When red blood cells have completed their life span of approximately 120 days, or when they are damaged, their membranes become fragile and prone to rupture.
Malignant porta hepatis lymph nodes, EC Metastatic tumors (usually from the gastrointestinal tract or the breast). Drugs; such as anabolic steroids ,chlorpromazine and ceftriaxone directly cause cholestasis.
1- Intraductal causes include neoplasms, stone disease, biliary stricture, parasites, primary sclerosing cholangitis, AIDS-related cholangiopathy, and biliary tuberculosis. 2- Extraductal obstruction caused by external compression of the biliary ducts may be secondary to neoplasms, pancreatitis, or cystic duct stones with subsequent gallbladder distension.
Gallstones may pass through the CBD and cause obstruction, larger stones can become lodged in the CBD and cause complete obstruction.
Scratch marks over the limbs suggest prolonged cholestasis or high-grade biliary obstruction.
Serum bilirubin: Regardless the cause conjugated serum bilirubin values are usually elevated. Initially, an increase in the conjugated bilirubin level occurs without affecting the unconjugated bilirubin level because obstruction of the CBD prevents excretion of already conjugated bilirubin into the duodenum. Intrahepatic obstruction: Both conjugated and unconjugated bilirubin fractions may increase in varying proportions. The unconjugated fraction may be increased because of the inability of the damaged cells to conjugate.
These levels are elevated in patients with diseases of the liver, biliary tract, and pancreas when the biliary tract is obstructed. Serum transaminases: Levels of these are only moderately elevated, may be markedly increased in cholangitis.
The presence of antimitochondrial antibodies, usually in high titers, is indicative of PBC.
When it is present, dark-colored urine seen in patients with obstructive jaundice or jaundice due to hepatocellular injury.
It is used for the initial evaluation of extrahepatic obstruction is suggested by the presence of dilated bile ducts.
The addition of intravenous contrast helps define vascular structures and the biliary tract.
Magntic Resonance Cholangiopancreatography provides a sensitive noninvasive method of detecting biliary and pancreatic duct stones, strictures, or dilatations or cancer. Relative contraindications include the presence of cardiac prosthetic valves, neurostimulators, metal prostheses, and penile implants.
Complications of this technique include pancreatitis, perforation, biliary peritonitis, sepsis, hemorrhage, and adverse effects from the dye. Percutaneous Tanshepatic Cholangiography is performed by a radiologist using fluoro-scopic guidance. Complications include peritonitis with possible intraperitoneal hemorrhage, sepsis, cholangitis, subphrenic abscess, and lung collapse. The accuracy of PTC in elucidating the cause and site of obstructive jaundice is 90-100% for causes within the biliary tract. Endoscopic ultrasound (EUS) combines endoscopy and US to provide remarkably detailed images of the pancreas and biliary tree. It uses higher-frequency ultrasonic waves compared to US (3.5 MHz vs 20 MHz) and allows diagnostic tissue sampling(FNA). EUS has been reported to have up to a 98% diagnostic accuracy in patients with obstructive jaundice. The positive of EUS-FNA for cytology in patients with malignant obstruction has been reported to be as high as 96%. Treatment of the underlying cause is the objective of the medical treatment of biliary obstruction.
Bile acid–binding resins, cholestyramine (4 g) or colestipol (5 g), dissolved in water or juice 3 times a day may be useful in the symptomatic treatment of pruritus associated with biliary obstruction. Deficiencies of vitamins A, D, E, and K may happened, include an individualized regimen for replacement of these vitamins as needed in the patient’s treatment. Treatment with parentally administered naloxone and, more recently, nalmefene, has improved pruritus in some patients. Resectability of neoplastic causes of biliary obstruction varies with respect to the location and extent of the disease. Nursing evaluation: the enfant bilirubin level should go to normal levels within 7 days of treatment. Guidelines for total water intake have been established by many regional and global authorities (EFSA, IoM, WHO). In the USA and Canada, adequate intakes of water in children are based on the median water intake from NHANES III data (Third National Health and Nutrition Examination Survey) (IoM, 2004). The most recent official guidelines for total water intakes have been published by the European Food Safety Authority (EFSA) in 2010. Based on guidelines, children have specific water needs until puberty, compared to adults (Table 1).
These references for total water intake include both water from food plus water from beverages of all kind, including drinking and mineral water.
Available data suggest that children do not drink enough and do not meet the daily recommended intake. A recent study has revealed that among healthy children (9-11 years old), 75% of the children did not drink water before going to school. Healthy eating is one of the key actions for obesity prevention, and healthy fluid consumption is part of a balanced diet.
Recently, a study has shown that the promotion of healthy hydration in elementary schools, by increasing water accessibility through water fountains and providing lessons to promote water consumption, was an efficient strategy to lower the risk of being overweight by 31% in the interventional group (Muckelbauer et al., 2009).
These first results suggest that increasing water consumption may have a positive impact on weight management in children.
In response to the growing burden of obesity, policy frameworks are introduced, particularly with respect to health promotion for children. Among its guidelines, the Institute of Medicine (2007, pp5) also encourages water as a healthier alternative at school: “Schools should make plain, unflavored water available for free throughout the school day, either in the form of bottled water or from water fountains”. Similarly in France, the National Plan for Nutrition and Health (PNNS, 2008) recommends: “Water can be consumed without restraint during and between meals. Childhood lifestyle programs recognize the importance of good hydration with water preferably by including it as part of key lifestyle measures. The EPODE program (Ensemble Prevenons l’Obesite des Enfants – Together Let’s Prevent Childhood Obesity) is a program of local interventions to prevent childhood obesity.
There is a consistent agreement among public health authorities and scientific societies regarding water and other types of fluid intakes. Our Expert Working Group meet regularly to discuss the importance of healthy hydration and to develop strategies to encourage patients and the general public to adopt healthier hydration practices.
Science, Technology and Medicine open access publisher.Publish, read and share novel research. Gujarati is the Indo-Aryan language of the Indian state of Gujarat – and of numerous migrant communities in many parts of the world. The name is undoubtedly that of the Gujjars, a widespread caste, traditionally cattle-farmers.
Old Gujarati, ancestor of both Gujarati and Rajasthani, is recorded in texts of the 12th to 14th centuries. Although the major regional dialects differ little, there are also social dialects of several kinds. Muslim speakers of Gujarati – now mostly settled in Pakistan, Bangladesh and Britain – tend to be at least trilingual, being familiar also with Urdu and having studied classical Arabic. In Kutch, in north-western Gujarat state, the 500,000 speakers of the Sindhi dialect Kacchi? use Gujarati as their literary language. The Gujarati script, which is similar to Devanagari but without the headstrokes or ‘washing line’, was standardised in its present form in the 19th century. Bhi?li? is spoken by the mountain tribes of Bhil, to the east and north-east of Gujarat state.
To the south of Bhili, Khandesi? is another group of hill dialects, with up to a million speakers.
Gujuri is the language of nearly half a million semi-nomadic herdsmen in Indian and Pakistani Kashmir and in Himachal Pradesh. Parya is a recently discovered Indo-Aryan language spoken by about 1,000 people in the Hissar valley, Tajikistan. A goniometer is often used in patients who have limitations of movement due to muscle tightness, joint stiffness or other conditions affecting their joint range of motion. The results of measurement is often written on the "Objective" portion of the physical therapist (PT) SOAP note.
Often, the normal side is measured for comparison with the measurement on the abnormal joint.
Disclaimer: The information obtained on Physical Therapy Notes (PT Notes) is not intended as a substitute for medical professional help or advice but is to be used only as an aid in understanding physical therapy and physical therapy treatments. Disclosure: You may have noticed that Advertisements and Affiliate links are included on this site. It accumulates in the blood because the uptake mechanism and the hepatic cells are overburdened by bilirubin that has already been conjugated but cannot be excreted. Levels parallel the levels of ALP and 5-prime-nucleotidase in conditions associated with cholestasis. ALT and AST levels are usually elevated to the same degree in patients with viral hepatitis and those with drug-induced liver damage.
However, in contrast to other nutrients, there is insufficient research into the amount of water required to prevent disease or improve health. For adults, it is considered that the contribution of food to total water intake represents about 20% (EFSA, 2010).
According to observational data from NHANES (USA), in children and adolescents between 4-19 years of age the mean daily total water intake is lower than the IoM adequate intake (beverage and food moisture) (Kant et al., 2010). Naturally, urine osmolality was elevated in those who did not drink anything before school.
In 2010, 43 million children (35 million in developing countries) were considered overweight and obese (Figure 6) and 92 million were at risk of overweight (de Onis et al., 2010). Then, if it proves to be an effective action, drinking water programs may contribute to weight management in children. They are based on modification of lifestyle practices such as physical activity, as well as encouraging a balanced diet, including recommendation to favor drinking water over other beverages.
In this context, more recently a set of tools to guide member states while setting their national action plan was published.
For example, the Food and Nutrition Service, part of US Department of Agriculture (2010), recently launched an initiative aimed at tackling childhood obesity. The OPAL theme “Water: The Original Cool Drink” aims to encourage children to replace sweetened drink consumption with plain tap water. Hyperthermia complements standard cancer treatments such as chemotherapy and radiation therapy in destroying tumour cells.2.
Bioimmunoadjuvants for the treatment of neoplastic and infectious disease: Coley's legacy revisited. A review of the influence of bacterial infection and of bacterial products (Coley's toxins) on malignant tumors in man; a critical analysis of 30 inoperable cases treated by Coley's mixed toxins, in which diagnosis was confirmed by microscopic examination selected for special study. Effects of thermal adaptation at 40 degrees C on membrane viscosity and the sodium-potassium pump in Chinese hamster ovary cells. The effect of hyperthermia on glucose transport in normal and thermal-tolerant Chinese hamster ovary cells. Hyperthermia, adriamycin transport, and cytotoxicity in drug-sensitive and -resistant Chinese hamster ovary cells. Heat shock-induced arrests in different cell cycle phases of rat C6-glioma cells are attenuated in heat shock-primed thermotolerant cells. Heat shock protein 70 inhibits the nuclear import of apoptosis-inducing factor to avoid DNA fragmentation in TF-1 cells during erythropoiesis.
Increased flux of free radicals in cells subjected to hyperthermia: detection by electron paramagnetic resonance spin trapping.
Heat-induced cellular damage and tolerance in combination with adriamycin for the PC-3 prostate cancer cell line: relationships with cytotoxicity, reactive oxygen species and heat shock protein 70 expression. Role of tumor necrosis factor alpha in hyperthermia-induced apoptosis of human leukemia cells. Nomadic members of the community are nowadays most commonly found far to the north, in Kashmir and Himachal Pradesh, where they speak Gujuri (see INDO-ARYAN LANGUAGES).
Gujarati literature really begins in the 15th century, however, with mystical poets such as Mirabai. One of the oldest communities of the diaspora is in East Africa, where Indian traders (Gujarati, Kacchi? and Konkani) were already established in the 1490s when Portuguese explorers reached the Indian Ocean.
Other dialects of Gujarati are Pattani (north), Surati or Surti (south) and Ka?thiya?wad?i? of Saurashtra. Gujjars keep buffaloes and cows, while Bakarwals, who speak the same language, keep goats and sheep. Its history is unknown – but linguistically it seems to belong with Rajasthani and Panjabi. A qualified physical therapist or physician should be consulted for any neuro-musculoskeletal problem prior to self-treatment. These ADs, Sponsors and Affiliates are clearly stated as such and we may receive earnings from those ADs and Affiliates if you decided to follow those links, and in some cases buy from them. The hemoglobin is phagocytosed by macrophages, and split into its heme and globin portions. The extreme sensitivity of GGT, as opposed to ALP, limits its usefulness; however, the level helps distinguish hepatobiliary disease as the cause of an isolated rise in ALP. A contrast agent is injected into these ducts, and x-ray images are taken to evaluate their caliber, length, and course. As a result, neither upper nor lower consumption thresholds have been linked to a specific benefit or risk. Results from the DONALD study (Germany) indicate that 49% of boys and 29% of girls between 4-11 year of age were considered not sufficiently hydrated (Stahl et al., 2007). However, what was more surprising was that urine osmolality was also elevated in children who drank large volumes of beverages other than water (Stookey et al., 2011). Given that data is limited, more research would be required to establish whether this strategy would be effective in real life conditions. Increasing the consumption of water in children has been identified as a priority area for action in the field of preventing childhood obesity (WHO, 2012).
Although it is too early to conclude whether it is effective, the “Let’s Move” program supports simple actions, such as recommendations for healthy eating pattern in school and at home, better food labeling, and increased daily physical activity for children. This program involves all stakeholders of a community to encourage families to adopt a healthy lifestyle (balanced diet and physical activity). In consequence, water is recommended as the beverage of choice by numerous professional organisations.Improving water intake is increasingly considered as a priority action for healthier lifestyle in children. Averill-Bates3[1] Department of Nutrition, University of California, Davis, California, USA[2] Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada[3] Departement des sciences biologiques, Universite du Quebec a Montreal, Succursale Centre-Ville, Montreal, Quebec, Canada1. Annual Report to the Nation on the status of cancer, 1975-2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Application of thermal stress for the improvement of health, 15-18 June 2004, Awaji Yumebutai International Conference Center, Awaji Island, Hyogo, Japan. Both Persian-Urdu and Sanskrit traditions of poetry continue to influence Gujarati authors.

Another dialect of historical importance is that of Kathiawari sailors, who travelled all over the world as steamship crewmen. This linguistic enclave was reinforced when Gujaratis were recruited in large numbers by both British and German governments to work in East Africa around 1990.
Nimadi, an isolated southern dialect in a mainly ‘tribal’ area, has developed special peculiarities. Most speakers own their winter pastures, moving to high meadows, ṭok, during the summer season, April to August. This website provides links to other organizations and websites as a service to our readers and is not responsible for the information, services, or products provided by these web sites, health professionals, or companies.
We assure you that advertisements presented on our website does not, in any way, affect or influence editorial physical therapy articles presented here. Moreover, while contribution of plain water (from 22% in 2-5 years old to 33% in adolescents) to water intake increases with age, main contributors of to water intake are beverages, i.e.
Drinking water fulfills hydration requirements without increasing solute load presented to the kidney and hence elevated urine osmolality. Among the healthier alternatives proposed, the one to make better beverage choices, choosing water instead of sugar-sweetened beverages. Among others, promoting healthier fluid intakes in children and adolescent is included in the prevention actions. IntroductionThe three mainstays for cancer treatment include surgical removal of tumors, radiation therapy and chemotherapy, which have led to improved patient survival for certain types of cancer, but there is still much room for improvement.
The statesman and writer Mohandas Karamchand Gandhi (1869-1948), born in the Gujarat town of Porbandar, helped to inspire a 20th-century renewal in the literature of his mother tongue.
An important caste dialect is that of the Parsis, clustering in the southern part of the state.
The owners of this website accept no responsibility for the misuse of information contained within this website. Most are based on intake surveys and theoretical calculations, and there is therefore a great amount of variability in worldwide reference values (Table 1).
A pilot study launched in 1992 in two French towns showed that the prevalence of overweight in children between 5 and 12 years old was significantly lower in both pilot towns compared to control ones, respectively 8.8% vs. Cancer is one of the leading causes of death worldwide and accounted for 7.6 million deaths (13% of all deaths) in 2008 (World Health Organization, 2012). They have a press and literature of their own, quite distinct from standard Gujarati in style and idiom. Many East African Gujaratis, faced with an increasingly uncertain future and mounting discrimination in newly independent East African countries – especially Uganda – migrated to Britain, where there are now a third of a million speakers of the language, many of them in the London areas of Wembley, Harrow and Newham and in Leicester, Coventry and Bradford.
However, there were increases in the incidence of other types of cancer, including those of the pancreas, kidney, thyroid and liver, as well as melanoma and adenocarcinoma of the esophagus, from 1999 to 2008.Over the past decades, the struggle against cancer has led to the discovery of new strategies to fight this disease and to bring hope to patients. These new strategies include hyperthermia (also commonly known as thermal therapy or thermotherapy), biological therapies (e.g. Moreover, a better understanding of the biological mechanisms involved in their anticancer action would certainly be beneficial.
Hyperthermia is one of the few strategies to be adopted as a promising therapy among the alternative methods to treat cancer.Hyperthermia is defined as moderate elevation in temperature.
Hyperthermia can either have a pathological origin, resulting from the fever response of the organism to viral or bacterial infections, or may occur during exposure to high temperatures as during heat stroke.
It is relatively recent as a clinical procedure, in which body tissues are exposed to elevated temperatures in the range of 39°C to 45°C. These high temperatures can damage and kill cancer cells with minimal injury to normal tissues [2]. During the last two decades, hyperthermia has been used as an efficient complement to standard cancer treatments such as radiation therapy and chemotherapy [2,3] (Figure 1).
A further advantage is that hyperthermia can eliminate drug-resistant and radio-resistant tumour cells. Another form of hyperthermia involves very high temperatures (> 60°C), which can destroy or «cook» tumours by a technique known as thermal ablation (see review, [4]).
Scientific historyThe use of heat to treat disease, including cancer, is a concept that dates back to early Egyptian times, over 5000 years ago (see review, [5]).
Indeed, the Egyptian medical papyrus recounts an attempt to treat breast cancer with a "heated stick" [6]. Likewise, many Greek doctors, among them Hippocrates, suggested cauterizing superficial tumours by using heated metal. Many ancient cultures, including the Roman, Chinese, Indian and Japanese cultures have used this concept for the treatment of a variety of diseases. During the late 1800s, there were numerous observations by astute clinicians of spontaneous remissions of cancer in patients suffering from a variety of infections [7]. Coley found 47 case reports in which simultaneous infection seemed to have caused the remission of an incurable neoplastic malignancy (see review, [8]).
In the late 1800s, he used “Coley’s Mixed Toxins” (bacterial pyrogenic toxins) as a deliberate fever-inducing treatment to control tumor growth [9].
Despite promising observations during several decades, these cancer treatments were difficult to administer in a controlled manner, and responses were unpredictable [10].
Using a different approach, Westermark reported the use of localized, non-fever producing heat treatments (42-44°C) by means of water-circulating cisterns that resulted in the long-term remission of inoperable cancer of the cervix [11].
As different techniques were developed, such as surgery, radiation therapy and chemotherapy, further development of hyperthermia for cancer treatment was put on the back burner.
There was a resurgence of interest in the use of hyperthermia in cancer treatment based on scientific studies initiated in the 1960s and 1970s.
These promising observations led to quantitative experimental studies and a rapid increase in our understanding of the biological effects of hyperthermia. Temperatures above 42°C were shown to kill cancer cells in a time- and temperature-dependent manner that was measured by the clonogenic cell survival assay [13]. However, despite numerous studies during at least three decades, which have improved our understanding of hyperthermia biology, the mechanisms involved in heat-induced cytotoxicity are still ill-defined [14]. Hyperthermia causes many changes in cells and leads to a loss of cellular homeostasis [15-17]. A key event appears to be protein denaturation and aggregation, which results in cell cycle arrest, inactivation of protein synthesis, and inhibition of DNA repair processes [18]. The viscosity of the plasma membrane decreases with increasing temperature [22], and this may be associated with altered transport functions of the membrane. Changes in membrane viscosity were linked to an elevation in the activity of the ATP-dependent sodium-potassium pump [22], which maintains Na+ and K+ levels across the plasma membrane against a concentration gradient. During hyperthermia, membrane permeability towards several compounds is altered, including polyamines, glucose, and anticancer drugs [23-25].
Despite the large number of documented cellular changes, the nature of the critical lesions that lead to cell death following heat treatment remains unknown.
Proteins appear to be the first target of hyperthermia in the clinically-relevant temperature range of 39 to 45°C (Figure 2).
The alteration of cellular homeostasis after exposure to hyperthermia entails a certain number of post-translational modifications such as glycosylation, acylation, phosphorylation, farnelysation and ubiquitination [18,26]. Several studies reported that hyperthermia can cause DNA fragmentation and the formation of double strand breaks (DBSs) [27,28], which could arise from the inhibition of DNA repair mechanisms [21]. However, it appears that nuclear protein damage may be the key factor rather than direct DNA damage itself.
Nuclear proteins, in particular, appear to be very sensitive to hyperthermia and undergo aggregation [21]. Levels of reactive oxygen species (ROS) were shown to increase after exposure to both lethal (?42°C) [29-31] and non-lethal (40°C) temperatures [32,33]. This would arise principally from the increased generation of ROS such as superoxide and hydrogen peroxide (H2O2), likely as a result of dysfunction of the mitochondrial respiratory chain. Other potential sources of increased ROS generation would be increased activity of superoxide-producing enzymes such as NADPH oxidase and xanthine oxidase at elevated temperatures.
Hyperthermia could also increase the reactivity of these ROS; indeed, the cytotoxicity of hydrogen peroxide was increased at elevated temperatures (41 to 43°C) compared to the physiological temperature (37°C) [34]. Hyperthermia also inactivated cellular antioxidant defenses against H2O2 such as the pentose phosphate pathway [35], which maintains the intracellular antioxidant glutathione in its reduced form, GSH [36]. An increase in the generation of ROS can cause oxidative damage to proteins, lipids and nucleic acids.
A hyperthermia-induced decrease in tumor growth was accompanied by an increase in lipid peroxidation in rabbits [37]. Another consequence of increased ROS generation by hyperthermia is that molecules such as H2O2 can perturb mitochondrial membrane potential [38]. A temperature-induced increase in cell metabolism could also cause acidosis of the tumor tissue [39,40]. Cytotoxicity of hyperthermiaAs a consequence of different cellular changes, hyperthermia causes mitotic catastrophe, permanent G1 arrest and a loss of clonogenic or reproductive cell capacity [21] (Figure 2). Another consequence is that cells can become sensitized to other cytotoxic modalities such as radiation [16]. Hyperthermia was reported to cause centrosomal dysfunction and mitotic catastrophe [42], which have been implicated in thermal radio-sensitization [43].
Hyperthermia (42 to 44°C) has been reported to cause chromatin condensation and apoptotic DNA fragmentation (formation of DNA ladders) leading to apoptosis in many different cell types including HeLa cells [44], T lymphocytes [45,46], HL-60 leukemic cells [47], and mice embryonic fibroblasts [48].
In rats treated with whole body hyperthermia (41.5°C for 2 h), both the extent and kinetics of hyperthermia-induced apoptosis differed between two different tumor types (fibrosarcoma and colon carcinoma) [49]. Additionally, the same study revealed another important advantage; the induction of apoptosis was higher in tumor tissues in comparison to normal tissues.
Several studies indicate that cancer cells are more susceptible to heat injury than normal cells [21,50]. This could be caused, at least in part, by the differential expression of heat shock proteins (Hsps) and other proteins involved in the cellular defense system against different stressors, including heat shock. However, there is no consistency in findings about heat sensitivity between tumor and normal cells [21].
The sensitivity of cells to heat also varies with phase of the cell cycle, where cells in S phase and mitosis were reported to be most sensitive [51].
Another reason for the use of hyperthermia in cancer treatment is the fact that tumor tissues are poorly vascularized in comparison to normal tissues.
This may lead to a differential heating, with higher temperatures being achieved in tumors compared with normal tissue, where heat may be dissipated by circulating blood. Hyperthermia also appears to be complementary to other forms of treatment by being able to destroy tumor cells that are relatively resistant to radiation therapy or chemotherapy.
Tumor cells located in the hypoxic centers of tumors are relatively resistant to chemotherapy due to poor drug delivery.
Several chemotherapeutic drugs also require oxygen to generate free radicals in order to cause tumor cytotoxicity. However, hypoxia has been shown to cause decreased proliferation, which may partially explain the reason for resistance of tumor cells to chemotherapy [52-54]. Cells located in hypoxic areas of tumors are also resistant to radiation therapy.Heating of human tumours is heterogeneous. Some areas of the tumour reach cytotoxic temperatures such as 43 to 45°C, whereas other areas only reach 39 to 42°C.
It is more difficult to heat larger or deep-seated tumours to cytotoxic temperatures that are adequate to cause cell death or vascular damage.Tumors are unable to adapt their blood circulation to the effects of high temperatures (?42°C), which enables hyperthermia to cut off the supply of nutrients and oxygen, leading to lower interstitial pH and a collapse in tumor vasculature [55]. Indeed, cells at lower (acidic) pH and decreased oxygen tension, as in the center of tumors, are more sensitive to heat treatment [56,57]. Cells that were deprived of glucose exhibited increased sensitivity to the cytotoxicity of hyperthermia [35]. This effect could be linked to a decrease in antioxidant defenses involving the glutathione redox cycle, since glucose metabolism, through the pentose phosphate pathway, is required for maintaining intracellular levels of GSH.
39° to 42°C) can increase tumor blood flow, which leads to improved tumor oxygenation [59,60]. This could render tumors more sensitive to radiation and certain anticancer drugs.Hyperthermia (?42°C) has been shown to cause vascular damage in rodent tumours, which leads to decreased oxygenation and necrosis [61]. Although, the vasculature of human tumours appears to be more resistant to hyperthermia than that of rodent tissues, hyperthermia has been shown to cause disturbances in the microcirculation of cancer tissue in human osteosarcoma [62].Milder temperatures in the range of 40 to 41°C appear to be able to stimulate various elements of the immune system, thus increasing immune surveillance and protecting against tumor growth (see reviews, [63-65]). Thermotolerance is an adaptive survival response induced by heat preconditioning whereby cells become resistant to a subsequent lethal insult such as that triggered by heat shock, reactive oxygen species (ROS), and environmental stressors including heavy metals [68,69]. If the level of stress is very low, cells attempt to survive by activating stress responses that protect essential biochemical processes such as DNA repair, protein folding, and the elimination of damaged proteins [70].
If the stress continues or is too severe, then the cell will likely die by apoptosis or necrosis.The acquisition of thermotolerance is characterized by numerous biochemical and molecular changes.
Hsp expression is regulated by a stress-responsive transcription factor known as heat shock factor 1 (HSF-1), through its interaction with the heat shock element (HSE) [74]. In addition, changes in the expression of about 50 to 200 other genes, not traditionally considered Hsps, have been found during or after heat stress (see review, [20]). These include genes for transcription factors, protein degradation, DNA repair enzymes, metabolic enzymes, cell cycle arrest, transport and detoxification, and signal transduction.
The reason for the induction of these other cell-protective pathways by heat shock is probably to protect nascent chain synthesis and folding, prevent protein misfolding and aggregation, and to promote recovery from stress-induced damage [75].
Proteomic analyses showed a change in the phosphorylation of 93 proteins between control RIF-1 and their thermotolerant derivatives, TR-RIF-1 cells [76].
These phosphorylated proteins are responsible for a range of cellular functions, which include chaperones, ion channels, signal transduction, transcription and translation, biosynthesis of amino acids, oxidoreduction, energy metabolism, and cell motility or structure.The heat shock response is highly conserved in all organisms from yeast to humans, which suggests that it is important for survival in a stressful environment [74]. In addition to heat, the heat shock response can be induced by other insults such as oxidative stress, heavy metals, ethanol, toxins and bacterial infections.
The major classes of Hsps induced by the heat shock response are Hsp90, Hsp70, Hsp60, and Hsp27. Many studies suggest a correlation between the accumulation of Hsp70 and the acquisition of a thermotolerant state in mammals, amphibians, insects [77-79] and fish [80]. Under conditions of stress, Hsp70s can prevent the formation of protein aggregates and assist the refolding of aggregated proteins into their native structures [19].
Other studies have shown that the state of thermotolerance correlated with an increase in the expression of Hsp110 [81]. Hsp110 is as effective as Hsp70 in preventing protein aggregation, and contributes, along with Hsp70 and Hsp40, to the refolding of denatured proteins.
In addition to their protective role against a subsequent lethal heat shock, Hsps are known to protect cells against other forms of stress, such as oxidative stress and radiation [82].Hsps play an important and yet complex role in the regulation of apoptosis. The specific roles of different Hsps such as Hsp27, Hsp60, Hsp70 and Hsp90 in the regulation of the mitochondrial and death receptor pathways of apoptosis have been reviewed [82-85].
The induction of apoptosis through the Fas death receptor can be regulated by Hsp70 and Hsp27 [86,87].
Hsp27 and Hsp70 can regulate the death receptor pathway of apoptosis by preventing t-Bid translocation to mitochondria, which in turn inhibits cytochrome c release [88, 89]. Hsp27, Hsp70, and Hsp90 can attenuate apoptosis upstream of mitochondria [91], as well as interfering with apoptosome formation, post-mitochondrial events, and caspase activation [92]. Furthermore, Hsp70 and phosphorylated Hsp27 can protect cells against oxidative stress, a potent activator of apoptosis [93,94].The development of thermotolerance by lethal hyperthermia has been the subject of intensive studies during the past three decades, whereas thermotolerance induced at mild, fever-range temperatures has received relatively little attention.
The development of thermotolerance by exposure of cells to mild hyperthermia (40°C) for 3 to 24 h led to the accumulation of Hsps 27, 32, 60, 70, 90 and 110 [32,95]. This phenomenon is of notable importance for fundamental research given that it is a physiological fever-range temperature and suggests that thermotolerance could protect healthy tissue against stressors during clinical therapies.
The activation of the mitochondrial pathway of apoptosis by moderate hyperthermia (42 to 43°C) was attenuated in these thermotolerant cells [44]. Similarly, activation of the death receptor signaling pathway through the Fas receptor by lethal heat shock (42 to 43°C) was inhibited in thermotolerant cells [32].
Furthermore, thermotolerance developed at 40°C protected cells against the induction of apoptosis by oxidative stress (H2O2), mediated through the mitochondrial and death receptor pathways [33,38].

This apoptosis-resistant phenotype could be conferred by increased levels of both Hsps (Hsps 27, 32, 60, 70, 90, and 110 kDa) and antioxidants (catalase, manganese superoxide dismutase, glutathione) [32,33]. Mild thermotolerance also inhibited hyperthermia-induced ROS generation [32], and this could be explained by the ROS-inhibitory effect of Hsps such as Hsp27 and Hsp70 [93,94].Hsps play overlapping roles in tumour development and growth by promoting cell proliferation and by inhibiting cell death pathways [98].
Hsp70 is a survival protein that is overexpressed in various malignant tumors and its expression correlates with increased cell proliferation, poor differentiation and poor therapeutic outcome in human breast cancer [99].
The increased expression of Hsp70 in tumors can prevent the activation of caspases and proteases, and thus abolish apoptotic cell death [98]. Moreover, the increased expression of Hsps appears to be involved in the acquisition of drug-resistant phenotypes. Several studies have reported that Hsp27 may be involved in the development of resistance to chemotherapeutic agents such as doxorubicin and cisplatin [100-104].
Hyperthermia in cancer therapyThe biological rational for the use of hyperthermia in cancer treatment is very strong.
Findings from in vitro studies generally indicate that there is no intrinsic difference in heat sensitivity between normal and tumour cells [105]. However, a tumour selective effect of hyperthermia could occur at higher temperatures in vivo.
In solid tumours, the vascular system is chaotic, which results in regions with hypoxia and low pH levels, compared to normal tissues. Therefore, hyperthermia can be beneficial by causing direct cytotoxicity to tumour cells, in addition to selective destruction of tumour cells in hypoxic and low pH environments within solid tumours. A further benefit is that mild hyperthermia can activate certain responses of the immune system, which could also provide protection against tumour growth [64,106].
Hyperthermia in combination with radiotherapy One of the most promising aspects of hyperthermia in cancer treatment is the ability to eliminate radiation-resistant tumour cells [see review, 5]. Indeed, this renders hyperthermia as one of the most effective radiation sensitizers known. The basis for this effect is that hyperthermia has the ability to kill cells that are under conditions of hypoxia, low pH and that are in the S-phase of cell division, which are all conditions that render cells resistant to radiation. The mechanisms responsible for heat-induced radio-sensitization are not entirely understood, particularly for milder temperatures [21]. For temperatures of 43°C and above, nuclear protein damage is considered to be a critical event [107]. It was suggested that hyperthermia interferes with the repair of radiation-induced DNA damage.
In support of this idea, hyperthermia increased the amount of radiation-induced chromosomal aberrations [13,108].
It was suggested that heat-induced enhancement of chromosomal aberrations could arise from the inhibition of repair of radiation-induced DNA damage.
Hyperthermia in combination with chemotherapy The combined use of regional hyperthermia with systemic chemotherapy has considerable potential in cancer treatment mainly because localized heat delivery could enhance cytotoxic activity of anticancer drugs within a defined target region.
This may lead to an improved therapeutic ratio by allowing targeting of chemotherapy, as can be achieved with radiation therapy. At present, targeted treatment with anticancer drugs can only be accomplished when they are administered either topically or intra-arterially. There is also evidence to suggest that the cytotoxic effects of hyperthermia and anticancer drugs may prove to be complementary. Tumour cells that are located in less well-vascularized regions of a tumour, such as the tumour center, may be relatively resistant to systemic chemotherapy because they are exposed to lower concentrations of drug. The benefit of hyperthermia is that it kills cells most efficiently in the low pH and hypoxic environment of the tumour core. Furthermore, the temperature achieved in poorly vascularized regions of the tumour may be higher because of less efficient cooling by circulating blood.
Another potential benefit is that regional hyperthermia at 40–43°C causes an increase in tumour blood supply [111].
Blood flow and vascular permeability, which are increased by hyperthermia, are critical factors for drug uptake [112].Laboratory and in vivo studies have shown that the combined use of hyperthermia and chemotherapy leads to increased cytotoxic effects of several anticancer drugs such as cisplatin, anthracyclines, cyclophosphamide, ifosfamide, nitrosoureas, bleomycin, mitomycin, and nitrogen mustards such as melphalan [16,25,105,113-118]. For drugs such as cisplatin, alkylating agents, and nitrosoureas, interactions between heat and drug are more than additive (or synergistic), whereas in other cases, interactions are simply additive [119]. For bleomycin and Adriamycin, there is a threshold temperature of about 42.5°C to 43°C for enhancement of drug cytotoxicity. 5-fluorodeoxyuridin and methotrexate) and Vinca alkaloids or taxanes have independent interactions with hyperthermia. In general, the most effective heat-drug sequence is drug treatment immediately before heat delivery. Possible mechanisms include improved drug delivery to the tumour due to increased blood perfusion, increased intracellular uptake of drugs, and increased rates of reaction of drugs with cellular targets (e.g.
Resistance to chemotherapeutic agents One of the major limitations to the successful use of chemotherapy in cancer treatment is the development of resistance to multiple anticancer drugs. Cross-resistance occurs between different anticancer agents that have distinct structures and mechanisms of cytotoxicity. Multidrug resistance (MDR) is characterized by cross-resistance to four classes of commonly used anticancer drugs such as Vinca alkaloids, anthracyclines, taxanes, and epipodophyllotoxins. Classical MDR was discovered about 35 years ago and was initially related to the overexpression of the cellular 170-kDa protein P-glycoprotein (Pgp) [120], a member of the ATP-binding cassette (ABC) transporters. This results in decreased levels of drugs inside cells, rendering the drugs less effective against the tumour cells. In addition to Pgp, several other transporter proteins have been implicated in MDR in human cancer: multidrug resistance-associated protein 1 (MRP1), lung resistance protein (LRP) and breast cancer resistance protein (BCRP) [121]. The overexpression of the protein MRP1 can cause cellular resistance to several anticancer drugs, including Adriamycin (doxorubicin), epipodophyllotoxins, and Vinca alkaloids such as vincristine, [123]. The substrate spectrum of MRP proteins also comprises amphiphilic anion conjugates of lipophilic compounds with glutathione (GSH), glucuronate, or sulfate [124], as well as cysteinyl leukotriene (LTC4), prostaglandins, and the anticancer drug methotrexate [125].Eventually, other distinct mechanisms were also implicated in the MDR phenotype [126]. These mechanisms engage other proteins involved in cellular defenses such as glutathione S-transferase (GST), an enzyme involved in the cellular detoxification of xenobiotics, which include certain anticancer drugs, toxins and environmental pollutants that undergo conjugation with the antioxidant GSH [127]. Other cellular defenses utilized by the MDR phenotype include metallothionein, thioredoxin, thymidylate synthase, dihydrofolate reductase, Hsps and topoisomerase II [126]. Clinical drug resistance appears to be a very complex and multifactorial problem [128] with multiple mechanisms involved.
There is often overlapping substrate specificity between different drug transporters, and they are commonly co-expressed in many normal tissues and tumours. To date, three generations of inhibitors have been used to increase the efficacy of chemotherapy by inhibiting transporter-mediated drug efflux.
However, the development of clinical inhibitors of ABC transporters as targets for clinical intervention in oncology has been difficult and new approaches are clearly needed. Hyperthermia and reversal of resistance to chemotherapeutic agents A beneficial effect of hyperthermia is its ability to reverse resistance to certain chemotherapeutic drugs [130]. Hyperthermia increased the cytotoxicity of anticancer drugs such as methotrexate [131], cisplatin [132], and mitomycin c [133] in cells exhibiting primary drug resistance. In addition, hyperthermia enhanced the cytotoxicity of melphalan in MDR Chinese hamster ovary CHRC5 cells that overexpress Pgp [117].
CHRC5 cells are resistant to anticancer drugs such as colchicine, Vinca alkaloids, Adriamycin, and melphalan [134].
Among the earlier strategies to overcome MDR, Pgp-modulating agents such as cyclosporin A and verapamil were developed.
These chemosensitizers appear to act by decreasing Pgp-mediated efflux of anticancer drugs from cells, which allows increased accumulation of drugs to more cytotoxic levels inside cells. However, clinical studies showed that these chemosensitizers were effective only at toxic doses [128].
Therefore, chemosensitizers with improved MDR-reversing ability and lower toxicity need to be developed, as well as novel approaches. Hyperthermia (42 to 43°C) showed beneficial effects by reversing MDR involving Pgp when melphalan or Adriamycin was combined with Pgp modulators such as cyclosporin A [135,136]) or verapamil [137,138]. When combined with hyperthermia (43°C), the Pgp modulator PSC 833 reduced resistance to vinblastine in MDR K562 leukaemia cells and MESSA leiomyosarcoma cells [139]. Moreover, ultrasound-induced hyperthermia (USHT) increased Adriamycin cytotoxicity in the MDR human lung adenocarcinoma cell line MV522 [140]. The alkylating agent melphalan is mainly detoxified through conjugation with GSH, which can be catalyzed by GST [141]. In addition to overexpression of Pgp, CHRC5 cells also overexpress the alpha and pi forms of GST, compared to the drug-sensitive AuxB1 cells [142]. Sensitivity of multidrug resistant cells to hyperthermiaAnother important advantage for the clinical use of hyperthermia is that MDR cells overexpressing Pgp or MRP1 do not display cross-resistance to heat [25,143].
Indeed, these MDR cells exhibit equivalent sensitivity to the cytotoxic and apoptosis-inducing effects of hyperthermia (41-45°C) as their drug-sensitive counterparts.
Moreover, drug-resistant sub-clones of human T-lineage acute lymphoblastic leukaemia (ALL) and acute myeloblastic leukaemia (AML) cells were as sensitive to hyperthermia as were the drug-sensitive sub-clones [144].
Results from these studies indicate that, in addition to enhancing drug cytotoxicity in resistant cells, hyperthermia alone can successfully eliminate MDR cells. Together, these findings clearly show that hyperthermia could be useful by destroying subpopulations of drug-resistant tumour cells, which have survived chemotherapy treatments, where the overexpression of Pgp and MRP1 is involved.Apoptosis is considered to be a physiological mechanism for the elimination of damaged and abnormal cells, such as tumour cells. One of the hallmark characteristics of tumour cells is their ability to evade destruction by apoptosis [145]. The up-regulation of different anti-apoptotic proteins, to provide a survival advantage, has been a frequent explanation for the resistance of cancer cells to elimination by apoptosis [146].
The induction of death receptor and mitochondria-mediated signaling pathways of apoptosis by hyperthermia (41 to 43°C) in MDR CHRC5 cells was compared to drug-sensitive CHO cells [147].
Differences were found between MDR and drug-sensitive cells in terms of induction of apoptosis by hyperthermia. For death receptor-mediated apoptosis, MDR cells contained higher levels of the anti-apoptosis protein c-FLIP and they had a lower level of activation of initiator caspase-8 and caspase-10 in response to hyperthermia.
In the mitochondria-mediated pathway of heat-induced apoptosis, MDR cells showed higher mitochondrial levels of the pro-apoptosis proteins Bax and tBid, more pronounced mitochondrial membrane depolarization, and increased levels of the apoptosome protein Apaf-1 (apoptosis protease activating factor 1).
The MDR cells appeared to show some resistance to death receptor-mediated apoptosis [147], in agreement with other studies in leukaemia cells [148, 149], but this resistance appeared to be compensated for by the pro-apoptosis changes in mitochondrial apoptosis. For the execution stage of apoptosis, the MDR and drug-sensitive cells showed similar levels of hyperthermia-induced caspase-3 activation, as well cleavage of caspase-3 substrates poly (ADP-ribose) polymerase (PARP) and inhibitor of caspase-activated DNase (ICAD) [147].
Similar levels of nuclear chromatin condensation were induced by hyperthermia, showing that overall, MDR cells are not resistant to hyperthermia-induced apoptosis compared to the drug-sensitive cells. Techniques to increase tumour temperaturesIn the cancer clinic, hyperthermia is administered by exposing tumour tissues to conductive heat sources, or non-ionizing radiation (e.g. Hyperthermia can be applied by either invasive or noninvasive techniques, using externally applied power. To increase tumour temperatures, hyperthermia can be applied by several different techniques: local hyperthermia by external or internal energy sources, perfusion hyperthermia of organs, limbs, or body cavities, and whole body hyperthermia [150]. Local hyperthermiaLocal hyperthermia entails elevating the temperature of superficial or deep-seated subcutaneous tumours while sparing the surrounding normal tissue, using external, intraluminal or interstitial heating modalities. To achieve internal heating, one of several types of sterile probes may be used, including thin heated wires, hollow tubes filled with warm water, implanted microwave antennae, radio-frequency electrodes and ultrasound.
Local hyperthermia has allowed the use of hyperthermia in conjunction with other modalities of antineoplastic therapy. Local hyperthermia is more appropriate for the treatment of solid tumours, rather than blood diseases such as leukaemia. Despite advances in the technology of heating, the non-homogeneous character of the treatment region (i.e. This means that it can be difficult to obtain a uniform regional rise in the temperature that is reproducible [151-155].
Perfusion hyperthermiaThis technique involves regional heating through the perfusion of a limb, organ (liver, pelvis, stomach), or body cavity using heated fluids [159-161]. In perfusion, the patient's blood can be removed, heated, and then pumped into the region that is to be heated internally. When applied to limbs without a cytotoxic agent, a temperature of about 43°C can be used for about two hours. Whole body hyperthermia Externally-induced whole body hyperthermia can be used to treat metastatic cancers that have spread throughout the body. Whole body hyperthermia can be applied using different methods and involves heating the patient to a maximum temperature of 41.8 to 42°C. Furthermore, improvements are required to heat effectively the deep-seated tumours that are localized in internal organs. Progress in the cancer clinicIn the cancer clinic, hyperthermia (40 to 44°C) is mainly used as an adjuvant to radiation and chemotherapy [2,5,16,150]. The major limitations of these conventional cancer treatments are lack of specificity and normal tissue toxicity. An important advantage of hyperthermia is that the cytotoxicity of radiotherapy and chemotherapy can be targeted to the tumour volume, thereby decreasing toxic side effects. The effectiveness of hyperthermia depends on the temperature rise and the duration of treatment at the elevated temperature.
At least 19 randomized studies using a combination of hyperthermia with radiotherapy, chemotherapy or both, have shown significant improvement in clinical outcome in oncology patients, without a significant increase in side effects [150]. These studies focused on many types of cancer including tumors of the head and neck, cervix, rectum, breast, brain, bladder, lung, esophagus, liver, appendix, prostate, peritoneal lining (mesothelioma), soft-tissue sarcoma and melanoma [2,3,105]. This could be partly due to inadequate monitoring of tumour temperatures or thermal dose, during heat treatments.
The temperature distribution throughout a tumour during clinical treatment is not homogeneous due to variable tissue properties and changes in blood flow [172] To ensure high quality of treatments, precise tumour temperature measurements and rigorous thermal dosimetric data are essential. Most hyperthermia centers obtain a sparse number of temperature measurements within intraluminal or interstitial catheters [173]. Thermal dose parameters are dependent on the number of measurement sites and on characteristics such as blood flow and tumor size [174].
It is eventually hoped that temperature measurements during hyperthermia treatment can be improved by measuring 3D thermal distribution in tumours by magnetic resonance imaging (MRI) techniques. Hyperthermia can cause some toxicity, including skin burns, but this is usually of limited clinical relevance [166]. Normal tissue damage and toxicity do not generally occur during 1 hour of treatment with temperatures that are below 44°C [175]. ConclusionThroughout the past two decades, hyperthermia has been used as a particularly efficient complement to standard cancer treatments such as radiation therapy and chemotherapy. Furthermore, considerable progress has been made in our understanding of the biology, physics and bioengineering involved in hyperthermia.
Significant improvement in clinical outcome has been demonstrated for many different types of tumours, including head and neck, breast, brain, bladder, cervix, rectum, lung, esophagus, liver, prostate, melanoma and sarcoma [150]. In Europe, hyperthermia is a standard for the treatment of cervical cancer and some sarcomas. It is a successful alternative for the treatment of other types of cancer such as brain, bladder, rectal and esophageal cancer. Moreover, transurethral microwave thermotherapy (TUMT) has been found to be safe and effective as an alternative to surgery and drug treatment for chronic urogenital pathologies such as benign prostatic hyperplasia [176]. Several problems associated with the acceptance of this promising treatment modality concern the limited availability of equipment for heating tumours, the lack of awareness concerning clinical results, and the lack of financial resources. Hyperthermia is currently under study in many clinical trials, particularly in Europe, Japan and the US, to improve and better understand this promising technique. AcknowledgementsFinancial support is gratefully acknowledged from the Natural Sciences and Engineering Research Council of Canada (NSERC) (DAB).

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  1. 28.04.2016 at 21:10:26

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