Pharma and Biotech Advances

The link between stress and depression has been widely investigated throughout scientific research for centuries, where multiple converging factors related to stress have been associated with inducing depressive symptoms and vice versa.

These factors include the dysregulation of the HPA axis, (neuroplasticity) neurotrophic factors, immune system and inflammatory processes.

 

Role of HPA axis:

The HPA axis has been implicated in the pathophysiology of both stress and depression and functions as the core stress response system. This allostatic, self-regulating process is activated in response to stressors and has also been found to regulate neuroplasticity. HPA axis hyperactivity has been found to be a common neurobiological change in depressed patients where it has been found in 70% of individuals with depression in past research conducted.

The hypothalamic paraventricular nucleus is the main centre located in the hypothalamus. In response to stressors, the HPA axis is activated, releasing corticotrophin-releasing factors (CRF). Research has found an increased CRF immune-reactivity in the Cerebrospinal fluid of individuals with depression (15).

Vasopressin, a neuropeptide that regulates blood pressure and anxiety, is co-expressed via parvocellular neurones, creating a synergistic interaction with CRF.

Studies have shown elevated concentrations of vasopressin in depressed patients, which could potentially contribute to hyperactivity of the HPA axis, whereas selective serotonin reuptake inhibitors (SSRIs) have been found to reverse this.

CRF and Vasopressin stimulate the release of adrenocorticotropic hormone (ACTH), which in turn binds to receptors on the adrenal cortex and increases the release of glucocorticoids; cortisol. Cortisol binds to either mineralocorticoid (MR) in the hypothalamus with high affinity or glucocorticoid receptors (GR) with lower affinity, both of which play a role in negative-feedback mechanisms. Studies suggest the dysregulation of the MR and GR in the HPA axis may lead to depression.

Increased levels of cortisol have been observed in the saliva, blood and urine of individuals with depression along with an increased adrenal gland activity.

Chronic activation of the HPA axis may lead to detrimental effects on the hippocampus, inhibiting neurogenesis.

Long term use of SSRIs and other antidepressants that block 5-HT and norepinephrine uptake has been shown to affect hyperactivity in the HPA axis in depressive patients in a study conducted by Jensen et al. This is supported further by studies that have found that long term treatment via SSRIs normalizes the HPA axis activity. Furthermore, within weeks 2 to 6 of antidepressant treatment, elevated concentrations of MR and GR have been studied, which corresponds to the clinical symptom improvement. This indicates elevated corticosteroid levels contribute to depressed symptoms.

Role of immune system and inflammatory responses:

The effects of the immune system and inflammatory responses on depression and psychological stress has been researched in over the last several decades.  

Chronic stress has been demonstrated to activate inflammatory responses through the activation of the sympathetic branch of the autonomic nervous system, which increases pro-inflammatory cytokines of the immune system such as such as tumour necrosis factor-alpha (TNF-α) and interleukin-1β. These cytokines have also been found to be elevated in depressed individuals indicating a link between stress, depressive symptoms and the immune system. This as excessive release of pro-inflammatory cytokines can lead to a decreased level of BDNFs and neurogenesis along with impaired neuroplasticity, factors of which have been associated with the origin of cognitive impairment and mood disorders.

Cytokines have also displayed the ability to increase monoamine re-uptake, thus reducing the concentrations of neurotransmitters in the brain and are thought to contribute to depressive symptoms such as cognitive dysfunction and insomnia.

 

The cytokine protein interleukin-1β beta is located primarily in the hypothalamus and is expressed through interacting with the interleukin-1R1 receptor. Chronic exposure to stress increases the release of the interleukin-1β in the hypothalamus, consequently inducing the activation of HPA axis and a decreased expression of BDNF. This cytokine is also linked with the regulation of the serotonin transporter gene, an important factor in SSRI antidepressants, suggesting a link between the immune system and depressive symptoms.

Although interleukin-1β plays a vital role in the modifying of neurotransmitters, other factors such as TNF-α, IL-2 and IL-6 also contribute to a lesser extent. Stress could potentially lead to serotonergic neurotransmission dysregulation which in turn could play a role in depressive symptoms. This is supported by a study conducted by Kraus et al, where healthy participants given low dosages of endotoxin, which increased the IL-6 and TNF-α concentrations positively correlated with depressive moods, anxiety and memory impairments. However, a correlation does not imply causation and therefore further research should be conducted to provide with a depth understanding.  

Furthermore, TNF-α, a multifunctional signaling molecule, is involved in activation of the HPA axis, leading to the release of CRFs, which may lead to hypercortisolism. This results in decreased activity of tryptophan hydroxylase and consequently a lower 5-HT synthesis. The activation of the HPA axis also stimulates the enzyme, indoleamine-2,3-dioxygenase. This catabolizes the α-amino acid, tryptophan through the kynurenine pathway, leading to decreased 5-HT synthesis and secretion. 3-hydroxykynurenine is produced through the catabolism of kynurenine resulting in the activation of the glutamatergic system through kynurenic acid and free radicals, this is an area researchers have linked to the pathogenesis of depression. 

TNF-α has serotonin reducing effects which indicates that inhibiting the signaling of TNF-α may alleviate depressive symptoms. This has the same effect as SSRIs, where serotonin re-uptake is blocked. This is further supported by research findings where deletion of the TNF-αR1 gene has led to decreased depressive symptoms in mice.

A more in depth understanding of the impact of pro-inflammatory cytokines responses in association to depressive symptoms has enabled studies aimed at finding treatment in relation to these processes to be conducted allowing studies to establish the efficacy of these cytokines in inhibiting depressive symptoms using in vivo procedures.

Diseases such as arthritis that initiate inflammatory responses have been linked to depression, where it is apparent that inflammation causes depression and the vice versa effect with depressed patients is possible. This can be linked to stress as studies have concluded that depressive patients had enhanced inflammatory response to psychological stress compared to those without depression, thus suggesting increased vulnerability. This can be supported by research that found depressed patients exhibited enhanced inflammatory responsiveness to mild psychosocial stress caused by public speaking through an increased IL-6 and NF-kappaB activity.

 

Neuroplasticity:

Neuroplasticity plays a vital role in the pathology of depression by affecting the regulation of neurogenesis, along with synaptic plasticity. Neurotrophic factors such as BDNF effect the neuronal plasticity and functioning of the brain along with the nervous system. The role of brain-derived neurotrophic factor (BDNF) has been assessed thoroughly, where lower BDNF levels in blood cells of depressed patients. Furthermore, abnormalities in BDNF functioning due to impaired receptors in the brain of depressed subjects.  BDNF has been suggested to decrease 5-HT uptake in vitro testing. Overall, BDNF has shown to be implicated in the pathogenic mechanisms of depression. Further studies are required to describe how BDNF is involved in these depressive symptoms.

There have also been strong links between stress and BDNF found in the brain. Exposure to stressors may lead to decreased hippocampal neurogenesis and BDNF expression. A study conducted by Makino et al indicated that chronic immobilization stress lead to decreased mRNA expression of BDNF in the brain. Furthermore, the role of BDNF on stress studied in rodents by exposure to corticosterone has also been found to decrease the BDNF expression in the brain (39). This was further supported as it was observed that the mRNA level of BDNF decreased in the hippocampus and frontal cortex when exposed to corticosterone, whereas the withdrawal of corticosterone lead to an increase BDNF level in the hippocampus. These studies have consistently demonstrated a decreased BDNF levels caused by stress that, however, could be reversed by antidepressant treatment.

Antidepressant drugs such as SSRI have also been demonstrated to increased BDNF expression in the cortical regions and hippocampus of the brain. To have a more in-depth understanding of the role of BDNF in antidepressants, a small dosage of BDNF protein was infused directly into the CA3 and DG region of the brain and concluded that this was sufficient enough to cause antidepressant-like response within 3 days, emphasising the importance of these regions for BDNF having antidepressant effects. Furthermore, a decrease in BDNF in the DG region was found to be vital for the antidepressant-like responses of conventional antidepressants such as SSRIs, suggesting BDNF in the DG region of the hippocampus is needed for antidepressant efficacy.

BDNF has also demonstrated antidepressant-like properties in rodents and can block antidepressant effects of drugs such as SSRIs via genetic deletion thus could potentially new render therapeutic targets. However, studies on rodents have found insufficient evidence for BDNF causing depression and thus argues that it is only an alternative component factor that potentially leads to depression.

Furthermore, the changes in pro-inflammatory cytokines due to prolonged activation of the inflammatory processes in the brain compromises cognitive function and neuroplasticity. This induces decreased neurogenesis, neurotrophins and neuron repair along with enhanced oxidative stress and neuron apoptosis.

Role of serotonin and vasopressin:

Serotonin and its receptors are a key target for SSRI drugs to alleviate depressive symptoms and contribute to symptoms of depression such as anxiety, pessimistic moods and sleep disturbance. Increased stress levels can also be linked to serotonin as the serotonergic system is closely linked to cortisol concentration. The 5HT 1A receptors are highly expressed on serotonergic neurons and located in the hippocampus playing a key role in stress anxiety and depression. Studies have correlated a decrease in 5HT1A receptors activity with increased stress levels. Mineralocorticoid receptors impact the 5HT1A receptor cells as their activity decreases under stressful conditions. In contrast to this, the auto receptors 5HT1B and are activated by stress. This could be used to explain reduced serotonergic activity in depressed patients through glucocorticoids caused by stressors.

Serotonin is a monoamine transmitter synthesized from tryptophan. Recent findings suggest that impaired functioning of serotonin could lead to depression through tryptophan. This is as changes in tryptophan concentrations have been found to lead to corresponding changes in the ability for neurons to produce 5-HT. The essential amino acid, tryptophan hydroxylase has been reported to have significantly lower concentrations in depressed individuals. Furthermore, this is also supported by research conducted where acute dietary manipulation where low-tryptophan supplemented with high neutral amino acid dosage lead to the depletion of tryptophan in depressed individuals. The neutral amino acids are thought to have increased the reduction of the serotonin in the brain via tryptophan depletion as it was used as competition with tryptophan for carrier-mediated brain uptake. It was found that this diet lead to the relapsing of depressed individuals taking antidepressant drugs such as fluoxetine and desipramine within several hours of indigestion. Moreover, these individuals were found to have improvements in depressive symptoms when provided by tryptophan supplements suggesting that alterations in the serotonin concentration in the brain has a significant impact on the intensity of the symptoms experienced by depressed patients and that robustness of the serotonergic neuronal activity is vital for the therapeutic response of specific antidepressants.

Furthermore, the Antidiuretic hormone, vasopressin impacts the HPA axis through binding to the V1b receptors located in the brain. Research over the years have consistently found elevated levels of vasopressin in depressed patients along with a hyperactive HPA axis. It has been found that depressed individuals have a higher number of V1b receptors compared to individuals that do not have depression. This suggests a link between vasopressin, the HPA axis and depression

Synthetic biology is the convergence of advances in chemistry, biology, computer science, and engineering that enables us to go from idea to product faster, cheaper, and with greater precision than ever before. A community of experts across many disciplines is coming together to create these new foundations for many industries, including medicine, energy and the environment.

MEDICAL APPLICATIONS

Synthetic circuits and pathways can be used for the controlled delivery of drugs as well as for gene and metabolic therapy. In some cases, sophisticated, kinetic control over drug release in the body may yield therapeutic advantages and reduce undesired side effects. Most hormones in the body are released in time-dependent pulses. Glucocorticoid secretion, for instance, has a circadian and ultradian pattern of release, with important transcriptional consequences for glucocorticoid-responsive cells. These mimic these patterns in the administration of synthetic hormones to patients with glucocorticoid-responsive diseases, such as rheumatoid arthritis, may decrease known side effects and improve therapeutic response.

ALTERNATIVE ENERGY

Recent advances in the development of genetic tools and in silico predictive capacity have facilitated the characterization and manipulation of algal genomes in the effort to develop designed algal biofuel production strains. Depending on the properties of fuel desired, microalgae have potential for producing lipids for conversion into biodiesel, for hydrogen production, and even as a source of ethanol; and several advances have been made to improve yields in each of these approaches. Algae can also produce complex hydrocarbons, for example terpenoids, which are useful both as biofuel additives and as valuable coproducts that could bolster the economic feasibility of the emerging algal biofuels industry.

COMPUTING APPLICATIONS

A biological computer refers to an engineered biological system that can perform computer-like operations, which is a dominant paradigm in synthetic biology. Researchers built and characterised a variety of logic gates in a number of organisms, and demonstrated both analogue and digital computation in living cells. They demonstrated that bacteria can be engineered to perform both analogue and/or digital computation. In human cells research demonstrated a universal logic evaluate that operates in mammalian cells in 2007. Subsequently, researchers utilised this paradigm to demonstrate a proof-of-concept therapy that uses biological digital computation to detect and kill human cancer cells in 2011.

BIO-SENSING

A biosensor refers to an engineered organism, usually a bacterium, that is capable of reporting some ambient phenomenon such as the presence of heavy metals or toxins. One such system is the Lux operon of Aliivibrio fischeri, which codes for the enzyme that is the source of bacterial bio luminous, and can be placed after a respondent promoter to express the luminescence genes in response to a specific environmental stimulus. One such sensor created consisted of a bio luminescent bacterial coating on a photosensitive computer chip to detect certain petroleum pollutants. When the bacteria sense the pollutant, they luminescence.

Microbes, collectively, include bacteria, viruses, fungi, and parasites. Antimicrobial drugs, such as antibiotics, have been successfully used to treat patients with bacterial and infectious diseases. Antibiotics may either kill or inhibit the growth of bacteria. Antibiotics are not effective against viruses such as the common cold or influenza.

 

Cephalosporin antibiotics:

Cephalosporin’s are a group of broad-spectrum antibiotics that are commonly used to treat infections caused by a wide variety of bacteria, including more serious infections such as septicaemia, pneumonia, meningitis, biliary-tract infections, peritonitis, and urinary-tract infections. Cephalosporin Mode of Action, Cephalosporins are a type of B-Lactam antibiotics closely related to the penicillins. They are bactericidal, with the same MOA as other beta-lactams. Cephalosporins disrupt synthesis of the peptidoglycan layer of bacterial cell walls. Peptidoglycan is a strong structural molecule specific to the cells walls of bacteria. With the cell wall structure compromised, the bactericidal result is lysis and death of the cell. Our cells do not have cells walls or peptidoglycan, therefore, B-lactam antibiotics are able to target bacterial cells without harming human cells.

 

Macrolide antibiotics:

 

Macrolide antibiotics have an antibacterial spectrum that is similar, but not identical, to that of penicillin, so are often used for people with a penicillin allergy or to treat penicillin-resistant strains of bacteria. Macrolide antibiotics are particular useful for treating lung and chest infections. They are also used for skin infections and some sexually transmitted infections. Macrolides exert their antibiotic effect by binding irreversibly to the 50S subunit of bacterial ribosomes. Ribosomes are the protein factories of the cell, and by binding to the ribosome, macrolides inhibit translocation of tRNA during translation (the production of proteins under the direction of DNA). Although the cells of humans also have ribosomes, these eukaryotic cellular protein factories differ in size and structure from the ribosomes of prokaryotes. This action is mainly bacteriostatic, meaning that bacterial growth and reproduction are inhibited, in contrast to bactericidal antibiotics which directly kill bacteria. Macrolides can be bactericidal in high concentrations.

 

Penicillin antibiotics:

 

Penicillin antibiotics are the most widely used groups of antibiotics. They are mainly broad-spectrum antibiotics that can be used for a wide variety of infections, such as respiratory tract infections, skin infections and urinary tract infections. Flucloxacillin is reserved for treating bacteria that are resistant to other penicillin’s. Penicillin’s, and other beta-lactam antibiotics, work by interfering with interpeptide linking of peptidoglycan, the a strong, structural molecule found specifically bacterial cell walls. Cell walls without intact peptidoglycan cross-links are structurally weak, prone to collapse and disintegrate when the bacteria attempt to divide. Since the eukaryotic cells of humans do not have cell walls, our cells are not damaged by penicillin’s.

 

Quinolone antibiotics:

 

These are broad-spectrum antibiotics that can be used to treat a wide range of infections, particularly urinary tract and respiratory infections. Quinolones are bactericidal drugs, meaning that they kill bacteria. These antibiotic drugs inhibit the bacterial DNA gyrase enzyme which is necessary for DNA replication. Since a copy of DNA must be made each time a cell divides, interfering with replication makes it difficult for bacteria to multiply. How DNA is packaged is very different in bacteria as opposed to eukaryotes. Bacteria supercoil DNA using DNA gyrase, whereas eukaryotes coil DNA around histone proteins. Because quinolones specifically target DNA gyrase, they do not interfere with human DNA.

Coronary heart disease occurs when there is a decrease in blood supply to the heart muscles due to narrowing and obstruction of the coronary arteries. This leads to myocardial ischemia, the lack of oxygen to the heart. Furthermore, it leads to a high demand for o2 due to myocardial hypertrophy due to hypertension.

 

This can be produced by thrombosis, where adhesion of platelets at plaque occur or plaque rupture occurs. Anaemia and hypertension are also the causes of this.

However, the main cause of coronary heart disease is atherosclerosis, where accumulation of lipids, macrophages and smooth muscle create a plaque. This dysfunction/ injury of the endothelium is caused by several factors such as mechanical stress (e.g. hypertension), biochemical abnormalities (e.g. diabetes, elevated LDL levels), genetics, infection and free radicals.

 

This injury increases the accumulation and permeability of oxidised LDL’s, which in turn is taken up by macrophages to generate foam cells causing fatty streaks.

 

This will progress further into a transitional plaque with the addition of extracellular lipids. Cholesterol precipitates into crystals, causing cell necrosis.

Cytokines are released by macrophages. Furthermore, the endothelium damage recruits more macrophages and promotes smooth muscle cell proliferation.

 

Collagen is produced by the smooth muscle cells leading to secondary fibrosis.

Cholesterol crystals, enzymes and debris leak out to induce calcification. This will lead to irreversible degenerate changes leading to a stable plaque.

Clinical manifestations are variable, where they can be asymptomatic (free of symptoms), cause angina pectoris or if severe and prolonged, can cause a heart attack.

Symptoms can include: Dizziness, fatigue, shortness of breath and chest discomfort.

There are 9 hallmarks of ageing; genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication. 

 

Genomic instability and telomere attrition are hallmarks of ageing. Endogenous or exogenous agents can stimulate a variety of DNA lesions that are schematically represented on a single chromosome. Excessive DNA damage or insufficient DNA repair favours the ageing process. This could affect nuclear or mitochondrial DNA. Elimination of damaged cells and telomerase reactivation help extend human health span.

 

Epigenetic alterations are another hallmark for ageing. These are alterations in acetylation and methylation of DNA or histones, as well as of other chromatin-associated proteins. These may induce epigenetic changes that contribute to the ageing process. Epigenetic drugs help extend human health span.

 

Another hallmark of ageing is loss of proteostasis which is the unfolding of proteins due to exogenous and endogenous stress. It also impairs proper folding during protein synthesis. Unfolded proteins are usually refolded by heat-shock proteins or targeted to destruction by the ubiquitin-proteasome or lysosomal (autophagic) pathways. Failure to refold or degrade unfolded proteins can lead to their accumulation and aggregation, resulting in proteotoxic effects. Activation of chaperones and protease systems help extend human health span.

 

Deregulated nutrient-sensing is the overview of the somatroph axis involving growth hormone (GH) and the insulin/insulin growth factor 1 (IGF-1) signalling pathway and its relationship to dietary restriction and ageing. Molecules that favour ageing are GH, IGF-1, PI3K, Akt and mTOR. Whereas PTEN, FOXO, AMPK, Sirt1 and PGC-1a are all molecules with anti-ageing properties. Inhibition of DR, IIS and mTOR help extend human health span, as well as the activation of AMPK and sirtuins.

 

Stress signals and defective mitochondrial function generate reactive oxygen species (ROS) that, below a certain threshold, induce survival signals to restore cellular homeostasis. However, at higher continued levels, it can contribute to ageing through mitochondrial dysfunction. Mitohormetics and mitophagy help extend human health span.

 

Cellular senescence prevents the proliferation of damaged cells, in young organisms, thus protecting from cancer and contributing to tissue homeostasis. In old organisms, the pervasive damage and the deficient clearance and replenishment of senescent cells results in their accumulation. This has a number of deleterious effects on tissue homeostasis, that contribute to ageing. Clearance of these senescent cells help extend human health span.

 

The final hallmarks of ageing are stem cell exhaustion and altered intracellular communication. Consequences of the exhaustion of haematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), satellite cells and intestinal epithelial stem cells (IESCs) include anaemia, osteoporosis, loss of muscle fibres and intestinal function. Neurohormonal signalling, such as renin-angiotensin, adrenergic, insulin-IGF1 signalling, tend to be deregulated. Inflammatory reactions increase, due to accumulation of pro-inflammatory tissue damage, failure to effectively clear pathogens and dysfunctional host cells, the propensity of senescent cells to secrete pro-inflammatory cytokines. Stem cell-based therapies help extend human health span with stem cell exhaustion whereas anti-inflammatory drugs and blood-borne juvenile factors allow extending the human health span for altered intracellular communication.

The human immunodeficiency virus (HIV) is a lentivirus (a subgroup of retrovirus) that causes HIV infection and over time acquired immunodeficiency syndrome (AIDS). HIV infects vital cells in the human immune system such as helper T cells (specifically CD4+ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells through a number of mechanisms, including pyroptosis of abortively infected T cells, apoptosis of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4+ T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections. Many HIV-positive people are unaware that they are infected with the virus. HIV-1 testing is initially by an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV-1. Specimens with a nonreactive result from the initial ELISA are considered HIV-negative unless new exposure to an infected partner or partner of unknown HIV status has occurred. f the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., western blot or, less commonly, an immunofluorescence assay (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or reactive by western blot are considered HIV-positive and indicative of HIV infection.

AIDS is not a virus but a set of symptoms (or syndrome) caused by the HIV virus. A person is said to have AIDS when their immune system is too weak to fight off infection, and they develop certain defining symptoms and illnesses. This is the last stage of HIV, when the infection is very advanced, and if left untreated will lead to death.Basic facts about AIDS include, AIDS stands for acquired immune deficiency syndrome, AIDS is also referred to as advanced HIV infection or late-stage HIV, AIDS is a set of symptoms and illnesses that develop as a result of advanced HIV infection which has destroyed the immune system, Treatment for HIV means that more people are staying well, with fewer people developing AIDS.HIV disease becomes AIDS when your immune system is seriously damaged. If you have less than 200 CD4 cells or if your CD4 percentage is less than 14%, you have AIDS. AIDS-related symptoms also includes serious weight loss, brain tumors, and other health problems. Without treatment, these opportunistic infections can kill you. AIDS is different in every infected person. A few people may die a few months after getting infected, but most live fairly normal lives for many years, even after they “officially” have AIDS. A few HIV-positive people stay healthy for many years even without taking antiretroviral medications (ART).

B lactam antibiotic:

Β-lactam antibiotics (beta-lactam antibiotics) are a class of broad-spectrum antibiotics, consisting of all antibiotic agents that contain a beta-lactam ring in their molecular structures. Thisincludes penicillin derivatives, cephalosporins (cephems), monobactams,and carbapenems. Most β-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics. Bacteria often develop resistance to β-lactam antibiotics by synthesizing a β-lactamase, an enzyme that attacks the β-lactam ring. To overcome this resistance, β-lactam antibiotics are often given with β-lactamase inhibitors such as clavulanic acid. β-lactam antibiotics are indicated for the prevention and treatment of bacterial infections caused by susceptible organisms. At first, β-lactam antibiotics were mainly active only against Gram-positive bacteria, yet the recent development of broad-spectrum β-lactam antibiotics active against various Gram-negative organisms has increased their usefulness.

Asthma is a long-term pulmonary condition, characterized by inflammation of the lower airways and episodes of airflow obstruction.  Asthma severity ranges from intermittent mild symptoms, such as coughs and wheezing, to severe, life-threatening attacks that require immediate hospital treatment. Obstruction of the airway in asthma is generally considered reversible, meaning that the obstruction of the lung can generally be resolved with treatment and in some cases can resolve spontaneously.

Clinical symptoms presented by asthma patients include coughing, shortness of breath, chest tightness and wheezing. The dominant physiological event that leads to these clinical symptoms is airway narrowing. Bronchoconstriction is the contraction of bronchial smooth muscle in response to exposure to a variety of IgE-dependent stimuli such as allergens and non IgE-dependent stimuli including exercise, cold air, and irritants. As the disease becomes more persistent and inflammation more progressive, other factors further limit airflow such us oedema and mucus hypersecretion. These changes are initially reversible but over the years, irreversible structural changes begin to take place. Scarring builds up leading to the thickening of the basement membrane which permanently reduces the airway diameter, this has been associated with a progressive loss of lung function.

Substances that trigger asthma differ from person to person. Extrinsic asthma, is caused by an increase in the production of IgE and airway inflammation in response to allergens whilst Intrinsic asthma is triggered in response to smoke, air pollution, stress, infections and exercise.

 

Extrinsic:

In some asthma patients, T-helper 2 cells, which are not typically found in normal lungs, are upregulated in the lungs; This increases eosinophil and antibody production therefore promotes inflammation. In other asthma patients low levels of t-helper cells and high levels of neutrophils have been observed. Neutrophils release IL- 8 which plays a key role in asthma, patients with the neutrophilic disease tend to have more severe asthma than patients with the eosinophilic disease.

Intrinsic:

A common intrinsic asthma is Nocturnal asthma. This type of asthma is related to circadian rhythms; at night cortisol and epinephrine levels decrease while histamine levels increase, these changes lead to bronchoconstriction resulting in worsened symptoms.

Asthma can also be exercise induced and may occur as a compensatory mechanism to warm and moisten the airways after exercise in cool and dry conditions.

Moreover, asthma can be drug-induced. Some drugs, for example aspirin can prevent the conversion of prostaglandins. This stimulates the release of leukotriene, a powerful bronchoconstrictor.

The liver is the largest organ in the body. It has many functions such as the role of metabolising carbohydrates, protein, and the fat delivered through portal circulation. They are also in charge of synthesis of plasma proteins and clotting factors. In addition, the liver stores vitamin B12and has the role of detoxification and excretion.

 

Toxic products can potentially be the result of the metabolism of alcohol. The major alcohol–metabolizing enzymes are alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1). Alcohol dehydrogenase converts alcohol to acetaldehyde, which can react with other proteins in the cell to generate hybrid molecules known as adducts. CYP2E1 also generates oxygen radicals. Elevated levels of oxygen radicals can generate a state of oxidative stress, which through various mechanisms leads to cell damage. The two can react with proteins to form MDA–protein and HNE– protein adduct. The conversion of ethanol to acetaldehyde and then acetate by ADH and ALDH leads to the reduction of NAD to NADH. The increased NADH/NAD ratio has profound effects on the metabolism of carbohydrates and lipids and leads to decreases in Gluconeogenesis and Fatty acid β-oxidation but increases in Ketogenesis and Fatty acid synthesis.

 

Another effect is alcoholic liver disease. Alcoholic liver disease is a group of structural and functional changes in the liver resulting from excessive alcohol consumption. Severity depends on amount and duration of alcohol consumption. The three stages of progression are Alcoholic fatty liver (mildest form), Alcoholic hepatitis (also causes degenerative changes and necrosis of liver cells) and Alcoholic cirrhosis (most advanced, diffuse scarring, disturbed liver function).

Fatty liver is the accumulation of fat globules in the cytoplasm of liver cells in response to injury or obesity (steatosis). It is common in heavy drinkers and alcoholics (increased NADH/NAD ratio) resulting in impaired liver function but injury is still reversible.

Alcoholic hepatitis results in irregularly shaped pink deposits are accumulated within the cytoplasm of liver cells: Mallory bodies (damaged intermediate filaments). This indicates that the cell has been irreparably damaged. Leukocytes accumulate in response to necrosis. Hepatocytes are replaced by connective tissue, which leads to progressive fibrous scarring throughout the liver.

 

Cirrhosis is the diffuse scarring of the liver from any cause with derangement of liver function and regeneration. The liver is converted into a mass of scar tissue containing the nodules of degenerating and regenerating liver cells, proliferating bile ducts and inflammatory cells. The liver architecture is lost (impaired liver function) and intrahepatic branches of hepatic artery and portal vein are constricted by scar tissue (portal hypertension). This results in blood pressure rising because venous return through the portal system is obstructed by scar tissue with low albumin production by liver as the impairment affects blood colloid osmotic pressure. This leads to excessive fluid leakage from the portal capillaries and the abdomen becomes distended by the accumulated fluids (ascites).

 

Benign tumours are rare in the urinary system, most tend to be malignant. These can occur at any point of the urinary system, obstructing urine flow and impairing renal failure. These can be further categorised into malignant renal tumours and urothelial tumours.

 

Malignant renal tumours comprise 1-2% of all malignant tumours. One example is renal cell carcinoma (RCC). RCCs arise from proximal tubular epithelium in the renal tubule. They are the most common renal tumour is adults and rarely present before the age of 40 and is the most common in male smokers of 50-70 years. RCCs are highly vascular tumours. Patients are asymptomatic but can occasionally present with haematuria, loin pain and a mass in the flank. Due to the asymptomatic nature of the tumour, metastasis is common at the time of diagnosis. Malaise, anorexia and up to 30% of weight loss can also occur. A rarer symptom is polycythaemia, which is only presented 5% of patients. Due to the secretion of renin by the tumour, some patients exhibit hypertension whereas anaemia occurs in other patients due to the depression of erythropoietin. Pyrexia is present in about 1/5 of patients whereas approximately 1/3 present with metastases. If the tumour is found to be on the left side, then further complications arise, and the varicocele may invade the renal vein (via the tumour) and obstruct drainage of the left testicular vein. RCCs are diagnosed through ultrasonography, which demonstrates the solid lesion and examines the patency of the renal vein and inferior vena cava. CT scanning or MRIs are then used to identify the renal lesion and involvement of the renal vein or inferior vena cava; however, the latter produces better results in comparison. Renal arteriography allows the revelation of the tumour’s circulation but is rarely used. Urine cytology is of no value as the tumour is of a malignant nature. The ESR of the patient may be raised. Liver biochemistry is abnormal at the start of the diagnosis but returns to normal after treatment. Partial or complete surgical removal of the kidney is recommended since cancer is unresponsive to radiation or chemotherapy. A nephrectomy is performed unless there are bilateral tumours present or the kidney is functioning poorly. In these scenarios, a more conservative approach is taken, and partial nephrectomy is carried out.

 

A rare renal tumour is nephroblastoma, as known as Wilms’ tumour, is the most common malignant cancer in children. This tumour is mainly seen within the first 3 years of life and may be bilateral. It usually occurs in one kidney, growing as a solitary mass. It is associated with several congenital defects, such as aniridia, hemihypertrophy and urinary tract abnormalities. Clinical manifestations include asymptomatic abdominal mass, high blood pressure, haematuria, urinary tract infections and weight loss. Diagnosis is established by ultrasound, CT scans and MRI. A combination of nephrectomy, radiotherapy and chemotherapy has improved survival rates to 90%.

 

The other type of urinary tract tumours is urothelial tumours. These account for 3% of deaths in all forms of malignancies and are uncommon below the age of 40. Predisposing factors are smoking, exposure to carcinogens and drugs and chronic inflammation. Most bladder cancers begin the inner bladder lining and usually develop to multiple invasive tumours to the surrounding structures as metastasis is common. It most frequently occurs in adult Caucasian men, but other people at risk are those with recurrent UTIs, long term catheter placement and chemical exposure. Painless haematuria is the most common presenting symptom of bladder malignancy, although pain may occur due to clot retention. Symptoms suggestive of UTIs may also occur due to absence of significant bacteriuria. Pain also results from local metastases. Transitional cell carcinomas in the kidney and ureter also present with haematuria and give rise to flank pain, especially if there is urinary tract obstruction present. Cytological examination of urine for malignant cells and renal imaging is performed in all patients. Cystoscopy is necessary unless pathology is found in the upper urinary tract. In cases where the tumour isn’t clearly outlined on ultrasonography or CT, retrograde ureterography is helpful. Treatment strategies include surgical removal of the tumour, radiation and chemotherapy. Cystectomy is the treatment most commonly used in which a new bladder is made out of the small bowel. If metastasis and recurrence occur, chemotherapy agents such as doxorubicin, mitomycin or cisplatin + 5FU are useful. Radical radiotherapy may be applied to patients over 70.

Breast cancer

Breast cancer is the uncontrolled growth of epithelial cells lining ducts and lobules of the breast and is the most common cancer among non-smoking women.  The main risk factors of breast cancer are a family history of breast cancer as well as mutations in the BRCA 1 and BRCA 2 genes, diet, exogenous hormones from oral contraception and postmenopausal hormone replacement therapy. Some symptoms of breast cancer are a hard-painless lump or swelling on the upper part of the breast.

Breast cancer screening, by mammography, is done for early detection of cancer. Treatment for breast cancer is dependent on the stage of the cancer; some treatments are surgery, where localised tumours are removed by a mastectomy, radiation therapy which can be applied to reduce recurrence, hormonal therapy, which includes medications such as tamoxifen which blocks the attachment of oestrogen to the receptor thus preventing cancer cells from getting the hormones required to grow and chemotherapy. 

Ovarian cancer

One tumour that may develop in the reproductive system is ovarian cancer. The aetiology of ovarian cancer is poorly understood with some established risk factors for ovarian cancer being age, use of hormone replacement therapy and inherited defective versions of the BRCA1 and BRCA2 genes. Furthermore, a consistent relationship has been observed between the risk of ovarian cancer and frequency and duration of ovulation and that early pregnancy reduces the risk. Although there is still some uncertainty over the tissue of origin of this cancer, the surface epithelium or epithelial lining of the fallopian tubes is the most likely source. Symptoms which are specific to this cancer are abdominal distension (pelvic mass), loss of appetite, abdominal pain and an increase in the frequency of urination

Determining the stage of ovarian cancer is very important in developing a treatment plan. At Stage 1, ovarian cancer is limited to one or both ovaries and can be detected by the serum tumour marker CA125. In Stage 2, ovarian cancer extends to the pelvis area. In Stage 3, ovarian cancer has spread to the abdominal region. In stage 4, ovarian cancer extends into the liver or to regions beyond the abdominal area.

The treatment used in the early stages of ovarian cancer is typically surgery which focuses on removing the tumour; whilst treatment in advanced stages includes chemotherapy based on carboplatin, which interferes DNA repair, and paclitaxel, a mitotic inhibitor which targets tubulin. 

Cervical cancer

Cervical cancer is when abnormal cells in the lining of the cervix grow in an uncontrolled way, the main symptom is unusual bleeding from the vagina. Cervical screening aims to prevent cervical cancer from developing and is vital as the lag time between infection and the appearance of the disease can be 40-50 years. The PAP smear test is a cheap and safe screening method but requires a well-trained cytologist to identify early changes. Other screening techniques used are liquid cytology and DNA testing for human papillomavirus. 

Prostate cancer

Another tumour that may develop in the reproductive system is prostate cancer. Although the cause of prostate cancer is unknown, some prominent factors that have been seen to increase the risk of developing it are age, family history, hormonal factors and obesity. The most common symptom that is experienced is urinary tract obstruction and the treatments of choice are radical prostatectomy or radiotherapy.

Testicular cancer

Furthermore, the most common cancer in men aged 15-35 is testicular cancer. This cancer is typically a teratoma, of mixed origin, and has many established risk factors including undescended testicles, fertility problems, family history and a previous testicular cancer. Common symptoms of this cancer are a painful mass in the testicles, a lump of swelling in the testicles and a heavy scrotum. 

There are three main stages of testicular cancer. In the earliest stage, stage 1, the cancer is only in the testicle. In stage 2 the cancer cells have spread into nearby lymph nodes, either in the abdomen or pelvis. In the final stage, the cancer has spread to distant lymph nodes, for example near the collarbone, or to other organs such as the lungs. A treatment for this cancer is adjuvant chemotherapy with cisplatin etoposide and bleomycin, this induces DNA damage leading to a 95% survival rate.