TREATMENT OF CANCER

Cancer can be treated by surgery, chemotherapy:

radiation therapy, hormonal therapy, targeted therapy (including immunotherapy such as monoclonal antibody therapy) and synthetic lethality. The choice of therapy depends upon the location and grade of the tumour and the stage of the disease, as well as the general state of the patient (performance status). A number of experimental cancer treatments are also under development. Under current estimates, two in five people will have cancer at some point in their lifetime.

Complete removal of cancer without damage to the rest of the body (that is, achieving cure with near-zero adverse effects) is the ideal goal of treatment and is often the goal in practice. Sometimes this can be accomplished by surgery, but the propensity of cancers to invade adjacent tissue or to

Spread to distant sites by microscopic metastasis often limits its effectiveness, and chemotherapy and radiotherapy can have a negative effect on normal cells. Therefore, cure with no negligible adverse effects may be accepted as a practical goal in some cases; and besides curative intent, practical goals of therapy can also include suppressing cancer to a subclinical state and maintaining that state for years of good quality of life (that is, treating cancer as a chronic disease), and palliative care without curative intent (for advanced-stage metastatic cancers).
Because "cancer" refers to a class of diseases, it is unlikely that there will ever be a single "cure for cancer" any more than there will be a single treatment for all infectious diseases. Angiogenesis inhibitors were once thought to have potential as a "silver bullet" treatment applicable to many types of cancer, but this has not been the case in practice.

The treatment of cancer has undergone evolutionary changes as an understanding of the underlying biological processes has increased. Tumour removal surgeries have been documented in ancient Egypt, hormone therapy and radiation therapy were developed in the late 19th Century. Chemotherapy, immunotherapy and newer targeted therapies are products of the 20th century. As new information about the biology of cancer emerges, treatments will be developed and modified to increase effectiveness, precision, survivability, and quality of life.
In theory, non-haematological cancers can be cured if entirely removed by surgery, but this is not always possible. When cancer has metastasized to other sites in the body prior to surgery, complete surgical excision is usually impossible. In the Halsted a model of cancer progression, tumours grow locally, and then spread to the lymph nodes, then to the rest of the body. This has given rise to the popularity of local-only treatments such as surgery for small cancers. Even small localized tumours are increasingly recognized as possessing metastatic potential.
Examples of surgical procedures for cancer include mastectomy for breast cancer, prostatectomy for prostate cancer, and lung cancer surgery for non-small cell lung cancer. The goal of the surgery can be either the removal of only the tumour or the entire organ. A single cancer cell is invisible to the naked eye but can regroup into a new tumour, a process called recurrence. For this reason, the pathologist will examine the surgical specimen to determine if a margin of healthy tissue is present, thus decreasing the chance that microscopic cancer cells are left in the patient.

In addition to removal of the primary tumour, surgery is often necessary for staging, e.g. determining the extent of the disease and whether it has metastasized to regional lymph nodes. Staging is a major determinant of prognosis and of the need for adjuvant therapy. Occasionally, surgery is necessary to control symptoms, such as spinal cord compression or bowel obstruction. This is referred to as palliative treatment.
Surgery may be performed before or after other forms of treatment. Treatment before surgery is often described as neoadjuvant. In breast cancer, the survival rate of patients who receive neoadjuvant chemotherapy is no different to those who are treated following surgery. Giving chemotherapy earlier allows oncologists to evaluate the effectiveness of the therapy, and may make removal of the tumour easier. However, the survival advantages of neoadjuvant treatment in lung cancer are less clear.
Radiation therapy (also called radiotherapy, X-ray therapy, or irradiation) is the use of ionizing radiation to kill cancer cells and shrink tumours. Radiation therapy can be administered externally via external beam radiotherapy (EBRT) or internally via brachytherapy. The effects of radiation therapy are localized and confined to the region being treated. Radiation therapy injures or destroys cells in the area being treated (the "target tissue") by damaging their genetic material, making it impossible for these cells to continue to grow and divide. Although radiation damages both cancer cells and normal cells, most normal cells can recover from the effects of radiation and function properly. The goal of radiation therapy is to damage as many cancer cells as possible while limiting harm to nearby healthy tissue. Hence, it is given in many fractions, allowing healthy tissue to recover between fractions.

Radiation therapy may be used to treat almost every type of solid tumour, including cancers of the brain, breast, cervix, larynx, liver, lung, pancreas, prostate, skin, stomach, uterus, or soft tissue sarcomas. Radiation is also used to treat leukaemia and lymphoma. Radiation dose to each site depends on a number of factors, including the radio sensitivity of each cancer type and whether there are tissues and organs nearby that may be damaged by radiation. Thus, as with every form of treatment, radiation therapy is not without its side effects. Radiation therapy kills cancer cells by damaging their DNA (the molecules inside cells that carry genetic information and pass it from one generation to the next) . Radiation therapy can either damage DNA directly or create charged particles (free radicals) within the cells that can in turn damage the DNA. Radiation therapy can lead to dry mouth from exposure of salivary glands to radiation. The salivary glands lubricate the mouth with moisture or spit. Post-therapy, the salivary glands will resume functioning but rarely in the same fashion. Dry mouth caused by radiation can be a lifelong problem. The specifics of your brain cancer radiation therapy plan will be based on several factors, including the type and size of the brain tumour and the extent of disease. External beam radiation is commonly used for brain cancer. The area radiated typically includes the tumour and an area surrounding the tumour.

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AMERICAN CANCER SOCIETY

The American Cancer Society (ACS) is a nationwide:

 voluntary health organization dedicated to eliminating cancer. Established in 1913, the society is organized into eleven geographical divisions of both medical and lay volunteers operating in more than 900 offices throughout the United States. Its home office is located in the American Cancer Society Centre in Atlanta, Georgia. The ACS publishes the journals Cancer, CA: A Cancer Journal for Clinicians and Cancer Cytopathology.

The society was founded on May 22, 1913, by 10 physicians and five businessmen in New York City under the name American Society for the Control of Cancer (ASCC). The current name was adopted in 1944. According to Charity Navigator the ACS is one of the oldest and largest volunteer health organizations.

At the time of founding, it was not considered appropriate to mention the word 'cancer' in public. Information concerning this illness was cloaked in a climate of fear and denial. Over 75,000 people died each year of cancer in just the United States. The top item on the founders' agenda was to raise awareness of cancer, before any other progress could be made in funding research. Therefore, a frenetic writing campaign was undertaken to educate doctors, nurses, patients and family members about cancer. Articles were written for popular magazines and professional journals. The ASCC undertook to publish their own journal, Campaign Notes, which was a monthly bulletin with information about cancer. They began recruiting doctors from all over the United States to help educate the public about cancer.
In 1936, Marjorie Illegal, an ASCC field representative, suggested the creation of a network consisting of new volunteers for the purpose of waging "war on cancer". From 1935 to 1938 the number of people involved in cancer control in the US grew from 15,000 to 150,000. According to Working to Give, The Women's Field Army, a group of volunteers working for the ASCC was primarily responsible for this increase.
The sword symbol, adopted by the American Cancer Society in 1928, was designed by George E. Durant of Brooklyn, New York. According to Durant, the two serpents forming the handle represent the scientific and medical focus of the society's mission and the blade expresses the "crusading spirit of the cancer control movement".
In 2013 the American Cancer Society embarked on a nationwide reorganization. The organization centralized its operations and consolidated, merging previous regional affiliates into the parent organization. It also required all employees to reapply for their jobs.
Its activities include providing grants to researchers, including funding 47 Nobel Laureate researchers, discovering the link between smoking and cancer, and serving one million callers every year through its National Cancer Information Centre. The 47 Nobel Prize laureates include James D. Watson, Mario Cape chi, Oliver Smithies, Paul Berg, E. Donnelly Thomas, and Walter Gilbert. The American Cancer Society's website contained a chronological listing of specific accomplishments in the fight against cancer, for example the unipod technological device of UTD, that the ACS had a hand in, including the funding of various scientists who went on to discover life-saving cancer treatments, and advocating for increased use of preventative techniques. More than two million people volunteer with the ACS which has over 3,400 local offices.
It also runs public health advertising campaigns, and organizes projects such as the Relay For Life and the Great American Smoke out. It operates a series of thrift stores to raise money for its operations. The ACS participates in the Hopkins 4K for Cancer, a 4000-mile bike ride from Baltimore to San Francisco to raise money for the society's Hope Lodge.
The society's allocation of funds for the fiscal year ending December 31, 2015, lists 75% of funds for Program Services (Patient Support 37%, Research 16%, Prevention 13.1%, Detection and Treatment 9.2%). The remaining 25% are allocated for supporting services (Fundraising 19.1%, and Management, General administration 5.5%). This meets the Better Business Bureau's Standards for Charity Accountability: Standard 8 (Program Service Expense Ratio) of at least 65% of total expenses spent on program activities.
In 2012 the American Cancer Society raised $934 million and spent $943 million prompting a national consolidation and cost-cutting reorganization.

John R. Seffrin, former CEO of the American Cancer Society, received $2,401,112 salary/compensation from the charity for the 2009-2010 fiscal years. This is the second most money given by any charity to the head of that charity, according to Charity Watch. The money included $1.5 million in a retention benefit approved in 2001, "to preserve management stability". Mr. Seffrin's compensation for the fiscal year ending August 31, 2012 was $832,355.
In 2017, it was announced that the American Cancer Society has integrated Mite Mobile Deposit and Mishap technology into its mobile fundraising app for iOS and Android platforms. This technology eliminates the need for participants to mail donation checks.

In 1994, the Chronicle of Philanthropy, a non-profit industry publication, released the results of the largest study of charitable and non-profit organization popularity and credibility conducted by Nye Lavelle & Associates. The study showed that the American Cancer Society was ranked as the 10th "most popular charity/non-profit in America" of over 100 charities researched with 38% of Americans over the age of 12 choosing "love" and "like a lot" for the American Cancer Society.

The Better Business Bureau lists American Cancer Society as an accredited charity meeting all of its Standards for Charity Accountability as of January 2012. Charity Navigator rates the society two of four stars for fiscal year 2011. According to Charity Navigator the society is directed to "eliminating cancer" and destroying it. Charity Watch rates American Cancer Society a "C", stating that the Society devotes 40% of its annual expenditures to administration, fundraising, etc., with the other 60% going to fund programs.
In 1995, the Arizona chapter of the American Cancer Society was targeted for its extremely high overhead. Two economists, James Bennett and Thomas DiLorenzo, issued a report analyzing the chapter's financial statements and demonstrating that the Arizona chapter used about 95% of its donations for paying salaries and other overhead costs, resulting in a 22 to 1 ratio of overhead to actual money spent on the cause.

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TUMOUR HETEROGENEITY

Tumour heterogeneity describes the observation:

that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity). A minimal level of intra-tumour heterogeneity is a simple consequence of the imperfection of DNA replication: whenever a cell (normal or cancerous) divides, a few mutations are acquired —leading to a diverse population of cancer cells. The heterogeneity of cancer cells introduces significant challenges in designing effective treatment strategies. However, research into understanding and characterizing heterogeneity can allow for a better understanding of the causes and progression of disease. In turn, this has the potential to guide the creation of more refined treatment strategies that incorporate knowledge of heterogeneity to yield higher efficacy.

Tumour heterogeneity has been observed in leukaemias, breast, prostate, colon, brain, esophagus, head and neck, bladder and gynaecological carcinomas, lip sarcoma, and multiple myeloma.
There are two models used to explain the heterogeneity of tumour cells. These are the cancer stem cell model and the clonally evolution model. The models are not mutually exclusive, and it is believed that they both contribute to heterogeneity in varying amounts across different tumour types.

The cancer stem cell model asserts that within a population of tumour cells, there is only a small subset of cells that are tumourigenic (able to form tumours). These cells are termed cancer stem cells (CSCs), and are marked by the ability to both self-renew and differentiate into non-tumourigenic progeny. The CSC model posits that the heterogeneity observed between tumour cells is the result of differences in the stem cells from which they originated. Stem cell variability is often caused by epigenetic changes, but can also result from clonally evolution of the CSC population where advantageous genetic mutations can accumulate in CSCs and their progeny (see below).
Evidence of the cancer stem cell model has been demonstrated in multiple tumour types including leukaemias, glioblastoma, breast cancer, and prostate cancer.

However, the existence of CSCs is still under debate. One reason for this is that markers for CSCs have been difficult to reproduce across multiple tumours. Further, methods for determining tumourigenic potential utilize xenograft models. These methods suffer from inherent limitations such as the need to control immune response in the transplant animal, and the significant difference in environmental conditions from the primary tumour site to the xenograft site (e.g. absence of required exogenous molecules or cofactors). This has caused some doubt about the accuracy of CSC results and the conclusions about which cells have tumourigenic potential.


The clonally evolution model was first proposed in 1976 by Peter Newell. In this model, tumours arise from a single mutated cell, accumulating additional mutations as it progresses. These changes give rise to additional subpopulations, and each of these subpopulations has the ability to divide and mutate further. This heterogeneity may give rise to sub clones that possess an evolutionary advantage over the others within the tumour environment, and these sub clones may become dominant in the tumour over time. When proposed, this model allowed for the understanding of tumour growth, treatment failure, and tumour aggression that occurs during the natural process of tumour formation.
Evolution of the initial tumour cell may occur by two methods:
Linear expansion

Sequentially ordered mutations accumulate in driver genes, tumour suppressor genes, and DNA repair enzymes, resulting in clonally expansion of tumour cells. Linear expansion is less likely to reflect the endpoint of a malignant tumour because the accumulation of mutations is stochastic in heterogenic tumours.
Branched expansion
Expansion into multiple subclonal populations occurs through a splitting mechanism. This method is more associated with tumour heterogeneity than linear expansion. The acquisition of mutations is random as a result of increased genomic instability with each successive generation. The long-term mutational accumulation may provide a selective advantage during certain stages of tumour progression. The Tumour microenvironment may also contribute to tumour expansion, as it is capable of altering the selective pressures that the tumour cells are exposed to.
Genetic heterogeneity is a common feature of tumour genomes, and can arise from multiple sources. Some cancers are initiated when exogenous factors introduce mutations, such as ultraviolet radiation (skin cancers) and tobacco (lung cancer). A more common source is genomic instability, which often arises when key regulatory pathways are disrupted in the cells. Some examples include impaired DNA repair mechanisms which can lead to increased replication errors, and defects in the mitosis machinery that allow for large-scale gain or loss of entire chromosomes. Furthermore, it is possible for genetic variability to be further increased by some cancer therapies (e.g. treatment with temozolomide and other chemotherapy drugs).

Mutational tumour heterogeneity refers to variations in mutation frequency in different genes and samples and can be explored by Musing. The aetiology of mutational processes can considerably vary between tumour samples from the same or different cancer types and can be manifested in different context-dependent mutational profiles. It can be explored by COSMIC mutational signatures or Mutagen.

Tumour cells can also show heterogeneity between their expression profiles. This is often caused by underlying epigenetic changes. Variation in expression signatures have been detected in different regions of tumour samples within an individual. Researchers have shown that convergent mutations affecting H3K36 methyltransferase SETD2 and his tone H3K4 demethylase KDM5C arose in spatially separated tumour sections. Similarly, MTOR, a gene encoding a cell regulatory kinas, has shown to be constitutively active, thereby increasing S6 phosphorylation. This active phosphorylation may serve as a biomarker in clear-cell carcinoma.


Mechanochemical heterogeneity is a hallmark of living eukaryotic cells. It has an impact on epigenetic gene regulation. The heterogeneous dynamic mechanochemical processes regulate interrelationships within the group of cellular surfaces through adhesion. Tumour development and spreading is accompanied by change in heterogeneous chaotic dynamics of mechanochemical interaction process in the group cells, including cells within tumour, and is hierarchical for the host of cancer patients. It is suggested that the heterogeneity of hypoxia in solid tumours is due to the mechanochemical reactions with oxygen nanobubbles. The biological phenomena of mechanochemical heterogeneity maybe used for differential gastric cancer diagnostics against patients with inflammation of gastric mucosa and for increasing ant metastatic activity of dendrite cells based on vaccines when mechanically heterogenized micro particles of tumour cells are used for their loading.

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NEUROEPIGENETICS

Neuroepigenetics is the study of how epigenetic:

changes to genes affect the nervous system. These changes may affect underlying conditions such as addiction, cognition, and neurological development. Neuroepigenetic mechanisms regulate gene expression in the neuron. Often, these changes take place due to recurring stimuli. Neuroepigenetic mechanisms involve proteins or protein pathways that regulate gene expression by adding, editing or reading epigenetic marks such as methylation or acetylating. Some of these mechanisms include ATP-dependent chromatin remodelling, LINE1, and prior protein-based modifications. Other silencing mechanisms include the recruitment of specialized proteins that methyl ate DNA such that the core promoter element is inaccessible to transcription factors and RNA polymerase. As a result, transcription is no longer possible. One such protein pathway is the REST co-repressor complex pathway. There are also several non-coding RNAs that regulate neural function at the epigenetic level. These mechanisms, along with neural his tone methylation, affect arrangement of synapses, neuroplasticity, and play a key role in learning and memory.

DNA methyltransferases (DNMTs) are involved in regulation of the electrophysiological landscape of the brain through methylation of CpGs. Several studies have shown that inhibition or depletion of DNMT1 activity during neural maturation leads to hypomethylation of the neurons by removing the cell's ability to maintain methylation marks in the chromatin. This gradual loss of methylation marks leads to changes in the expression of crucial developmental genes that may be dosage sensitive, leading to neural degeneration. This was observed in the mature neurons in the dorsal portion of the mouse pros encephalon, where there were significantly greater amounts of neural degeneration and poor neural signalling in the absence of DNMT1. Despite poor survival rates amongst the DNMT1-depleted neurons, some of the cells persisted throughout the lifespan of the organism. The surviving cells reaffirmed that the loss of DNMT1 led to hypomethylation in the neural cell genome. These cells also exhibited poor neural functioning. In fact, a global loss of neural functioning was also observed in these model organisms, with the greatest amounts neural degeneration occurring in the pros encephalon.

Other studies showed a trend for DNMT3a and DNMT3b. However, these DNMT's add new methyl marks on unmethylated DNA, unlike DNMT1. Like DNMT1, the loss of DNMT3a and 3b resulted in neuromuscular degeneration two months after birth, as well as poor survival rates amongst the progeny of the mutant cells, even though DNMT3a does not regularly function to maintain methylation marks. This conundrum was addressed by other studies which recorded rare loci in mature neurons where DNMT3a acted as maintenance DNMT. The Gfap locus, which codes for the formation and regulation of the cytoskeleton of astrocytes, is one such locus where this activity is observed. The gene is regularly methylated to down regulate glioma related cancers.

DNMT inhibition leads to decreased methylation and increased synaptic activity. Several studies show that the methylation-related increase or decrease in synaptic activity occurs due to the up regulation or down regulation of receptors at the neurological synapse. Such receptor regulation plays a major role in many important mechanisms, such as the 'fight or flight' response. The glucocorticoid receptor (GR) is the most studied of these receptors. During stressful circumstances, there is a signalling cascade that begins from the pituitary gland and terminates due to a negative feedback loop from the adrenal gland. In this loop, the increase in the levels of the stress response hormone results in the increase of GR. Increase in GR results in the decrease of cellular response to the hormone levels. It has been shown that methylation of the I7 axon within the GR locus leads to a lower level of basal GR expression in mice. These mice were more susceptible to high levels of stress as opposed to mice with lower levels of methylation at the I7 axon. Up-regulation or down-regulation of receptors through methylation leads to change in synaptic activity of the neuron.

CpG Islands (CGIs) are regulatory elements that can influence gene expression by allowing or interfering with transcription initiation or enhancer activity. CGIs are generally interspersed with the promoter regions of the genes they affect and may also affect more than one promoter region. In addition they may also include enhancer elements and be separate from the transcription start site. Hypermethylation at key CGIs can effectively silence expression of tumour suppressing genes and is common in gliomas. Tumour suppressing genes are those which inhibit a cell's progression towards cancer. These genes are commonly associated with important functions which regulate cell-cycle events. For example, PI3K and p53 pathways are affected by CGI promoter hypermethylation, this includes the promoters of the genes CDKN2/p16, RB, PTEN, TP53 and p14ARF. Importantly, glioblastomas are known to have high frequency of methylation at CGIs/promoter sites. For example, Epithelial Membrane Protein 3 (EMP3) is a gene which is involved in cell proliferation as well as cellular interactions. It is also thought to function as a tumour suppressor, and in glioblastomas is shown to be silenced via hypermethylation. Furthermore, introduction of the gene into EMP3-silenced neuroblasts results in reduced colony formation as well as suppressed tumour growth. In contrast, hypermethylation of promoter sites can also inhibit activity of oncogenes and prevent tumorigenesis. Such oncogenic pathways as the transformation growth factor (TGF)-beta signalling pathway stimulate cells to proliferate. In glioblastomas the over activity of this pathway is associated with aggressive forms of tumour growth. Hypermethylation of PDGF-B, the TGF-beta target, inhibits uncontrolled proliferation.

Global reduction in methylation is implicated in tumorigenesis. More specifically, wide spread CpG demethylation, contributing to global hypomethylation, is known to cause genomic instability leading to development of tumours. An important effect of this DNA modification is its transcriptional activation of oncogenes. For example, expression of MAGEA1 enhanced by hypomethylation interferes with p53 function.

Aberrant patterns of his tone modifications can also take place at specific loci and ultimately manipulate gene activity. In terms of CGI promoter sites, methylation and loss of acetylating occurs frequently at H3K9. Furthermore, H3K9 dimethylation and trimethylation are repressive marks which, along with bivalent differentially methylated domains, are hypothesized to make tumour suppressing genes more susceptible to silencing. Abnormal presence or lack of methylation in glioblastomas is strongly linked to genes which regulate apoptosis, DNA repair, cell proliferation, and tumour suppression.

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HYPERTENSION

Hypertension (HTN or HT), also known as high blood:

 pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure typically does not cause symptoms. Long-term high blood pressure, however, is a major risk factor for coronary artery disease, stroke, heart failure, atria fibrillation, peripheral vascular disease, vision loss, chronic kidney disease, and dementia.
High blood pressure is classified as either primary (essential) high blood pressure or secondary high blood pressure. About 90–95% of cases are primary, defined as high blood pressure due to nonspecific lifestyle and genetic factors. Lifestyle factors that increase the risk include excess salt in the diet, excess body weight, smoking, and alcohol use. The remaining 5–10% of cases is categorized as secondary high blood pressure, defined as high blood pressure due to an identifiable cause, such as chronic kidney disease, narrowing of the kidney arteries, an endocrine disorder, or the use of birth control pills.

Blood pressure is expressed by two measurements, the systolic and diastolic pressures, which are the maximum and minimum pressures, respectively. For most adults, normal blood pressure at rest is within the range of 100–130 millimetres mercury (mmHg) systolic and 60–80 mmHg diastolic. For most adults, high blood pressure is present if the resting blood pressure is persistently at or above 130/80 or 140/90 mmHg. Different numbers apply to children. Ambulatory blood pressure monitoring over a 24-hour period appears more accurate than office-based blood pressure measurement.

Lifestyle changes and medications can lower blood pressure and decrease the risk of health complications. Lifestyle changes include weight loss, physical exercise, decreased salt intake, reducing alcohol intake, and a healthy diet. If lifestyle changes are not sufficient then blood pressure medications are used. Up to three medications can control blood pressure in 90% of people. The treatment of moderately high arterial blood pressure (defined as >160/100 mmHg) with medications is associated with an improved life expectancy. The effect of treatment of blood pressure between 130/80 mmHg and 160/100 mmHg is less clear, with some reviews finding benefit and others finding unclear benefit. High blood pressure affects between 16 and 37% of the population globally. In 2010 hypertension was believed to have been a factor in 18% of all deaths (9.4 million globally).
Hypertension is rarely accompanied by symptoms, and its identification is usually through screening, or when seeking healthcare for an unrelated problem. Some people with high blood pressure report headaches (particularly at the back of the head and in the morning), as well as light-headedness, vertigo, tinnitus (buzzing or hissing in the ears), altered vision or fainting episodes. These symptoms, however, might be related to associated anxiety rather than the high blood pressure itself.
On physical examination, hypertension may be associated with the presence of changes in the optic funds seen by ophthalmoscope. The severity of the changes typical of hypertensive retinopathy is graded from I to IV; grades I and II may be difficult to differentiate. The severity of the retinopathy correlates roughly with the duration or the severity of the hypertension.
Hypertension with certain specific additional signs and symptoms may suggest secondary hypertension, i.e. hypertension due to an identifiable cause. For example, Cushing's syndrome frequently causes truncal obesity, glucose intolerance, moon face, a hump of fat behind the neck/shoulder (referred to as a buffalo hump), and purple abdominal stretch marks. Hyperthyroidism frequently causes weight loss with increased appetite, fast heart rate, bulging eyes, and tremor. Renal artery stenos is (RAS) may be associated with a localized abdominal bruit to the left or right of the midline (unilateral RAS), or in both locations (bilateral RAS). Coarctation of the aorta frequently causes a decreased blood pressure in the lower extremities relative to the arms, or delayed or absent femoral arterial pulses. Pheochromocytoma may cause abrupt ("paroxysmal") episodes of hypertension accompanied by headache, palpitations, pale appearance, and excessive sweating.

Severely elevated blood pressure (equal to or greater than a systolic 180 or diastolic of 110) is referred to as a hypertensive crisis. Hypertensive crisis is categorized as either hypertensive urgency or hypertensive emergency, according to the absence or presence of end organ damage, respectively.

In hypertensive urgency, there is no evidence of end organ damage resulting from the elevated blood pressure. In these cases, oral medications are used to lower the BP gradually over 24 to 48 hours.
In hypertensive emergency, there is evidence of direct damage to one or more organs. The most affected organs include the brain, kidney, heart and lungs, producing symptoms which may include confusion, drowsiness, chest pain and breathlessness. In hypertensive emergency, the blood pressure must be reduced more rapidly to stop ongoing organ damage; however, there is a lack of randomized controlled trial evidence for this approach.
Hypertension occurs in approximately 8–10% of pregnancies. Two blood pressure measurements six hours apart of greater than 140/90 mm Hg are diagnostic of hypertension in pregnancy. High blood pressure in pregnancy can be classified as pre-existing hypertension, gestational hypertension, or pre-eclampsia.

Pre-eclampsia is a serious condition of the second half of pregnancy and following delivery characterised by increased blood pressure and the presence of protein in the urine. It occurs in about 5% of pregnancies and is responsible for approximately 16% of all maternal deaths globally. Pre-eclampsia also doubles the risk of death of the baby around the time of birth. Usually there are no symptoms in pre-eclampsia and it is detected by routine screening. When symptoms of pre-eclampsia occur the most common are headache, visual disturbance (often "flashing lights"), vomiting, and pain over the stomach, and swelling. Pre-eclampsia can occasionally progress to a life-threatening condition called eclampsia, which is a hypertensive emergency and has several serious complications including vision loss, brain swelling, seizures, kidney failure, pulmonary edema, and disseminated intravascular coagulation (a blood clotting disorder).
In contrast, gestational hypertension is defined as new-onset hypertension during pregnancy without protein in the urine.
Hypertension results from a complex interaction of genes and environmental factors. Numerous common genetic variants with small effects on blood pressure have been identified as well as some rare genetic variants with large effects on blood pressure. Also, genome-wide association studies (GWAS) have identified 35 genetic loci related to blood pressure; 12 of these genetic loci influencing blood pressure were newly found.

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PEDIATRIC INTENSIVE CARE UNIT

A paediatric intensive care unit (also paediatric):

usually abbreviated to PICU (/ˈpɪkjuː/), is an area within a hospital specializing in the care of critically ill infants, children, and teenagers. A PICU is typically directed by one or more paediatric intensivists or PICU consultants and staffed by doctors, nurses, and respiratory therapists who are specially trained and experienced in paediatric intensive care. The unit may also have nurse practitioners, physician assistants, physiotherapists, social workers, child life specialists, and clerks on staff, although this varies widely depending on geographic location. The ratio of professionals to patients is generally higher than in other areas of
The hospital, reflecting the acuity of PICU patients and the risk of life-threatening complications. Complex technology and equipment is often in use, particularly mechanical ventilators and patient monitoring systems. Consequently, PICUs have a larger operating budget than many other departments within the hospital.

Go ran Hoagland is credited with establishing the first paediatric ICU in 1955. The PICU was located at Children’s Hospital of Goteborg in Sweden. The first PICU in the United States, although commonly thought to be the unit at the Children’s Hospital of Philadelphia in 1967 by John Downers was established at Kings County Hospital, East Flatbush, Brooklyn, NY by Dr. Ramon Rodriguez-Torres in 1966.The establishment of these units would eventually lead to hundreds of PICUs being developed across North American and Europe. This number is still increasing in present day.

There were a variety of factors that lead to the development of PICUs. John Downers identified five specialties of medicine that aided in the development. These specialties included adult respiratory ICUs, neonatal intensive care, paediatric general surgery, paediatric cardiac surgery, and paediatric anaesthesiology.
Between 1930 and 1950 the poliomyelitis epidemic had created a greater need for adult respiratory intensive care, including the iron lung. There were times when children would contract polio and would have to be treated in these ICUs as well. This contributed to the need for a unit where critically ill children could be treated. Respiratory issues were also increasing in children because neonatal intensive care units were increasing the survival rates of infants. This was due to advances in mechanical ventilation. However, this resulted in children developing chronic lung diseases, but there was not a specific unit to treat these diseases.
Advancements in paediatric general surgery, cardiac surgery, and anaesthesiology were also a driving factor in the development of the PICU. The surgeries that were being performed were becoming more complicated and required more extensive postoperative monitoring. This monitoring could not be performed on the regular paediatric unit, which led to Children’s Hospital of Philadelphia’s development of the first PICU. Advancements in pediatric anaesthesiology resulted in anaesthesiologist treating pediatric patients outside of the operating room. This caused paediatricians to obtain skills in anaesthesiology in order to make them more capable of treating critically ill pediatric patients. These pediatric anaesthesiologists eventually went on to develop run PICUs.

There are a variety of PICU characteristics that allow the healthcare providers to deliver the most optimal care possible. The first of these characteristics is the physical environment of the PICU. The layout of the unit should allow the staff to constantly observe the patients they are caring for. The staff should also be able to rapidly respond to the patients if there is any change in the patient’s clinical status.
Correct staffing is the next vital component to a successful PICU. The nursing staffs are highly experienced in providing care to the most critical patients. The nurse to patient ratio should remain low, meaning that the nurses should only be caring for 1-2 patients depending on the clinical status of the patients. If the patient's clinical status is critical, then they will require more monitoring and interventions than a patient that is stable.
In most cases, the nurses and physicians are caring for the same patients for a long period of time. This allows the providers to build rapport with the patients, so that all of the patient’s needs are fulfilled. The nurses and physicians must work together as a collaborative team to provide optimal care. The successful collaboration between nurses and physician has resulted in lower mortality rates not just in PICUs, but all intensive care units.
As medicine has matured over time, the development of the paediatric intensive care unit has expanded to maintain a level one and a level two PICU. Among these two different levels, they are able to provide critical care and stabilization for each child before transferring to a different acuity.

In the level one PICU, health care team members must be capable of providing a wide variety of care that typically involves intensive, rapidly changing, and progressive approach. In the level two PICU, patients will present with less complex acuity and will be more stable.
As a PICU nurse, extended knowledge and certifications may be required. Recognition and interpretation are two of the many required skills for a PICU nurse. This allows nurses to be able to detect any changes in the patient's condition and to respond accordingly. Other skills may include route of administration, resuscitation, respiratory and cardiac interventions, preparation and maintenance of patient monitors, and psycho-social skills to ensure comfort of patient and family.

There are a variety of certificates that are required for registered nurses to acquire in order to work in the PICU. One of these certifications is the Critical Care Registered Nurse (pediatric) certificate. This certificate allows nurses to care for critically ill pediatric patients in any setting, not just the PICU. Other certificates include cardiopulmonary resuscitation, pediatric basic life support, and pediatric advance life support.
In the PICU, it is important that all team members hold a wide variability of training and experience in order to provide high quality care. Due to different priorities among inter-professionals, the PICU care team includes many different roles. (Physicians, nurses, pharmacists, respiratory therapists, child life, intensivists, cardiologists, physical / occupational therapists, social workers) Each member of the inter-professional team is highly skilled and trained to deliver the best care for each and every child. It is important for each one to introduce themselves to the family and to explain their role to hopefully expand understanding to family members.

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EMERGENCY MEDICAL SERVICES

Emergency medical services (EMS):

also known as ambulance services or paramedic services are emergency services which treat illnesses and injuries that require an urgent medical response, providing out-of-hospital treatment and transport to definitive care. They may also be known as a first aid squad, FAST squad, emergency squad, rescue squad, ambulance squad, ambulance corps, and life squad or by other initialises such as EMAS or EMARS. In most places, the EMS can be summoned by members of the public (as well as medical facilities, other emergency services, businesses and authorities) via an emergency telephone number which puts them in contact with a control facility, which will then dispatch a suitable resource to deal with the situation. Ambulances are the primary vehicles for delivering EMS, though some also use cars, motorcycles, aircraft or boats. EMS agencies may also operate the non-emergency patient transport service, and some have units for technical rescue operations such as extrication, water rescue, and search and rescue.

As a first resort, the EMS provides treatment on the scene to those in need of urgent medical care. If it is deemed necessary, they are tasked with transferring the patient to the next point of care. This is most likely an emergency department of a hospital. Historically, ambulances only transported patients to care, and this remains the case in parts of the developing world. The term "emergency medical service" was popularised when these services began to emphasise diagnosis and treatment at the scene. In some countries, a substantial portion of EMS calls do not result in a patient being taken to hospital.

Training and qualification levels for members and employees of emergency medical services vary widely throughout the world. In some systems, members may be present who are qualified only to drive ambulances, with no medical training. In contrast, most systems have personnel who retain at least basic first aid certifications, such as basic life support (BLS). In English-speaking countries, they are known as paramedics and emergency medical technicians, with the former having additional training such as advanced life support (ALS). Physicians and nurses also provide pre-hospital care to varying degrees in different countries.

Emergency care in the field has been rendered in different forms since the beginning of recorded history. The New Testament contains the parable of the Good Samaritan, in which a man who has been beaten is cared for by a passing Samaritan. Luke 10:34 (NIV) – "He went to him and bandaged his wounds, pouring on oil and wine. Then he put the man on his own donkey, took him to an inn and took care of him." During the middle Ages, the Knights Hospitalet was known for rendering assistance to wounded soldiers in the battlefield.
The first use of the ambulance as a specialized vehicle, in battle came about with the ambulances volantes designed by Dominique Jean Larry (1766–1842), Napoleon Bonaparte's chief surgeon. Larry was present at the battle of Spires, between the French and Prussians, and was distressed by the fact that wounded soldiers were not picked up by the numerous ambulances (which Napoleon required to be stationed two and half miles back from the scene of battle) until after hostilities had ceased, and set about developing a new ambulance system. Having decided against using the Norman system of horse litters, he settled on two- or four-wheeled horse-drawn wagons, which were used to transport fallen soldiers from the (active) battlefield after they had received early treatment in the field. Larry’s projects for 'flying ambulances' were first approved by the Committee of Public Safety in 1794. Larry subsequently entered Napoleon's service during the Italian campaigns in 1796, where his ambulances were used for the first time at Udine, Padua and Milan, and he adapted his ambulances to the conditions, even developing a litter which could be carried by a camel for a campaign in Egypt.
A major advance was made (which in future years would come to shape policy on hospitals and ambulances) with the introduction of a transport carriage for cholera patients in London during 1832. The statement on the carriage, as printed in The Times, said "The curative process commences the instant the patient is put in to the carriage; time is saved which can be given to the care of the patient; the patient may be driven to the hospital so speedily that the hospitals may be less numerous and located at greater distances from each other". This tenet of ambulances providing instant care, allowing hospitals to be spaced further apart, displays itself in modern emergency medical planning.
The first known hospital-based ambulance service operated out of Commercial Hospital, Cincinnati, Ohio (now the Cincinnati General) by 1865. This was soon followed by other services, notably the New York service provided out of Bellevue Hospital which started in 1869 with ambulances carrying medical equipment, such as splints, a stomach pump, morphine, and brandy, reflecting contemporary medicine.

Another early ambulance service was founded by Jaromir V. Mundy, Count J. N. Wilczek, and Eduard Lamezan-Salins in Vienna after the disastrous fire at the Vienna Ring heater in 1881. Named the "Vienna Voluntary Rescue Society," it served as a model for similar societies worldwide.
In June 1887 the St John Ambulance Brigade was established to provide first aid and ambulance services at public events in London. It was modelled on a military-style command and discipline structure.

Also in the late 19th century, the automobile was being developed, and in addition to horse-drawn models, early 20th century ambulances were powered by steam, gasoline, and electricity, reflecting the competing automotive technologies then in existence. However, the first motorized ambulance was brought into service in the last year of the 19th century, with the Michael Reese Hospital, Chicago, taking delivery of the first automobile ambulance, donated by 500 prominent local businessmen, in February 1899. This was followed in 1900 by New York City, who extolled its virtues of greater speed, more safety for the patient, faster stopping and a smoother ride. These first two automobile ambulances were electrically powered with 2 hp motors on the rear axle.

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