Characterising the homeostatic and hedonic markers of the susceptible phenotype

Over the years, approaches to obesity prevention and treatment have gone from focusing on genetic and other biological factors to exploring a diversity of diets and individual behavior modification interventions anchored primarily in the power of the mind, to the recent shift focusing on societal interventions to design ";temptation-proof"; physical, social, and economic environments. In spite of repeated calls to action, including those of the World Health Organization (WHO), the pandemic continues to progress. WHO recently projected that if the current lifestyle trend in young and adult populations around the world persist, by 2012 in countries like the USA, health care costs may amount to as much as 17.7% of the GDP. Most importantly, in large part due to the problems of obesity, those children may be the first generation ever to have a shorter life expectancy than that of their parents. This work presents the most current research and proposals for addressing the pandemic. Past studies have focused primarly on either genetic or behavioral causes for obesity, however today's research indicates that a strongly integrated program is the best prospect for success in overcoming obesity. Furthermore, focus on the role of society in establishing an affordable, accessible and sustainable program for implementing these lifestyle changes is vital, particularly for those in economically challenged situations, who are ultimately at the highest risk for obesity. Using studies from both neuroscience and behavioral science to present a comprehensive overview of the challenges and possible solutions, The brain-to-society approach to obesity prevention focuses on what is needed in order to sustain a healthy, pleasurable and affordable lifestyle.

Homeostatic epistemology : reliability, coherence and coordination in a Bayesian virtue epistemology

How do agents with limited cognitive capacities flourish in informationally impoverished or unexpected circumstances? Aristotle argued that human flourishing emerged from knowing about the world and our place within it. If he is right, then the virtuous processes that produce knowledge, best explain flourishing. Influenced by Aristotle, virtue epistemology defends an analysis of knowledge where beliefs are evaluated for their truth and the intellectual virtue or competences relied on in their creation. However, human flourishing may emerge from how degrees of ignorance are managed in an uncertain world. Perhaps decision-making in the shadow of knowledge best explains human wellbeing—a Bayesian approach? In this dissertation I argue that a hybrid of virtue and Bayesian epistemologies explains human flourishing—what I term homeostatic epistemology. Homeostatic epistemology supposes that an agent has a rational credence p when p is the product of reliable processes aligned with the norms of probability theory; whereas an agent knows that p when a rational credence p is the product of reliable processes such that: 1) p meets some relevant threshold for belief (such that the agent acts as though p were true and indeed p is true), 2) p coheres with a satisficing set of relevant beliefs and, 3) the relevant set of beliefs is coordinated appropriately to meet the integrated aims of the agent. Homeostatic epistemology recognizes that justificatory relationships between beliefs are constantly changing to combat uncertainties and to take advantage of predictable circumstances. Contrary to holism, justification is built up and broken down across limited sets like the anabolic and catabolic processes that maintain homeostasis in the cells, organs and systems of the body. It is the coordination of choristic sets of reliably produced beliefs that create the greatest flourishing given the limitations inherent in the situated agent.

Acute compensatory eating following exercise is associated with implicit hedonic wanting for food

The efficacy of exercise to promote weight loss could potentially be undermined by its influence on explicit or implicit processes of liking and wanting for food which in turn alter food preference. The present study was designed to examine hedonic and homeostatic mechanisms involved in the acute effects of exercise on food intake. 24 healthy female subjects were recruited to take part in two counterbalanced activity sessions; 50 min of high intensity (70% max heart rate) exercise (Ex) or no exercise (NEx). Subjective appetite sensations, explicit and implicit hedonic processes, food preference and energy intake (EI) were measured immediately before and after each activity session and an ad libitum test meal. Two groups of subjects were identified in which exercise exerted different effects on compensatory EI and food preference. After exercise, compensators (C) increased their EI, rated the food to be more palatable, and demonstrated increased implicit wanting. Compensators also showed a preference for high-fat sweet food compared with non-compensators (NC), independent of the exercise intervention. Exercise-induced changes in the hedonic response to food could be an important consideration in the efficacy of using exercise as a means to lose weight. An enhanced implicit wanting for food after exercise may help to explain why some people overcompensate during acute eating episodes. Some individuals could be resistant to the beneficial effects of exercise due to a predisposition to compensate for exercise-induced energy expenditure as a result of implicit changes in food preferences.

Liking vs. wanting food : importance for human appetite control and weight regulation

Current train of thought in appetite research is favouring an interest in non-homeostatic or hedonic (reward) mechanisms in relation to overconsumption and energy balance. This tendency is supported by advances in neurobiology that precede the emergence of a new conceptual approach to reward where affect and motivation (liking and wanting) can be seen as the major force in guiding human eating behaviour. In this review, current progress in applying processes of liking and wanting to the study of human appetite are examined by discussing the following issues: How can these concepts be operationalised for use in human research to reflect the neural mechanisms by which they may be influenced? Do liking and wanting operate independently to produce functionally significant changes in behaviour? Can liking and wanting be truly experimentally separated or will an expression of one inevitably contain elements of the other? The review contains a re-examination of selected human appetite research before exploring more recent methodological approaches to the study of liking and wanting in appetite control. In addition, some theoretical developments are described in four diverse models that may enhance current understanding of the role of these processes in guiding ingestive behaviour. Finally, the implications of a dual process modulation of food reward for weight gain and obesity are discussed. The review concludes that processes of liking and wanting are likely to have independent roles in characterising susceptibility to weight gain. Further research into the dissociation of liking and wanting through implicit and explicit levels of processing would help to disclose the relative importance of these components of reward for appetite control and weight regulation.

The regulation of food intake in humans

Knowledge of the regulation of food intake is crucial to an understanding of body weight and obesity. Strictly speaking, we should refer to the control of food intake whose expression is modulated in the interests of the regulation of body weight. Food intake is controlled, body weight is regulated. However, this semantic distinction only serves to emphasize the importance of food intake. Traditionally food intake has been researched within the homeostatic approach to physiological systems pioneered by Claude Bernard, Walter Cannon and others; and because feeding is a form of behaviour, it forms part of what Curt Richter referred to as the behavioural regulation of body weight (or behavioural homeostasis). This approach views food intake as the vehicle for energy supply whose expression is modulated by a metabolic drive generated in response to a requirement for energy. The idea was that eating behaviour is stimulated and inhibited by internal signalling systems (for the drive and suppression of eating respectively) in order to regulate the internal environment (energy stores, tissue needs).

Natural and engineered kallikrein inhibitors: an emerging pharmacopoeia

The kallikreins and kallikrein-related peptidases are serine proteases that control a plethora of developmental and homeostatic phenomena, ranging from semen liquefaction to skin desquamation and blood pressure. The diversity of roles played by kallikreins has stimulated considerable interest in these enzymes from the perspective of diagnostics and drug design. Kallikreins already have well-established credentials as targets for therapeutic intervention and there is increasing appreciation of their potential both as biomarkers and as targets for inhibitor design. Here, we explore the current status of naturally occurring kallikrein protease-inhibitor complexes and illustrate how this knowledge can interface with strategies for rational re-engineering of bioscaffolds and design of small-molecule inhibitors.

Influence of culture conditions on the molecular signature of mesenchymal stem cells

Cell based therapies require cells capable of self renewal and differentiation, and a prerequisite is the ability to prepare an effective dose of ex vivo expanded cells for autologous transplants. The in vivo identification of a source of physiologically relevant cell types suitable for cell therapies is therefore an integral part of tissue engineering. Bone marrow is the most easily accessible source of mesenchymal stem cells (MSCs), and harbours two distinct populations of adult stem cells; namely hematopoietic stem cells (HSCs) and bone mesenchymal stem cells (BMSCs). Unlike HSCs, there are yet no rigorous criteria for characterizing BMSCs. Changing understanding about the pluripotency of BMSCs in recent studies has expanded their potential application; however, the underlying molecular pathways which impart the features distinctive to BMSCs remain elusive. Furthermore, the sparse in vivo distribution of these cells imposes a clear limitation to their in vitro study. Also, when BMSCs are cultured in vitro there is a loss of the in vivo microenvironment which results in a progressive decline in proliferation potential and multipotentiality. This is further exacerbated with increased passage number, characterized by the onset of senescence related changes. Accordingly, establishing protocols for generating large numbers of BMSCs without affecting their differentiation potential is necessary. The principal aims of this thesis were to identify potential molecular factors for characterizing BMSCs from osteoarthritic patients, and also to attempt to establish culture protocols favourable for generating large number of BMSCs, while at the same time retaining their proliferation and differentiation potential. Previously published studies concerning clonal cells have demonstrated that BMSCs are heterogeneous populations of cells at various stages of growth. Some cells are higher in the hierarchy and represent the progenitors, while other cells occupy a lower position in the hierarchy and are therefore more committed to a particular lineage. This feature of BMSCs was made evident by the work of Mareddy et al., which involved generating clonal populations of BMSCs from bone marrow of osteoarthritic patients, by a single cell clonal culture method. Proliferation potential and differentiation capabilities were used to group cells into fast growing and slow growing clones. The study presented here is a continuation of the work of Mareddy et al. and employed immunological and array based techniques to identify the primary molecular factors involved in regulating phenotypic characteristics exhibited by contrasting clonal populations. The subtractive immunization (SI) was used to generate novel antibodies against favourably expressed proteins in the fast growing clonal cell population. The difference between the clonal populations at the transcriptional level was determined using a Stem Cell RT2 Profiler TM PCR Array which focuses on stem cell pathway gene expression. Monoclonal antibodies (mAb) generated by SI were able to effectively highlight differentially expressed antigenic determinants, as was evident by Western blot analysis and confocal microscopy. Co-immunoprecipitation, followed by mass spectroscopy analysis, identified a favourably expressed protein as the cytoskeletal protein vimentin. The stem cell gene array highlighted genes that were highly upregulated in the fast growing clonal cell population. Based on their functions these genes were grouped into growth factors, cell fate determination and maintenance of embryonic and neural stem cell renewal. Furthermore, on a closer analysis it was established that the cytoskeletal protein vimentin and nine out of ten genes identified by gene array were associated with chondrogenesis or cartilage repair, consistent with the potential role played by BMSCs in defect repair and maintaining tissue homeostasis, by modulating the gene expression pattern to compensate for degenerated cartilage in osteoarthritic tissues. The gene array also presented transcripts for embryonic lineage markers such as FOXA2 and Sox2, both of which were significantly over expressed in fast growing clonal populations. A recent groundbreaking study by Yamanaka et al imparted embryonic stem cell (ESCs) -like characteristic to somatic cells in a process termed nuclear reprogramming, by the ectopic expression of the genes Sox2, cMyc and Oct4. The expression of embryonic lineage markers in adult stem cells may be a mechanism by which the favourable behaviour of fast growing clonal cells is determined and suggests a possible active phenomenon of spontaneous reprogramming in fast growing clonal cells. The expression pattern of these critical molecular markers could be indicative of the competence of BMSCs. For this reason, the expression pattern of Sox2, Oct4 and cMyc, at various passages in heterogeneous BMSCs population and tissue derived cells (osteoblasts and chondrocytes), was investigated by a real-time PCR and immunoflourescence staining. A strong nuclear staining was observed for Sox2, Oct4 and cMyc, which gradually weakened accompanied with cytoplasmic translocation after several passage. The mRNA and protein expression of Sox2, Oct4 and cMyc peaked at the third passage for osteoblasts, chondrocytes and third passage for BMSCs, and declined with each subsequent passage, indicating towards a possible mechanism of spontaneous reprogramming. This study proposes that the progressive decline in proliferation potential and multipotentiality associated with increased passaging of BMSCs in vitro might be a consequence of loss of these propluripotency factors. We therefore hypothesise that the expression of these master genes is not an intrinsic cell function, but rather an outcome of interaction of the cells with their microenvironment; this was evident by the fact that when removed from their in vivo microenvironment, BMSCs undergo a rapid loss of stemness after only a few passages. One of the most interesting aspects of this study was the integration of factors in the culture conditions, which to some extent, mimicked the in vivo microenvironmental niche of the BMSCs. A number of studies have successfully established that the cellular niche is not an inert tissue component but is of prime importance. The total sum of stimuli from the microenvironment underpins the complex interplay of regulatory mechanisms which control multiple functions in stem cells most importantly stem cell renewal. Therefore, well characterised factors which affect BMSCs characteristics, such as fibronectin (FN) coating, and morphogens such as FGF2 and BMP4, were incorporated into the cell culture conditions. The experimental set up was designed to provide insight into the expression pattern of the stem cell related transcription factors Sox2, cMyc and Oct4, in BMSCs with respect to passaging and changes in culture conditions. Induction of these pluripotency markers in somatic cells by retroviral transfection has been shown to confer pluripotency and an ESCs like state. Our study demonstrated that all treatments could transiently induce the expression of Sox2, cMyc and Oct4, and favourably affect the proliferation potential of BMSCs. The combined effect of these treatments was able to induce and retain the endogenous nuclear expression of stem cell transcription factors in BMSCs over an extended number of in vitro passages. Our results therefore suggest that the transient induction and manipulation of endogenous expression of transcription factors critical for stemness can be achieved by modulating the culture conditions; the benefit of which is to circumvent the need for genetic manipulations. In summary, this study has explored the role of BMSCs in the diseased state of osteoarthritis, by employing transcriptional profiling along with SI. In particular this study pioneered the use of primary cells for generating novel antibodies by SI. We established that somatic cells and BMSCs have a basal level of expression of pluripotency markers. Furthermore, our study indicates that intrinsic signalling mechanisms of BMSCs are intimately linked with extrinsic cues from the microenvironment and that these signals appear to be critical for retaining the expression of genes to maintain cell stemness in long term in vitro culture. This project provides a basis for developing an “artificial niche” required for reversion of commitment and maintenance of BMSC in their uncommitted homeostatic state.

Under the carpet : the politics and trauma of patient harm

Few studies have investigated iatrogenic outcomes from the viewpoint of patient experience. To address this anomaly, the broad aim of this research is to explore the lived experience of patient harm. Patient harm is defined as major harm to the patient, either psychosocial or physical in nature, resulting from any aspect of health care. Utilising the method of Consensual Qualitative Research (CQR), in-depth interviews are conducted with twenty-four volunteer research participants who self-report having been severely harmed by an invasive medical procedure. A standardised measure of emotional distress, the Impact of Event Scale (IES), is additionally employed for purposes of triangulation. Thematic analysis of transcript data indicate numerous findings including: (i) difficulties regarding patients‘ prior understanding of risks involved with their medical procedure; (ii) the problematic response of the health system post-procedure; (iii) multiple adverse effects upon life functioning; (iv) limited recourse options for patients; and (v) the approach desired in terms of how patient harm should be systemically handled. In addition, IES results indicate a clinically significant level of distress in the sample as a whole. To discuss findings, a cross-disciplinary approach is adopted that draws upon sociology, medicine, medical anthropology, psychology, philosophy, history, ethics, law, and political theory. Furthermore, an overall explanatory framework is proposed in terms of the master themes of power and trauma. In terms of the theme of power, a postmodernist analysis explores the politics of patient harm, particularly the dynamics surrounding the politics of knowledge (e.g., notions of subjective versus objective knowledge, informed consent, and open disclosure). This analysis suggests that patient care is not the prime function of the health system, which appears more focussed upon serving the interests of those in the upper levels of its hierarchy. In terms of the master theme of trauma, current understandings of posttraumatic stress disorder (PTSD) are critiqued, and based on data from this research as well as the international literature, a new model of trauma is proposed. This model is based upon the principle of homeostasis observed in biology, whereby within every cell or organism a state of equilibrium is sought and maintained. The proposed model identifies several bio-psychosocial markers of trauma across its three main phases. These trauma markers include: (i) a profound sense of loss; (ii) a lack of perceived control; (iii) passive trauma processing responses; (iv) an identity crisis; (v) a quest to fully understand the trauma event; (vi) a need for social validation of the traumatic experience; and (vii) posttraumatic adaption with the possibility of positive change. To further explore the master themes of power and trauma, a natural group interview is carried out at a meeting of a patient support group for arachnoiditis. Observations at this meeting and members‘ stories in general support the homeostatic model of trauma, particularly the quest to find answers in the face of distressing experience, as well as the need for social recognition of that experience. In addition, the sociopolitical response to arachnoiditis highlights how public domains of knowledge are largely constructed and controlled by vested interests. Implications of the data overall are discussed in terms of a cultural revolution being needed in health care to position core values around a prime focus upon patients as human beings.

Markers of chronic disease in offenders in a high secure correctional centre in Queensland

This study aimed to gauge the presence of markers of chronic disease, as a basis for food and nutrition policy in correctional facilities. One hundred and twenty offenders, recruited from a Queensland Correctional Centre, provided informed consent and completed both dietary interviews and physical measurements. Mean age of the sample was 35.5 ± 12 years (range = 19–77 yrs); mean age of the total population (n = 945) was 32.8 ± 10 years (range = 19–80 yrs). Seventy-nine participants also provided fasting blood samples. The mean body mass index (BMI) was 27 ± 3.5 kg/m2; 72% having a BMI > 25 kg/m2. Thirty-three percent were classified overweight or obese using waist circumference (mean = 92 ± 10 cm). Mean blood pressure measurement was systolic = 130 ± 14 mmHg and diastolic = 73 ± 10 mmHg. Twenty-four percent were classified as hypertensive of whom three were on antihypertensive medication. Eighteen percent had elevated triglycerides, and 40% unfavourable total cholesterol to HDL ratios. Homeostatic Model Assessment (HOMA scores) were calculated from glucose and insulin. Four participants were insulin resistant, two of whom had known diabetes. Metabolic syndrome, based on waist circumference (adjusted for ethnicity), blood lipids, blood pressure and plasma glucose indicated that 25% (n = 20) were classified with metabolic syndrome. Eighty-four percent (n = 120) reported some physical activity each day, with 51 percent participating ≥two times daily. Fifty-four percent reported smoking with an additional 20% having smoked in the past. Findings suggest that waist circumference rather than weight and BMI only should be used in this group to determine weight status. The data suggest that markers of chronic disease are present and that food and nutrition policy must reflect this. Further analysis is being completed to determine relevant policy initiatives.

The interaction between exercise, appetite and food intake : implications for weight control

Exercise could indirectly affect body weight by exerting changes on various components of appetite control, including nutrient and taste preferences, meal size and frequency, and the drive to eat. This review summarizes the evidence on how exercise affects appetite and eating behavior and in particular answers the question, “Does exercise induce an increase in food intake to compensate for the increase in energy expenditure?” Evidence will be presented to demonstrate that there is no automatic increase in food intake in response to acute exercise and that the response to repeated exercise is variable. The review will also identify areas of further study required to explain the variability. One limitation with studies that assess the efficacy of exercise as a method of weight control is that only mean data are presented—the individual variability tends to be overlooked. Recent evidence highlights the importance of characterizing the individual variability by demonstrating exercise-induced changes in appetite. Individuals who experience lower than theoretically predicted reductions in body weight can be characterized by hedonic (eg, pleasure) and homeostatic (eg, hunger) features.

Achilles tendinopathy has an aberrant strain response to eccentric exercise

Purpose: Eccentric exercise has become the treatment of choice for Achilles tendinopathy. However, little is known about the acute response of tendons to eccentric exercise or the mechanisms underlying its clinical benefit. This research evaluated the sonographic characteristics and acute anteroposterior (AP) strain response of control (healthy), asymptomatic, and symptomatic Achilles tendons to eccentric exercise. Methods: Eleven male adults with unilateral midportion Achilles tendinopathy and nine control male adults without tendinopathy participated in the research. Sagittal sonograms of the Achilles tendon were acquired immediately before and after completion of a common eccentric rehabilitation exercise protocol and again 24 h later. Tendon thickness, echogenicity, and AP strain were determined 40 mm proximal to the calcaneal insertion. Results: Compared with the control tendon, both the asymptomatic and symptomatic tendons were thicker (P < 0.05) and hypoechoic (P < 0.05) at baseline. All tendons decreased in thickness immediately after eccentric exercise (P < 0.05). The symptomatic tendon was characterized by a significantly lower AP strain response to eccentric exercise compared with both the asymptomatic and control tendons (P < 0.05). AP strains did not differ in the control and asymptomatic tendons. For all tendons, preexercise thickness was restored 24 h after exercise completion. Conclusions: These observations support the concept that Achilles tendinopathy is a bilateral or systemic process and structural changes associated with symptomatic tendinopathy alter fluid movement within the tendon matrix. Altered fluid movement may disrupt remodeling and homeostatic processes and represents a plausible mechanism underlying the progression of tendinopathy.

Loss of breast epithelial marker hCLCA2 promotes epithelial to mesenchymal transition and indicates higher risk of metastasis

Transition between epithelial and mesenchymal states is a feature of both normal development and tumor progression. We report that expression of chloride channel accessory protein hCLCA2 is a characteristic of epithelial differentiation in the immortalized MCF10A and HMLE models, while induction of epithelial-to-mesenchymal transition by cell dilution, TGFβ or mesenchymal transcription factors sharply reduces hCLCA2 levels. Attenuation of hCLCA2 expression by lentiviral small hairpin RNA caused cell overgrowth and focus formation, enhanced migration and invasion, and increased mammosphere formation in methylcellulose. These changes were accompanied by downregulation of E-cadherin and upregulation of mesenchymal markers such as vimentin and fibronectin. Moreover, hCLCA2 expression is greatly downregulated in breast cancer cells with a mesenchymal or claudin-low profile. These observations suggest that loss of hCLCA2 may promote metastasis. We find that higher-than-median expression of hCLCA2 is associated with a one-third lower rate of metastasis over an 18-year period among breast cancer patients compared with lower-than-median (n=344, unfiltered for subtype). Thus, hCLCA2 is required for epithelial differentiation, and its loss during tumor progression contributes to metastasis. Overexpression of hCLCA2 has been reported to inhibit cell proliferation and is accompanied by increases in chloride current at the plasma membrane and reduced intracellular pH (pHi). We found that knockdown cells have sharply reduced chloride current and higher pHi, both characteristics of tumor cells. These results suggest a mechanism for the effects on differentiation. Loss of hCLCA2 may allow escape from pHi homeostatic mechanisms, permitting the higher intracellular and lower extracellular pH that are characteristic of aggressive tumor cells.

The hyperthermic patient

Concepts used in this chapter include: Thermoregulation:- Thermoregulation refers to the body’s sophisticated, multi-system regulation of core body temperature. This hierarchical system extends from highly thermo-sensitive neurons in the preoptic region of the brain proximate to the rostral hypothalamus, down to the brain stem and spinal cord. Coupled with receptors in the skin and spine, both central and peripheral information on body temperature is integrated to inform and activate the homeostatic mechanisms which maintain our core temperature at 37oC1. Hyperthermia:- An imbalance between the metabolic and external heat accumulated in the body and the loss of heat from the body2. Exertional heat stroke:- A disorder of excessive heat production coupled with insufficient heat dissipation which occurs in un-acclimated individuals who are engaging in over-exertion in hot and humid conditions. This phenomenon includes central nervous system dysfunction and critical dysfunction to all organ systems including renal, cardiovascular, musculoskeletal and hepatic functions. Non-exertional heat stroke:- In contrast to exertional heatstroke as a consequence of high heat production during strenuous exercise, non-exertional heatstroke results from prolonged exposure to high ambient temperature. The elderly, those with chronic health conditions and children are particularly susceptible.3 Rhabdomylosis:- An acute, sometimes fatal disease characterised by destruction of skeletal muscle. In exertional heat stroke, rhabdomylosis occurs in the context of strenuous exercise when mechanical and/or metabolic stress damages the skeletal muscle, causing elevated serum creatine kinease. Associated with this is the potential development of hyperkalemia, myoglobinuria and renal failure. Malignant hyperthermia:- Malignant hyperthermia is “an inherited subclinical myopathy characterised by a hypermetabolic reaction during anaesthesia. The reaction is related to skeletal muscle calcium dysregulation triggered by volatile inhaled anaesthetics and/or succinylcholine.”4 Presentation includes skeletal muscle rigidity, mixed metabolic and respiratory acidosis, tachycardia, hyperpyrexia, rhabdomylosis, hyperkalaemia, elevated serum creatine kinease, multi-organ failure, disseminated intravascular coagulation and death.5

The hypothermic patient

Concepts used in this chapter include: Thermoregulation:- Thermoregulation refers to the body’s sophisticated, multi-system regulation of core body temperature. This hierarchical system extends from highly thermo-sensitive neurons in the preoptic region of the brain proximate to the rostral hypothalamus, down to the brain stem and spinal cord. Coupled with receptors in the skin and spine, both central and peripheral information on body temperature is integrated to inform and activate the homeostatic mechanisms which maintain our core temperature at 37oC.1 Body heat is lost through the skin, via respiration and excretions. The skin is perhaps the most important organ in regulating heat loss. Hyporthermia:- Hypothermia is defined as core body temperature less than 350C and is the result of imbalance between the body’s heat production and heat loss mechanisms. Hypothermia may be accidental, or induced for clinical benefit i.e: neurological protection (therapeutic hypothermia). External environmental conditions are the most common cause of accidental hypothermia, but not the only causes of hypothermia in humans. Other causes include metabolic imbalance; trauma; neurological and infectious disease; and exposure to toxins such as organophosphates. Therapeutic Hypothermia:- In some circumstances, hypothermia can be induced to protect neurological functioning as a result of the associated decrease in cerebral metabolism and energy consumption. Reduction in the extent of degenerative processes associated with periods of ischaemia such as excitotoxic cascade; apoptotic and necrotic cell death; microglial activation; oxidative stress and inflammation associated with ischaemia are averted or minimised.2 Mild hypothermia is the only effective treatment confirmed clinically for improving the neurological outcomes of patient’s comatose following cardiac arrest.3