics, 2015. Deaths Related to Drug Poisoning in England and Wales: 2014 , London: HM Government. Office for National Statistics, 2015. Drug Misuse: Findings from the 2014/2015 Crime Survey for England and Wales, London: Home Office . Office for National Statistics, 2016. Alcohol Related Deaths in the United Kingdom: Registered in 2014, London: HM Government . Office for National Statistics, 2016. Statistics on Drugs Misuse: England, 2016 [NS]. [Online] Available at: http://content.digital.nhs.uk/catalogue/PUB2 1159 [Accessed 13 March 2017].

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Pierce, J., 1969. Delinquency and Heroin Addiction in Britain. The British Journal of Criminology, April, 9(2), pp. 108-124. Platt, S., 1995. Moral Panic. New Statesman & Society, 11 November, 8(380), p. 14. Reuter, P. & Stevens, A., 2007. An Analysis of UK Drug Policy, London: UK Drug Policy Commission. Rolles, S. A., 2007. Prohibition is an Ideologicallgy Driven Failure. The British Medical Journal, 22 November.335(1060). Sessa, B. & Nutt, D., 2015. Making a medicine out of MDMA. The British Journal of Psychiatry, January, 1(206), pp. 4-6. Strathdee, S. A., Beletsky, L. & Kerr, T., 2014. HIV, Drugs, and the Legal Environment. International Journal of Drug Policy, 16 September, 26(1), pp. 27-32. Syvertsen, J. et al., 2010. Managing la malilla: Exploring Drug Treatment Experiences Among Injection Drug Users in Tijuana, Mexico, and Their Implications for Drug Law Reform. International Journal of Drug Policy, November, 21(6), pp. 459-465. The Economist, 2014. Title The Difference Between legalisation and Decriminalisation: The Economist Explains. The Ecomomist (online), 18 June.

Townsend, M., Asthana, A. & Campbell, D., 2006. Heroin UK. [Online] Available at: http://www.theguardian.com/society/2006/de c/24/drugsandalcohol.drugs [Accessed 1 March 2016]. Vogel, L., 2014. Decriminalize Drugs and Use Public Health. CMAJ, 8 July, 186(10), p. 356. Voth, E., 1996. Legalisation Would Be Likely To Result in Increased Use. British Medical Journal, 312(636). Wilson, C., 2016. Youâ&#x20AC;&#x2122;re not hallucinating, MPs really did pass crazy bad drug law. [Online] Available at: https://www.newscientist.com/article/207481 3-youre-not-hallucinating-mps-really-didpass-crazy-bad-drug-law/ [Accessed 6 March 2016]. Withnall, A., 2015. UN to call on governments around the world to decriminalise all drugs, says Richard Branson. [Online] Available at: http://www.independent.co.uk/news/uk/home -news/un-to-call-on-governments-aroundthe-world-to-decriminalise-all-drugs-saysrichard-branson-a6699851.html [Accessed 31 January 2016].

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each-police-warn.html [Accessed 28 February 2016].

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Colour changes due to interference at the wings of blue Rhopalocera Alice de Sampaio Kalkuhl (alice.desampaiokalkuhl@student.manchester.ac.uk) Faculty of Biology, Medicine and Health, The University of Manchester, U.K.

Abstract When observing a Rhopalocera moving one might see slight colour changes. This work explains a mathematical model for iridescence to show that the colour change is due to interference of light at the wings and not due to the perception of the observer.

where th wave vector k is defined as: (3)

2π 2d

In these cases the incidence angle leads to cos(θ)≈ 1 because it is very small.

Introduction Rhopalocera have diverse species out of which many have colourful wings. The structure of the scales in these wings allows for several interferences to happen when light is reflected from the wings. Some of these interferences are observable and result in an impression of colour change.

Model of the conditions for constructive interference For the model we can assume that the scales on the wings of the Rhopalocera resemble the steps of a staircase. The height of such a “step” is d (Barder 2010). For a constructive interference of light hitting the wing of the Rhopalocera the phase difference Δφ between two rays must be equal to 2π and the light must cover a distance of 2d.

(2) λ = 2dcos(θ)

This condition cannot be fulfilled by light of other significantly different colours. This is because there are so many scales

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which is related to the wavelength λ in

Figure 1: Path of light in regard of the angle θ.

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(1) Δ ϕ= 2kd= 2 π

on the Rhopalocera wing that most of the waves are deconstructed. Yet the light that is reflected is not monochromatic because there is a finite number of scales. When a Rhopalocera flaps its wings the light no longer hits it perpendicular and the distance that it has to cover is d 1+ d 2 as it has to cover d on its way 1

there and d2 on its way back. Following a variation of Bragg's law as shown in figure 1 for cos(θ) can no longer be assumed to be approximately 1 (Bragg & Bragg 1913). The slight change results in a different colour to be seen by and observer of the Rhopalocera. Therefore even an immobile observer will see the colour changes when the Rhopalocera flaps its wings.

Example

therefore the colour change is visible (Geissler 1991).

Discussion The model shows that colour variations during the movement of Rhopalocera wings is not due to the perception of the Rhopalocera but due to interferences caused by the form and the arrangement of the scales. One additional condition for the observation of the colour change is that the Rhopalocera either flaps its wings with a low frequency or rests them in a position. There the the colour change is not evident, because the Homo sapiens eye is limited in its ability to distinguish colours and therefore can not detect any change. Therefore, some Rhopalocera might appear monochromatic even though they are not.

Acknowledgements

Figure 2: The same Ropalocera photographed from an angle of θ≈30° on the left and θ≈0° on the right.

Bibliography Bader, F. (2010) Physik SII (General Edition) Dorn/Bader p. 211 Bragg, W.H. & Bragg, W.L. (1913) The reflection of X-rays by Crystals available at http://rspa.royalsocietypublishing.org/conten t/royprsa/88/605/428.full.pdf Geissler, T. (1991) Scriptenreihe Technik Grundstudium Physik Theorie und Aufgaben (2nd Edition) Verlag Shake

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The size d of a step is 220nm. In this case indigo (λ ≈ 440nm) is the colour that is reflected via a constructive interference. Now if the Ropalocera flaps its wings in a way that θ is 30° the wavelength λ will be approximately 413nm because of (4). Light of such a wavelength is violet and

I would like to thank Dr. Judith McGovern, Simon Schröder, Ben Craven, Meirin Evans and Kalis Ravel for their help, their time and their constructive critique.

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The split-brain studies and what they unveiled about the brain and the mind Elena Gutierrez (elena.gutierrez@student.manchester.ac.uk) Faculty of Biology, Medicine and Health, The University of Manchester, U.K.

The First Split-Brain Studies Despite the first callosotomies being pursued in the 1940s by van Wagenen and Herren, in an attempt to treat extreme cases of epilepsy (van Wagenen and Herren, 1940), it wasn’t until thirty years later that what is now known as modern split-brain research started (Gazzaniga et al., 1962, reviewed in Gazzaniga, 2005). Owing to the efforts of Joseph Bogen (Bogen and Gazzaniga, 1965) and to Roger Sperry’s studies of split-brain animals (Myers and Sperry, 1958), it was possible to develop more thorough approaches to the assessment of hemispheric function. Moreover, they gathered evidence in support of the hypothesis that severing the callosum led to significant impairment of the

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The cerebral cortex of the human brain, and that of other vertebrates, could be described as a ‘double organ’, formed by two hemispheres capable of functioning independently from one another if surgically disconnected (Gazzaniga, 1967). High connectivity between the two halves is ensured by the corpus callosum, a bundle consisting of 200 to 800 million axon fibres. The nerve fibres coordinate sensory-motor areas and, mainly, association areas (Bloom and Hind, 2005); furthermore, they balance excitation and inhibition between the two hemispheres (Yazgan et al., 1995). Being the largest white matter structure in the brain, the callosum allowed for the high level of specialisation of the human brain by ensuring powerful and fast transmission of information between the hemispheres (Gazzaniga, 2000). Its surgical section, and the seemingly tragic loss of interhemispheric communication, is at the basis of the ‘split-brain’ studies, and it has provided us with great insight into crucial aspects of the brain and the mind. In fact, the disruption of the callosum allowed to test the two hemispheres separately and to establish their different specialisations. The splitbrain studies showed how the fundamental asymmetry of the left and right hemispheres reflects on the most diverse neural processes, encompassing language, memory and the interpretation

of reality. Split-brain patients provided evidence of the hemispherical verbal dominance, while challenging models of ‘memory encoding’ which assigned the ability to record information perceived through the senses (‘encoding’) to one specific hemisphere, and the ability to recall a piece of information from the past (‘retrieval’) to the other hemisphere (Tulving et al., 1994). Moreover, the two halves of the brain performing tasks unknowingly of and with no input from one another highlighted how differently they perceive reality and, most strikingly, how one of them manipulates it.

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Introduction

The Left-Right Asymmetry

The Consequences of Asymmetry on Memory

One of the most peculiar characteristics observed in split-brain patients was that, despite the drastic procedure they underwent, this seemed to have had little effect on their normal cognition and sense of self (Gazzaniga, 1970). Nevertheless, the apparent absence of dramatic deficits in their mental abilities only provided the researchers with further proof that the study of such subjects would have been a reliable way to understand the lateralization of the human brain (Reuter-Lorenz and Miller, 1998). In particular, the split-brain studies highlighted the hemispherical asymmetry in verbal versus nonverbal abilities and analytic versus holistic

The different specialisations of the left hemisphere for verbal information and of the right hemisphere for visual and spatial information can be further applied to the topic of memory. In fact, the study of split-brain patients disputed popular models such as the Hemispheric Encoding/Retrieval Asymmetry (HERA) model (Gazzaniga, 2000). Focusing in particular on episodic memory, the HERA model suggests a specialisation of the left hemisphere for encoding, while the retrieval process would be primarily a right-hemispheric function (Tulving et al., 1994). However, when a split-brain patient was tested using faces as stimuli instead of words, the right hemisphere

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processing (Reuter-Lorenz and Miller, 1998). Interestingly, regarding the verbal-nonverbal dichotomy, further studies on other patients revealed that it is actually possible for the right half of the brain to develop some degree of competence in speech and language (Gazzaniga, 2000). Most striking was the case of patient P.S., who, despite undergoing a complete callosotomy, was still able to verbally respond to visual stimuli presented to his right hemisphere, as well as process nouns, rhymes and higher concepts with both halves of his brain (Le Doux et al., 1977; Gazzaniga et al., 1979). Another “anomaly” was patient J.W., who reportedly developed the ability to name 60% of right-hemispheric stimuli after more than ten years since undergoing the procedure (Baynes et al., 1995; Gazzaniga et al., 1996). These cases clearly don’t disprove the wellestablished concept of the general dominance of the left hemisphere over language processes, but do raise the question of brain plasticity in adult individuals (Gazzaniga, 2000).

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communication between the two halves of the brain (Myers and Sperry, 1958). These results were enough to perform another complete callosotomy on a human patient, a World War II veteran suffering from life-threatening seizures (Gazzaniga et al., 1962). After the procedure, the patient was shown simple images, so that they were exclusively in either the left or the right hemisphere’s visual field. The patient was always able to point at them, but, if asked to verbally describe what he saw, when the image was transmitted only to his right brain the reply was that he could not see anything. Both hemispheres could see the image, but only the left hemisphere could ‘talk about it’ (Gazzaniga et al., 1962), a finding consistent with the notion of the left hemisphere’s dominance for verbal processes (Milner, 1971). This was the irrefutable proof of the double nature of the human brain and of the major role of the corpus callosum in the integration of processes between the two hemispheres. This discovery paved the way to innovative research into the structure of the brain for years to come.

As for the distinction between analytic and holistic processing, early studies on split-brain patients suggested a lefthemispheric superiority over interpretation of details opposed to the right-hemispheric specialisation for the identification of the overall configuration (Reuter-Lorenz and Miller, 1998). In a simple but effective experiment, Gazzaniga (interviewed in Singer et al., 1997, reviewed in Reuter-Lorenz and Miller, 1998) showed split-brain patient J.W. paintings of fruits arranged in structures resembling faces. As expected, when the image was in the visual field of the right hemisphere, the subject reported seeing a face; when the left hemisphere was presented with the same painting, he could only perceive it as a group of fruits (Reuter-Lorenz and Miller, 1998). Even so, despite many other experiments supporting this division of perception, there have been claims that the method itself could be fallacious, as the task (facial recognition) used to assess general hemispheric specialisation might be too specific. For this reason, the conclusions may not be applicable to holistic processing of other objects as well (Moscovitch et al., 1997).

The Asymmetry in Cognitive Processes The identification of asymmetries in the brain made it possible to gain a better insight into the associated cognitive

Moreover, Phelps and Gazzaniga (1992) attempted to evaluate the input of the right hemisphere to the ‘interpreter’. Two split-brain patients were presented with a series of stimuli during two different runs. In the first run, the stimuli were in chronological order. During the second run, the images were presented in a

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Hemispherical Image Processing

processes of the mind and seemingly abstract concepts such as consciousness (Reuter-Lorenz and Miller, 1998). It is thought that thanks to its dominance of language processing, the left hemisphere is responsible for the ‘ongoing conscious narrative’ (Reuter-Lorenz and Miller, 1998) that strives to rationalise all other nonverbal emotions and behaviours, what Gazzaniga defined as the ‘interpreter’ (Gazzaniga, 1995). This unique capacity was put to the test in 2000, when Gazzaniga showed splitbrain patient P.S. two distinct images, so that the right hemisphere would only see a snowy landscape and the left one only a chicken claw, simultaneously. Gazzaniga then asked P.S. to choose, from a series of pictures in full view, the two that were most closely associated with the ones he had just been shown. The patient correctly picked a chicken with his right hand and a shovel with his left hand. However, when asked to give an explanation, he replied ‘Oh, that's simple. The chicken claw goes with the chicken, and you need a shovel to clean out the chicken shed’ (Gazzaniga, 2000). The response of the left hand was dictated by the right hemisphere seeing snow, but the left half of his brain – which had only seen a chicken claw – came up with a justification for the decision by using the information in its possession for this task. This powerful interplay between hypotheses and explanations may very well be the root of the undeniable but hardly explainable sense of an integrated self which makes us feel individuals (Gazzaniga, 2000).

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performed better than the left one, despite the task requiring deep encoding (Miller et al., 2002). This supported the idea that the hemispheric asymmetry in memory might actually arise from the type of material encoded rather than from the process itself (Miller et al., 2002).

Altogether, the high level of specialisation presented by both hemispheres does imply that they also have distinct limitations. For example, while the left hemisphere shows decreased perceptual functions, the right hemisphere has very limited cognitive functions (Gazzaniga, 2000). Furthermore, an abnormality in the hemispheric dominance over spatial

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Conclusion

processing can lead to conditions such as developmental dyslexia. In fact, its cause has been proposed to be the interference of the right-hemispheric holistic approach with the left-hemispheric ‘phonetic-sequential strategy’, which is essential to read phonetically coded languages like English (Witelson, 1977). The significant consequences of disrupting the functional balance between the hemispheres clearly highlight the importance of cooperation between the two. Communication between the hemispheres provides us with the inestimable ability to elaborate our perception of the world with opposite approaches and, then, to integrate the two. Being able to study and manipulate such ability through split-brain research has impacted both the scientific and lay community tremendously. The work carried out by Sperry, Gazzaniga and Bogen, and the concept of an innate duality of our mind, has been absorbed by the popular culture, which oversimplified it to the point of merely assigning creative qualities to the right hemisphere and a more logic nature to the left hemisphere (Wolman, 2012; Shen, 2014). More overwhelmingly, the ability to see two minds simultaneously at work and yet unaware of one another succeeded in shedding light on complex topics such as consciousness and the sense of the self. However, what is most important in my opinion is how the split-brain studies made it clear that it was possible to approach such apparently abstract matters with a proven scientific method.

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random order, interspersed with additional images to act as distractors. The distractors were either, related to the original series (within-scene distractors) or unrelated (out-of-scene distractors). The patients were then asked to recognise which images had already appeared in the original (‘old’) display. Results showed that, while both hemispheres were able to correctly identify ‘old’ images, the left hemisphere was more likely to incorrectly identify within-scene distractors as original pictures because they would fit into the interpretative scheme instinctively constructed by the hemisphere (Phelps and Gazzaniga, 1992). The finding provided further proof that the lefthemisphere tends to evaluate information as a whole, and is therefore almost entirely responsible for our interpretation of the world. It also highlighted one of the benefits of having a ‘double cortex’: the ‘interpreter’ is fundamental for human condition, as it gave us the possibility to go beyond simple observation of facts, and to be able to deal with more complex situations, evolving as a species (Gazzaniga, 2000). Even so, it can be a detrimental property, as it also deeply affects the accuracy of perception. It is only thanks to the ability of the right hemisphere to store an authentic account of the facts that this complementary system works as a whole (Metcalfe et al., 1995).

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Gazzaniga M.S. (1970). The Bisected Mind. New York: Appleton-Century-Crofts.

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Gazzaniga M.S. (1967). ‘Split Brain in Man’, Scientific American, 217(2), 24-29.