Pathophysiology of Glucose Metabolism and Its Treatment

Yup, it's yet another post about diabetes. (See here, here, here and here for my previous posts on diabetes.) Most of the content in this lecture was covered in the earlier posts, so I'm just going to cut straight to the bits that I haven't spoken about before.

Glucose Regulating Hormones

Firstly, a quick note on glucose regulating hormones. Insulin responds to increased blood glucose, causing blood glucose to go back down. There are four hormones that do the opposite (i.e. make blood glucose go up when it is low): glucagon, adrenaline, glucocorticoids and growth hormone.

Type 1 Diabetes Treatment

Obviously, people with type 1 diabetes need to take exogenous insulin. In the "basal-bolus regimen," patients take long-acting insulin at bedtime to maintain basal levels of insulin, and rapid-acting insulin (kicks in after around 5-15min) before they eat. This intensive regimen requires at least four injections a day, but it gives decent control over glucose levels.

Just like any other treatment, insulin therapy is not without its risks. If you give too much insulin, hypoglycaemia may result (see here for notes on insulin shock). Weight gain is also a potential side effect, as insulin is important in storage of various macronutrients. Finally, if the injection site is not rotated, scarring and lipohypertrophy or lipoatrophy may occur at the injection site.

There are several new treatments that are being developed in order to eliminate the need for needles. The bionic pancreas is a "closed-loop system" that continuously monitors glucose levels and delivers insulin or glucagon as necessary. Microneedle patches are small patches that have nanoparticles with a glucose sensor and insulin.

Type 2 Diabetes Treatment

The main treatments for type 2 diabetes are weight loss (which works for <10% of patients), oral hypoglycaemic agents, insulin, and treatment of associated conditions. In this post, I will go into a little bit more detail into some of the hypoglycaemic agents.

Metformin

Metformin is a biguanide that helps to decrease gluconeogenesis in the liver, but the exact mechanism is unknown. It is the drug of first choice as it does not cause hypoglycaemia or weight gain, and may even cause a decrease in colorectal cancer risk. Side-effects include gastrointestinal problems (which are usually transient) and lactic acidosis (though this is extremely rare).

Sulfonylureas

Sulfonylureas bind to the SUR1 receptor on β-cells, blocking the potassium channels, which in turn stimulates insulin release (see here for an explanation as to why). As sulfonylureas' mechanism of action relies on stimulation of insulin release, patients taking this drug must still have some functional β-cells.

Sulfonylureas are not the drug of first choice (they are the drug of second choice) due to drug-drug interactions (DDIs) and side effects. Sulfonylureas bind albumin in the blood and are metabolised in the liver, similar to many other drugs. DDIs tend to cause hypoglycaemia. Unlike metformin, hypoglycaemia is a possible side-effect of sulfonylureas, as well as weight gain. Nevertheless, sulfonylureas are often co-adminstered with metformin or are given to patients that cannot tolerate metformin.

Thiazolidinediones (TZDs/Glitazones)

See here. Effects can take weeks to develop.

α-Glucosidase Inhibitors

These drugs inhibit α-glucosidase in the intestines, thus inhibiting the breakdown of maltose into glucose and slowing absorption of glucose. Side-effects include bloating, flatulence and diarrhoea.

SGLT2 Inhibitors

These drugs block reabsorption of glucose in the proximal tubule so that more of it will be excreted in the urine.

Incretin-Based Therapies

Incretins, such as GLP-1, are gut peptides that increase insulin release after food (which is why insulin levels rise more after oral glucose, rather than IV glucose). Incretins are usually broken down by enzymes such as DPP-4. Incretin-based therapies include GLP1 mimetics such as exenatide and DPP-4 inhibitors such as sitagliptin. These drugs work to stimulate insulin release, and may also increase β-cell function and mass.

Introduction to Diabetes Mellitus

Yup, another post about diabetes... as if this post, this post and this post weren't enough for you :P

History of Diabetes

Diabetes has been around for a very long time. As early as 1500BC, the Ancient Egyptian physician Hesy-Ra wrote about a disease involving frequent urination. Another early text called the Susruta (which was written by an Indian physician of the same name), dating from around 1500-600BC, also wrote about some symptoms of diabetes (frequent urination, thirst, and so on). Other ancient physicians that mentioned diabetes include Appolonius of Memphis (~250BC) and Aretaeus the Cappodacian (~1st century AD).

Types of Diabetes

As you (hopefully) know, the main types of diabetes are type 1 and type 2. Patients with type 1 diabetes have β-cell destruction for some reason (sometimes some kind of autoimmune disease), but they only start showing symptoms when there are less than around 10% of their total β-cells remaining. Patients with type 2 diabetes acquire insulin resistance. At first, β-cell activity increases in order to compensate, but eventually β-cell function declines. It's important to note that decline in β-cell function doesn't occur in everyone: some people with insulin resistance do not develop diabetes. Type 2 diabetes is associated with metabolic syndrome, which is discussed here.

Aside from type 1 and type 2 diabetes, there are many other types of diabetes. These include gestational diabetes, other genetic conditions (e.g. mitochondrial conditions), pancreatic destruction (due to surgery, pancreatitis, etc.), endocrinopathies (e.g. Cushing's syndrome), drug/chemical-induced diabetes (e.g. glucocorticoids, atypical antipsychotics), infections (e.g. congenital rubella) and other immune problems (e.g. anti-insulin receptor antibodies). Phew! That was quite a list!

Diagnostic Criteria

Diagnostic criteria for diabetes are as follows:

• Fasting glucose >= 7mmol/L (normal < 6.1, though some other sources say 3.5 - 5.5 mmol/L)
• Random glucose test or 2hr post 75g glucose (in oral glucose tolerance test) >= 11.1 mmol/L (normal < 7.8)
• HbA1c (glycosylated haemoglobin) >= 6.5% (normal 4-6%. <7% indicates good control, >8% indicates poor control)

If your values are between the "normal" and "diabetic" ranges, you may be considered to have IFG (impaired fasting glucose) or IGT (impaired glucose tolerance). These conditions are also sometimes known as "pre-diabetes."

Prevalence

• Age- Type 2 diabetes becomes more prevalent as you get older, as living longer gives your β-cells more time to crash and burn.
• Geographical location- The Western Pacific area (Australia and surrounding islands) has one of the highest rates of diabetes. Some of the small islands near Australia have particularly high rates of diabetes.
• Ethnicity- Caucasians seem to have the lowest risk of developing diabetes. Many indigenous populations are at relatively high risk of diabetes.
• Genetics- Type 1 diabetes has a genetic component. If one person has diabetes, the chance that a monozygotic twin also has it is 50%, whereas the chance for a sibling is 5%, the chance for the father is 6%, and the chance for the mother is 2%. The "high-risk" HLA alleles are DR3, DR4 and DQ8.

Function of Insulin

See earlier post: Glucose Metabolism and Diabetes

Insulin was discovered by Banting and Best in 1921 and was used for treatment in 1922.

Insulin signals via the insulin receptor, which I have discussed here.

Insulin Resistance

As mentioned above, type 2 diabetes is associated with insulin resistance. Insulin resistance affects various different parts of the body: adipose tissue increases lipolysis and decreases triglyceride clearance and glucose uptake, muscle tissue decreases triglyceride clearance and glucose uptake, and the liver increases glucose output and decreases glucose uptake. Insulin resistance is associated with increased central abdominal fat, particularly intra-abdominal fat (not subcutaneous fat, which is why liposuction isn't always helpful). It's important to note that even lean people can have a lot of central abdominal fat.

There are several theories as to why abdominal fat leads to insulin resistance. The "lipid oversupply hypothesis" simply suggests that the oversupply of lipids to muscle leads to insulin resistance. The "adipokine hypothesis" suggests that signalling molecules secreted by adipose tissue, such as leptin, can lead to insulin resistance. PPARγ agonists (glitazones/TZDs) stimulate uptake of fat by subcutaneous fat cells, reducing fatty acid supply to the muscles and liver, which in turn reduces insulin resistance.

Now for a note on brown fat, which I've discussed in more detail here. Brown fat in adults is sometimes known as "beige fat." Studies have suggested that during exercise, muscles release irisin, which may help convert white fat to beige fat.

Complications

See previous post: Diabetes Mellitus

Some pathways that may lead to hyperglycaemic damage include the polyol, hexosamine, protein kinase C and AGE pathways. These pathways are most associated with microvascular complications (i.e. damage to small blood vessels of the eyes, kidneys etc.). Macrovascular complications (e.g. coronary heart disease) are more related to an acceleration of atherosclerosis, which in turn might be due to an increase in prothrombotic cytokines. New medications for diabetes must be tested for cardiovascular outcomes, given that diabetes tends to raise risk for cardiovascular disease.

Nociception and Pain

Review the physiology of nociception and forms of stimulus energy that activate them

Nociception (excitation of sensory neurons by potentially damaging stimuli) is caused by activation of nociceptors, which can be activated by mechanical, thermal, and/or chemical energy. Nociceptors are found in the skin and also in deep tissues, and respond to different stimuli (some respond to only one type of stimulus, while others are polymodal- that is, they respond to multiple types of stimuli). Nociceptors that respond to mechanical stimuli tend to have relatively high thresholds compared to the other types of nociceptors.

Define the difference between nociception and pain

Nociception, as I just mentioned, is the excitation of sensory neurons by potentially damaging stimuli. Pain is a subjective perception, which may or may not occur in the presence of nociception as it can be modulated independently.

Explain the physiological basis of fast and slow pain and central pain pathways

"Fast sharp" pain and "slow dull" pain are caused by different nerve fibres. "Fast sharp" pain is caused by Aδ fibres, which are myelinated (and therefore fast) and have small receptive fields. "Slow dull" pain is caused by C fibres, which are unmyelinated and have larger receptive fields.

I didn't quite understand the central pain pathways (neuroscience is not my forte), but to my understanding, the pathway that has been studied the most is the spinothalamic pathway. Sensory nerves cross over in the spinal cord and travel to the thalamus, and then to the primary somatosensory cortex, association cortex, and so on. There are also projections to the reticular formation and central lateral thalamus, which are responsible for arousal and autonomic responses, and projections to the insula and cingulate cortex, which are responsible for emotional responses.

Another important point to touch on is the concept of "referred pain"- the idea that we might get pain in an area other than the affected area (e.g. pain in the left arm during a heart attack). "Referred pain" might be due to convergent wiring- sensory nerves from the skin and the affected organ synapse onto the same interneuron in the spine, and the brain can't figure out where the signal originated from, so you perceive the pain as coming from all of the regions that send signals to that interneuron.

Describe the mechanisms of hyperalgesia and allodynia

Hyperalgesia is increased intensity of pain from normally painful stimuli, whereas allodynia is pain from normally non-painful stimuli. Hyperalgesia and allodynia may be due to peripheral tissue damage, lesions to dorsal roots or alterations in the excitability of central circuits.

First, let's look at peripheral tissue damage. When tissue is damaged, it releases a whole bunch of stuff, like potassium, bradykinin, serotonin, and prostaglandins. All of these substances can increase the excitability of nociceptors. Nociceptors can also release substance P, which stimulates histamine release from mast cells, which also increases the sensitivity of nociceptors. Therefore, peripheral tissue damage can cause hyperalgesia. Even surrounding undamaged tissue can experience hyperalgesia.

I don't really have any examples of lesions to dorsal roots, but I do have an example for an alteration in the central circuit. Lesions to the thalamus can cause thalamic pain syndrome, which is chronic severe pain caused by lesions to the thalamus. Other kinds of pain that occur in the absence of nociception include phantom limb pain, and possibly also migraines.

Explain some mechanisms of modulation of pain and pain relief including intrinsic analgesic pathways

As well as nociceptive fibres, we also have non-nociceptive afferents, such as Aα and Aβ fibres. Non-nociceptive fibres can activate inhibitory interneurons, reducing the transmission of pain signals. Aα and Aβ fibres can be activated by rubbing the skin.

Descending "analgesic pathways" can also help modulate pain. These pathways mainly use norepinephrine and serotonin, and can act via two main pathways. Firstly, they can directly inhibit transmission of nociception (just like Aα and Aβ fibres), or they can indirectly inhibit it via enkephalin-releasing interneurons. Enkephalin binds to opiate receptors, and can influence the amount of Ca²⁺ uptake (and therefore neurotransmitter release) in presynaptic nociceptive neurons, as well as hyperpolarise post-synaptic neurons. Opiates relieve pain by activating the same pathway. (See here for more information on analgesic drugs.)

Glucose Metabolism and Diabetes

And now we're up to what seems like the obligatory diabetes lecture for the semester...

Big Picture – energy metabolism
Control of energy substrates
Carbohydrate (main external source of energy)
ATP (Adenosine triphosphate – ‘holds’ the energy for internal use)
Glycolysis / Krebs Cycle / Electron Transport Chain

*sighs internally*

• Glycolysis and the Pentose Phosphate Pathway
• The TCA Cycle
• Electron Transport Chain and Oxidative Phosphorylation
• Extracting Energy from Food

Control of blood glucose / Insulin / Diabetes

We use glucose at a more or less constant rate, but since we're not eating at a more or less constant rate (okay, I guess some people do, but let's just ignore them for now), our supply of glucose is pulsatile. Therefore, in order to stop glucose levels from spiking and dipping, we need some hormones to regulate our glucose levels. Insulin is the main hormone that stops glucose levels from getting too high, and glucagon stops glucose levels from getting too low.

Insulin is produced in the beta-cells of the Islets of Langerhans in the pancreas. (Beta-cells make up roughly 75% of cells in the Islets of Langerhans, which in turn make up around 1% of the pancreas.) As described here, insulin is originally transcribed as preproinsulin. When it enters the rough ER, it is cleaved to form proinsulin. Finally, in the Golgi apparatus, it is cleaved to form the A and B chains (which are connected via disulfide linkages) and C-peptide.

Insulin secretion is stimulated by glucose, amino acids, and glucagon, and inhibited by somatostatin and the sympathetic nervous system. Glucose is the main regulator, however, so let's look at glucose. Glucose enters beta-cells via GLUT2 transporters and undergoes glycolysis to form ATP. ATP closes ATP-sensitive K⁺ channels, causing depolarisation. Depolarisation opens voltage-sensitive Ca²⁺ channels, causing an influx of calcium, which in turn causes release of insulin-containing vesicles. 60% of secreted insulin is removed from the blood on first pass through the liver, which is why C-peptide, not insulin, is used as an indicator of beta-cell function.

Insulin receptors are heterotetramers with two extracellular alpha-chains and two intracellular beta-chains. The beta-chains have tyrosine kinase activity. I've discussed the insulin receptor in more detail here.

Insulin has slightly different effects on different organs:

• Liver- Stimulates glycolysis, glycogenesis, lipogenesis, and protein deposition. Inhibits gluconeogenesis and glycogenolysis. End result is lowering of blood glucose and storage of energy.
• Skeletal muscle- Upregulates GLUT4 (an insulin-dependent glucose transporter). Stimulates glycogenesis, glycolysis, and protein deposition. Inhibits glycogenolysis and protein degradation. End result is lowering of blood glucose, storage of energy, and maintenance of muscle mass.
• Adipose tissue- Upregulates GLUT4. Stimulates glycolysis, shuttling of phosphoenolpyruvate to glycerol, shuttling of acetyl-CoA to free fatty acids, and lipoprotein lipase expression (and, by extension, free fatty acid uptake from VLDL). Inhibits hormone sensitive lipase. End result is lowering of blood glucose and storage of energy as triglyceride.

What happens if we have insufficient insulin? Insufficient insulin results in diabetes, as discussed here and here. Without insulin, lots of gluconeogenesis occurs (due to lack of inhibition), keeping blood glucose levels high. Ketone body metabolism also occurs, placing diabetic patients at risk of ketoacidosis.

HDL and Cholesterol

I've already covered a bit of this here, but not very well, so here we go again!

Structure and function of cholesterol

See earlier post: Lipids- Cholesterol

The necessity of cholesterol becomes more apparent in deficiencies, such as in Smith-Lemli-Opitz syndrome. In this syndrome, there is a mutation in the DHCR7 gene which codes for 7-dehydrocholesterol reductase, the final enzyme required in the production of cholesterol. As such, people with Smith-Lemli-Opitz syndrome have insufficient cholesterol, and have a range of abnormalities ranging from microcephaly to limb malformations to congenital heart defects.

Cholesterol absorption and biosynthesis

Absorption

Absorption of dietary cholesterol is very poor, as plant sterols compete for the same transporters, and some cholesterol moves out of enterocytes and back into the gut lumen. Cholesterol enters cells through NPC1L1 transporters (cholesterol cannot diffuse across the plasma membrane very well). Once inside the cell, it can be converted to cholesterol ester and packaged into chylomicrons, as described here. Alternatively, cholesterol can move back into the gut lumen via ABCG5/8 channels or into HDL via ABCA1 channels.

Excretion

Excretion of cholesterol mainly occurs via the bile. Hepatocytes can convert cholesterol into bile acids, which enter bile through BSEP channels. Alternatively, cholesterol can enter the bile via ABCG5/8 channels. Not all cholesterol in the bile is excreted- a lot of it is reabsorbed.

Biosynthesis

Some cholesterol can also be synthesised by cells. The five major steps are as follows:

1. Acetyl-CoA converted to HMG-CoA via HMG-CoA synthase
2. HMG-CoA converted to mevalonate via HMG-CoA reductase. (This is the rate-limiting step, which is why it's targeted by statins.)
3. Mevalonate converted to isopentenyl pyrophosphate (IPP)
4. IPP converted to squalene
5. Squalene converted to cholesterol

Cholesterol homeostasis and regulation of cell cholesterol

As mentioned in my last post, entry of LDL causes downregulation of HMG CoA reductase, an increase in ACAT expression, and a decrease in LDL receptors. But how is cholesterol regulated?

Wonder no more! Cholesterol can be sensed by the SREBP protein, which is located in the membrane of the endoplasmic reticulum. When cholesterol levels decrease, SREBP is cleaved by SCAP, causing it to "bud off" from the ER and move to the Golgi and then into the nucleus. Once in the nucleus, it acts as a transcription factor, where it regulates HMG-CoA reductase expression. (Remember, HMG-CoA reductase is the limiting factor in cholesterol production!)

HDL formation and metabolism
Reverse cholesterol transport

HDL formation starts with nascent HDL, which is either secreted by the liver and intestine, or formed as a byproduct of chylomicron and VLDL metabolism. More specifically, nascent HDL is sometimes made up of the "surface remnants" from chylomicron and VLDL metabolism. Cells of the body have cholesterol ester hydrolase, which converts cholesterol ester to cholesterol, which moves out of cells and into HDL via ABCA1. HDL then converts cholesterol back to cholesterol ester via an enzyme called LCAT, which is activated by Apo-A1. When the cholesterol has been esterified, HDL becomes mature.

There are a couple of different fates of HDL. Firstly, cholesterol ester in HDL can be transferred between HDL and LDL via an enzyme called CETP. Alternatively, HDL can be taken up into the liver and adrenal glands by the SR-B1 receptor.

Why HDL is protective against atherosclerosis

HDL can protect against atherosclerosis in several ways:

• Inhibits recruitment of macrophages to arteries
• Inhibits arterial smooth muscle proliferation
• Inhibits arterial smooth muscle contraction (HDL increases NO production, causing vasodilation)
• Mediates transport of cholesterol from cells

Antibiotic Resistance

In my last post, I discussed antibiotics. In this post, I'm going to discuss what happens when bacteria are resistant to antibiotics! Hooray! (not...)

Understand how antimicrobial resistance has arisen and spread in bacterial populations

Antimicrobial resistance in populations comes about due to selective pressures. Without selective pressures, only a small number of microbes will have resistance, but when exposed to an antimicrobial agent, only those microbes with resistance will be able to survive and reproduce, such that resistant microbes eventually become dominant in the population.

Antimicrobial resistance has probably been around for as long as there have been microbes. For example, some microbes living in soil secrete their own antimicrobial agents, so neighbouring microbes may have gained resistance. Of course, nowadays we are mainly interested in looking at resistance to conventional antibiotics. There are many reasons why microbes may be developing resistance: some doctors may be prescribing antibiotics unnecessarily, some patients may not be complying with treatment (allowing some microbes to survive and mutate), and the use of antibiotics in agriculture may be problematic. One of the more problematic agricultural antibiotics is avoparcin, which is a glycopeptide (like vancomycin), and gives cross-resistance to vancomycin. It has been hypothesised that vancomycin resistance might be linked to antibiotic use in animals.

Understand the genetics of antibiotic resistance

Sometimes, resistance is already coded within bacterial genes. Other times, mutations might be acquired from mutations, vertical transfer via chromosomes, or horizontal transfer via transfer of chromosomal genes or transfer of genes on mobile genetic elements. These mobile genetic elements include plasmids, transposons, and integrons. Plasmids are self-replicating circular dsDNA that come in a few varieties. Conjugative plasmids can transfer information between bacteria, while R plasmids (which may also be conjugative) encode antibiotic resistance. Transposons and integrons are linear dsDNA that cannot self-replicate. Integrons can integrate into transposons, and transposons can integrate into chromosomes or plasmids.

In the process of conjugation, two bacterial cells must first come together. Sometimes this occurs through retraction of a sex pilus, which is a structure that is present on some bacterial cells. A "conjugation tube" forms between the two bacteria, and plasmid DNA replication begins. While DNA replication occurs, the free DNA strand begins moving through the conjugation tube. In the recipient cell, the free strand is replicated. The end result is that each cell ends up with a full copy of the plasmid.

Know the five mechanisms of antibiotic resistance and some examples

The main mechanisms are as follows:

1. Decreased influx of antibiotic (e.g. permeability barriers)
2. Increased efflux of antibiotic (e.g. efflux pumps)
3. Antibiotic inactivation (e.g. beta-lactamases, aminoglycoside-modifying enzymes)
4. Antibiotic target site alteration (e.g. altered pencillin-binding-proteins / transpeptidases, altered DNA gyrase)
5. Antibiotic target amplification or alternate pathway (e.g. producing more folate to overcome folate synthesis inhibitors)

Be able to describe selected clinically important resistances

Streptococcus pneumoniae

S. pneumoniae is a common cause of ear infections, but since antibiotics don't penetrate the middle ear very well, there's a high chance that treatment isn't 100% effective. As such, a small number of bacteria are left hanging around and are able to mutate. Some S. pneumoniae has developed penicillin resistance via mutation of penicillin-binding proteins (i.e. antibiotic target site alteration). Since very high level resistance is unusual, it can usually be overcome by increasing the dose of penicillin.

Staphylococcus aureus

S. aureus has a particularly nasty form called MRSA (methicillin-resistant S. aureus), which is also known as a "superbug." MRSA contains the Staphylococcal Cassette Chromosome mec (SCCmec), which is a mobile genetic element that integrates into the S. aureus chromosome. SCCmec contains the antibiotic resistance gene mecA, which codes for PBP2a, which does not bind beta-lactam antibiotics. Usually alternative antibiotics, such as vancomycin, are required to treat this bad boy.

β-lactamase resistance in Gram negatives

Most beta-lactamase resistance is due to beta-lactamases in Gram-negative bacteria. Extended-spectrum beta-lactamases (ESBLs) are resistant to penicillins, cephalosporins, and monobactams (but not to carbapenems). ESBLs can be inhibited by clavulanic acid, which is why clavulanic acid is often packaged together with some antibiotics (e.g. amoxicillin-clavulanate). Some bacteria have carbapenemases which, as their name suggests, are also capable of hydrolysing carbapenems. Recently, a new carbapenemase, called New Delhi metallo-beta-lactamase (NDM-1), has been discovered. It is found on a plasmid encoding the bla_NDM gene, and has spread rapidly. If you have a superbug with this carbapenemase, you're pretty much stuck with the polymixins and tigecycline.

Other resistances

Aside from beta-lactams, bacteria have also developed resistance to some other antibiotics (sneaky buggers!). To defend against aminoglycosides, some bacteria have inactivating enzymes (e.g. streptomycin acetyltransferase) and/or have a decreased expression of porins, decreasing membrane permeability to aminoglycosides. To defend against the MLSB group (macrolides, lincosamide, streptogramin B), some bacteria methylate 16S rRNA to alter the binding site and/or have increased efflux through multidrug resistance (MDR) efflux pumps. Bacteria can also defend against tetracyclines by increasing efflux through a specific Tet pump.

Understand the implications of antibiotic resistance and strategies to address the problem

Obviously, antibiotic resistance is kind of problematic. When bacteria are resistant, it narrows down our treatment choices and we might be stuck with only very toxic drugs (or, worse still, no options at all). Some strategies that have been suggested to address this problem include:

• Use more specific agents if possible (rather than broad-spectrum)
• Avoid vancomycin unless necessary
• Only prescribe if required, and prescribe for the optimal duration
• Shorten hospital stays (less likelihood of a patient getting a nosocomial infection and needing antibiotics)
• Prevent infections (via immunisation, sanitation etc.)

Antibacterial agents and susceptibility testing

This post was mainly a recap of this lecture from PHAR2210, but with some more details. Enjoy!

Know the terminology describing the general characteristics of antimicrobial agents and drugs

• Broad spectrum- Antibiotic inhibits or kills lots of things (e.g. tetracycline inhibits Gram positives and negatives, as well as Chlamydia and Rickettsia)
• Narrow spectrum- Inhibits or kills only a few things (e.g. pencillin G only kills Gram positives)
• Bacteriostatic- Inhibits growth, but doesn't kill (e.g. chloramphenicol)
• Bactericidal- Kills microbes (e.g. penicillins)
• Toxic dose- Dose at which the drug becomes too toxic for the host
• Therapeutic dose- Dose needed to treat the infection
• Therapeutic index- Toxic dose divided by therapeutic dose. The larger the therapeutic index, the better

Know the five main mechanisms of antibacterial action

The five main mechanisms are as follows:

1. Inhibiting protein synthesis
2. Inhibiting cell wall synthesis
3. Metabolic antagonists/antimetabolites (i.e. blockers of enzymatic activity etc.)
4. Inhibition of nucleic acid synthesis
5. Cell membrane disruption

I'll expand on these in the next section...

Be able to describe the effect, mechanism of action, group members and spectrum of activity for the antibiotics given as examples in each case

A lot of the drugs that I'm about to mention have already been mentioned here, but time to go into more detail! Yay!

Protein synthesis inhibitors

The main classes of drugs here are aminoglycosides, tetracyclines, macrolides, and chloramphenicol. With the exception of aminoglycosides, which are bactericidal, most protein synthesis inhibitors are bacteriostatic.

Aminoglycosides, such as streptomycin, gentamicin and kanamycin, bind to the 16S rRNA of the 30S ribosomal subunit at the A site. They inhibit translation elongation and make ribosomes error-prone. Aminoglycosides are effective against Gram-negative bacteria, particularly enteric bacteria and Pseudomonas aeruginosa. However, they are quite toxic.

Tetracyclines, such as tetracycline, chlortetracycline (tetracycline with an extra -Cl), doxycycline (extra -OH) and minocycline (extra N(CH₃)₂) also bind to the 16S rRNA in the 30S subunit. They block the binding of incoming aminoacyl-tRNAs to the A site. Tetracyclines are broad-spectrum drugs that work against Gram-positives and Gram-negatives, as well as Chlamydia, Mycoplasma, and Rickettsia.

Macrolides, such as erythromycin and clindamycin, bind to the 23S rRNA in the 50S ribosomal subunit. They are quite bulky drugs that "plug" the ribosomal tunnel. They are also quite broad-spectrum and are able to act against Gram-positives, mycoplasmas, and some Gram-negatives. A related drug called clindamycin inhibits peptidyl transferase and is good against anaerobes.

Chloramphenicol, like macrolides, bind to the 23S rRNA in the 50S subunit. They affect the binding of aminoacyl-tRNA to the A-site. Chloramphnicol is broad-spectrum but is very toxic, so it is only used in life-threatening situations or in topical treatment of conjunctivitis.

Cell wall synthesis inhibitors

Cell wall synthesis inhibitors have very good selective toxicity as they only target components of cell walls, which humans don't have. Many cell wall inhibitors block transpeptidation, which is the last step in bacterial cell wall synthesis, and are usually bactericidal. During this step, an amino group in one chain attacks the second last D-alanine of the other chain, forming a peptide link. This may form a direct crossbridge (as in E. coli) or a different kind of interbridge (e.g. S. aureus has a pentaglycine crossbridge). Either way, transpeptidation is mediated by transpeptidases, which are also known as penicillin-binding proteins (PBPs).

The most well-known cell wall synthesis inhibitor is probably penicillin. Penicillins contain a beta-lactam ring, which resembles the terminal D-alanyl-D-alanine in peptidoglycans, thus blocking cell wall formation. Cell walls are actually kind of important for bacteria- without it, they can't resist osmotic pressure, so they are easily lysed. Cephalosporins (e.g. cefoxitin) also function in the same way- they are somewhat structurally different to penicillin, but they still have the beta-lactam ring.

Another class of cell wall synthesis inhibitor is the glycopeptides. Glycopeptides bind to the D-alanyl-D-alanine in peptidoglycans. They are relatively narrow-spectrum, limited to Gram-positives, but they can be useful as last-resort drugs in some cases (e.g. MRSA). An example of a glycopeptide is vancomycin (which also happens to be my favourite "nuke" in Microbe Invader).

Metabolic antagonists/antimetabolites

Sulfonamides and trimethoprim are both metabolic antagonists, and are often combined into one drug (trimethoprim-sulfamethoxazole). Sulfonamides block the first step in the folic acid pathway by competing with PABA. Trimethoprim blocks a later step by inhibiting the dihydrofolate reductase enzyme. The end result is that folic acid is not produced, and since bacteria require folic acid to form DNA bases, they're kind of screwed when this pathway is blocked. Both sulfonamides and trimethoprim are bacteriostatic.

Inhibition of nucleic acid synthesis

Nucleic acid synthesis inhibitors, which are mostly bactericidal, have poor selective toxicity because synthesis pathways are pretty similar between eukaryotes and prokaryotes. Quinolones and fluoroquinolones inhibit DNA gyrase (the enzyme that uncoils parent DNA), while rifampin inhibits RNA polymerase. Quinolones and fluoroquinolones vary in specificity, whereas rifampin is a narrow spectrum drug used for tuberculosis and some Gram-negatives.

Cell membrane disruption

Cell membrane disruptors are also bactericidal and have poor selective toxicity. The main class here are polymixins, such as Polymixin B and colistin (a.k.a. Polymixin E). They are narrow-spectrum and are mainly used topically for Gram-negative infections.

Understand the three methods of antibacterial susceptibility testing described

Antibacterial susceptibility tests are often used to determine MIC (minimal inhibitory concentration), which is the lowest concentration of a drug required to prevent bacterial growth. There are three main methods used: disk diffusion tests, Etests, and broth and agar dilution tests.

Disk diffusion tests (a.k.a. Kirby-Bauer tests)

In disk diffusion tests, the microbe is spread onto an agar plate. Sterile paper disks impregnated with an antibiotic are placed onto the surface of the plate. If the antibiotic kills off the microbe, there will be a clear zone around that disk, also known as an inhibition zone. The size of the inhibition zone can be used to determine MIC.

Etests

Etests are kind of like disk diffusion tests in that the microbe is spread onto an agar plate. Instead of disks, Etests use plastic strips that have a concentration gradient of an antibiotic, which is labelled with a scale. The strips are placed on the agar plate so that the lowest concentration of antibiotic is at the centre of the disk. The MIC can be determined by finding the place where the inhibition zone intersects with the strip.

Broth and agar dilution tests

In a broth dilution test, the microbe is added to a bunch of different broths, each containing a different concentration of the antibiotic. The MIC is the tube with the lowest concentration of antibiotic without any bacterial growth. Agar dilution tests are similar, but they use a concentration gradient of antibiotic across the agar (I *think*).

Sensorimotor Integration and Balance

Explain and compare the feed-forward and feed-back mechanisms of postural control

Feed-back mechanisms compensate for a loss of posture. When you lose posture, sensory systems detect this, and a compensatory response occurs. We seem to have a "bottom-up" strategy for this: we stabilise our ankles first, then our knees, then hips, trunk, and so on.

Feed-forward mechanisms are used in voluntary movements, and improve with learning. Feed-forward mechanisms can predict a disturbance, and over time reprogram your body's response so that you become better at handling said disturbance. For example, if you try roller-skating for the first time, there's a good chance that you'll fall on your arse pretty quickly because you're not used to it. Over time, however, your feed-forward mechanisms will predict the changes that occur when you're rolling, and you'll automatically compensate (and therefore stop falling on your arse).

Identify the primary sensory systems that contribute to balance and posture

The main sensory systems that contribute to balance and posture are the proprioceptive system, the visual system and the vestibular system. Let's start with proprioception!

The main proprioceptive receptors are the muscle spindle, the Golgi tendon organ, and joint receptors. Muscle spindles have "polar regions" (ends) made up of actin and myosin. Gamma motor endings, which are located in the middle of the spindle, maintain the sensitivity of muscle spindles. The Golgi tendon organ, located at the musculotendinous junction, is made up of mechanosensitive Ib fibres which are compressed during contraction, causing firing of action potentials. Finally, joint receptors change their firing rate as joint position changes.

The proprioceptive receptors are important in the stretch reflex: when muscle is stretched, the muscle spindles pick this up, causing inhibition of further stretch. The stretch reflex can be modulated by the gamma motor neurons, which regulate the sensitivity of the spindle and prevent it from completely slackening. In cases where there is high gain and/or latency (see here for explanations of these terms), oscillations can occur. An example of this is decerebrate rigidity, caused by lesions of the brain stem in the cerebellum and/or brain stem. Decerebrate rigidity is characterised by increased muscle stiffness, spasticity or clonus (rapid contractions and relaxations in response to stretch).

Describe the different types of eye movement and associated motor control processes

The visual system also contributes to balance and posture, so let's have a look at vision! There are a whole bunch of eye movements that can occur:

• Vestibulo-ocular: Vestibular input stabilises the eyes during rapid head movement
• Optokinetic: Visual input stabilises the eyes during slow head movement
• Saccades: Sharp movements that bring objects into focus
• Smooth pursuit: Eyes follow a moving target
• Vergence: Adjust for viewing at different depths/distances

Describe the vestibular contribution to the control of eye movement and postural reflexes

The main vestibular receptors are the otoliths and semicircular canals, all of which are located in the ear. The otolith organs include the utricle, which detects horizontal acceleration, and the saccule, which detects vertical acceleration. The semicircular canals detect rotational acceleration. As mentioned above, vestibular receptors are important in the vestibulo-ocular reflex, which stabilises the eyes during head movement. Vestibular problems may also generate nystagmus (a rapid, swinging motion of the eyes).

Aside from the vestibulo-ocular reflex, there are several other reflexes that are generated from the vestibular system. The vestibulocollic (neck) and vestibulospinal (limb) reflexes use input from the utricle and saccule. When the head moves back, arms and legs extend, but when the head moves forward, arms and legs flex.

Allograft-Transmissible Infections

Diseases can be passed from person to person via transplants. How do we prevent this? Read on...

Transmissibility of infectious agents

For a pathogen to be transmitted via allograft, it must give rise to asymptomatic infection in the donor (symptomatic donors are generally excluded from the get-go), be present in the allograft, and survive storage and processing of the allograft. Bacteria (e.g. T. pallidum and M. tuberculosis), viruses (e.g. Hep B and HIV), protozoa (e.g. malaria and toxoplasma), and prions (e.g. Creutzfeldt-Jakob Disease) can be transmitted via allografts.

Allograft contamination

Allografts can be contaminated when in situ or during processing. An example of in situ contamination is Clostridium sordelli sepsis. During the dying process, gut microorganisms can pass through the intestinal wall. Hypoxic cadaveric tissue "selects" for anaerobes (such as C. sordelli), which sporulate as nutrient levels decrease. Spores are very hardy, so they may survive allograft processing. Thankfully, in situ contamination is quite rare and has not been reported in Australia. Exogenous contamination occurs when an allograft is contaminated during processing. The most common organisms in exogenous contamination are Staphylococcus species.

Preventing transmission

There are several ways in which we can try and prevent transmission of an allograft-transmissible infection. For starters, we can implement stringent donor selection criteria. If someone has been exposed to an infectious disease (e.g. by going to a country where an outbreak has occurred), they may be deferred for the length of the incubation period. Certain high-risk behaviours may also require a deferral or exclude the donor entirely. The grafts themselves may also be screened for certain diseases, such as syphilis and Hep B. There is a small chance that such screening may come up with false negatives, due to a testing "window period" (the time between infection and first detection of the pathogen), but this is a very low chance. Nucleic acid testing (NAT) reduces the length of the window period and thus reduces the risk of false negatives, but it is quite expensive and may not be worth it in some cases. (Also, waiting for a NAT result may compromise the viability of the organ.)

Using aseptic technique is also important. Processing of grafts is done in a "cleanroom," as mentioned here. Processed grafts can also be sent off for microbiological culturing for screening purposes. In the case of living donors, milled bone can be washed in saline before being sent for microbiological culturing. For cadaveric donors, the allograft is washed in sterile water (and the water is sent off for culturing), and membrane filtration is applied. Also, with cadaveric donors, time is important: the body must have been refrigerated within 12 hours after death, and tissue retrieval must occur within 24 hours after death.

Monitoring for post-transplant infections is critical not just for the infected patient, but also for the purposes of keeping our graft supply safe. Emerging infections, such as the Zika virus, need to be assessed for the possibility of transmission via allograft.

This is kind of unrelated, but there were two slides on Zika virus, so I guess I'll expand on it here. Zika was originally discovered in a rhesus monkey in Zika forest in Uganda. It is transmitted by certain mosquitoes, but can also be transmitted via sex or transfusions. During the 2007 outbreak in Micronesia, it was generally mild, with short-lived symptoms. However, during the more recent 2015 Brazil outbreak, the virus was associated with microcephaly and Guillain-Barré Syndrome. The RNA of Zika virus is detectable in urine, blood and semen.

Risk of infection

One way to quantitate the risk of a certain infection is to multiply the incidence rate (rate of newly acquired infections) by the duration of the window period. Risk can be communicated to patients by using the Calman scale, which compares numbers like "1 in 100 000" to something that might be more easily understood, such as "probability of death from a train accident."

An Overview of Organ and Tissue Donation: Ethics and Logistics

Another lecture on transplantation! A lot of this was covered in previous posts, so be prepared for some links :P

Pathways to donation

See previous post: Organ Transplant: The Surgeon's Perspective

For this post, we'll mainly be talking about donations after death (i.e. complete cessation of blood circulation and/or brain function). Brain death can be caused by a variety of causes, such as haemorrhage, oedema, trauma, hypoxia (from cardiac arrest, drowning, etc.), and tumours. Usually, injury leads to brain swelling, then intracranial hypertension, ischaemia, and brain death. Brain death can be determined by clinical testing and/or radiological imaging, such as 4-vessel angiography and radionuclide scanning.

Legal requirements

There are several legal requirements for organ donation. Firstly, a certificate of death is needed to prove that the donor is, indeed, dead (you wouldn't want to rip out someone's heart if they're still alive!). Next consent is required- from the donor (if they consented before death), from the next-of-kin, and from the coroner. Certain designated officers at the hospital should also be notified.

Referral process

Firstly, the family of a potential donor needs to be informed about the death and about the donation process. These are obviously difficult conversations to have, so there is specialised training for clinicians who are going to deal with this. Next up you have to deal with consent, as I just stated above. When the decision to donate has been made, information is gathered about the donor and a variety of tests (e.g. serology, tissue typing, and nucleic acid testing) are done in order to ensure safety and match up donor to recipient. Matching is done according to compatible blood type and size. The sickest patients are prioritised.

Different organs have different optimal age ranges. Hearts can be donated from those less than 60 years, livers from those less than 80 years, pancreas from 3-50 years (islet cells 10-70 years), lungs from 5-70 years, intestines less than 50 years, and kidneys less than 80 years.

Surgical retrieval

See previous post: Organ Transplant: The Surgeon's Perspective

After donation

After donation, there is some documentation and follow-up. The donor family is supported, and the recipient is monitored for adverse events following transplantation.

Motor Control

This lecture had so many details :/

Describe the hierarchical organisation of motor system from a structural and functional perspective

I'm not really sure what we're supposed to know here, so here's a description of the diagram on the "Hierarchical organisation of motor control" slide. Motor areas in the cerebral cortex can send signals to the spinal cord, either directly or via the brainstem. From the spinal cord, motor neurons in the ventral horn can innervate muscles, causing movement. There are also accessory areas, such as the thalamus, basal ganglia, and cerebellum, which play roles in motor control.

There is also some kind of hierarchy of motor control when it comes to voluntary movement. The first step is the "strategy" (figuring out what needs to be done), which is carried out in the prefrontal cortex, posterior parietal cortex, and basal ganglia. The next step are "tactics" (figuring out how to do what needs to be done), which takes place in the pre-motor cortex and supplementary motor area (SMA). The SMA is important in mental rehearsal of actions (i.e. imagining what you need to do without actually doing it). The third and final step is execution (getting stuff done), which uses the primary motor cortex, brain stem, and spinal cord. Once again, other inputs are received by the somatosensory cortex, cerebellum, basal ganglia, and so on.

Describe the similarities and differences between voluntary movements, reflex movements and rhythmic motor patterns

Voluntary movements are, well, voluntary. We choose to do them, and we get better at them as we practice them. Reflex responses are rapid and involuntary, and the amplitude of response may depend on the eliciting stimulus. Rhythmic motor patterns combine aspects of both voluntary and reflex movements- initiation is usually voluntary, but continuation of the movement is usually reflexive. An example of a rhythmic motor pattern is walking- you usually choose to start walking somewhere, but then once you start walking, you can keep walking without having to think about what you're doing.

Describe the physiological properties of motor units and their recruitment during voluntary and reflex movements.

Motor units consist of a motor neuron and all of the muscle fibres that it innervates. The innervation ratio is the number of muscle fibres innervated by a single motor neuron. Different muscles have different innervation ratios: for example, eye muscles have a low innervation ratio for fine control, whereas muscles that need powerful (but not necessarily accurate) movements, such as the gastrocnemius, have a much higher innervation ratio.

Motor units may be made up of predominantly slow-twitch or fast-twitch muscle fibres. (All of the fibre types are described here.) Again, the types of muscle fibres depend on the muscle type. A muscle that plays a more postural role, such as the soleus, has more slow-twitch fibres. A muscle that requires more power, such as the gastrocnemius, has more fast-twitch fibres.

According to Henneman's size principle, smaller motor neurons have the lowest threshold for synaptic activation, so they are recruited first. As smaller motor neurons are more likely to innervate slow-twitch muscle fibres, slow motor units tend to be recruited first. As intensity increases, more fast units will be recruited.

Identify the muscle receptors and explain their role in spinal reflexes.

The main muscle receptors involved in spinal reflexes are muscle spindles (which detect muscle length) and Golgi tendon organs (which, if I remember correctly, detect the amount of force on the muscle). Cutaneous receptors may also be involved in these reflexes, and descending inputs from the brain stem and cortex may also provide input into the reflex response. Reflexes can be classified according to a three-level hierarchy: control of individual muscles, control of muscles around a joint, and control of muscles at several joints.

A common example of a spinal reflex is the muscle tendon reflex. When a muscle is stretched, it sends signals to the spinal cord via Ia afferent neurons. In the spinal cord, Ia afferent neurons synapse with motor neurons that stimulate the agonist muscle, causing reflex contraction. At the same time, Ia afferent neurons synapse with inhibitory motorneurons, which synapse with another motor neuron, causing reflex relaxation of the antagonist muscle.

Since rhythmic locomotor behaviour also has some things in common with reflex movements, I'm going to discuss it here. To my understanding, rhythmic locomotor behaviour is mainly due to inhibitory interneurons in the spinal cord. When the flexor is activated, the extensor is inhibited, and vice versa. Tonic descending input can also play a role, but it is not necessary: cats with a spinal transection will still display rhythmic locomotor behaviour.

Identify the principal descending pathways in the spinal cord.

Before I talk about descending pathways, I'm going to talk about the layout of the spinal cord itself. As I mentioned earlier, motor neurons are located in the ventral horn of the spinal cord. "Pools" of motor neurons refer to all of the neurons that go to a muscle or to a group of muscles. These "pools" of neurons are laid out in a certain way: motor neurons innervating proximal muscles are located medially, neurons innervating distal muscles are located laterally, neurons innervating extensor muscles are located ventrally (i.e. towards the front), and neurons innervating flexor muscles are located dorsally (i.e. towards the back).

Aside from motor neurons, there are also interneurons and propriospinal neurons within the spinal cord. Medial propriospinal neurons project bilaterally (i.e. on both sides), span large lengths of the spinal cord, and coordinate trunk muscles on both sides of the body. Lateral propriospinal neurons project ipsilaterally (i.e. on the same side) and over shorter distances, and are used to innervate distal limb muscles.

Now it's time to info-dump a bunch of stuff about descending pathways! Tighten your seatbelts, because there's a lot to learn.

Descending pathways can be divided into two main categories: indirect pathways, which run from the brainstem to the spinal cord, and direct pathways, which run from the cortex to the spinal cord. Indirect pathways, which include the vestibulospinal and reticulospinal tracts, are mostly important in complex polysynaptic pathways regulating posture. Direct pathways, which include the corticospinal tract, are mostly important in innervating lateral motor neurons that innervate distal limb muscles, which are important for voluntary movements.

Vestibulospinal Tract

The vestibulospinal tracts arise from the vestibular nucleus, which in turn receives input from the vestibular system (balance organs in the ear). The vestibular nucleus also has connections with the cerebellum and reticular formation. There are both lateral and medial vestibulospinal tracts. The lateral vestibulospinal tract acts ipsilaterally, and excites extensor muscles. The medial tract acts bilaterally, and excites axial muscles. The vestibulospinal tracts are largely responsible for reflexes that help align the head and body.

Reticulospinal Tract

The reticulospinal tracts receive input from the vestibular system, cerebellum, lateral hypothalamus, globus pallidus, and sensorimotor cortex. The medial, or pontine (i.e. arising from the pons) tract acts ipsilaterally, and excites axial and extensor muscles. The lateral, or medullary (i.e. arising from the medulla) tract acts bilaterally, and inhibits extensor muscles while it excites flexor muscles.

Corticospinal Tract

The corticospinal tracts receive input from the primary motor cortex, supplementary motor area (SMA), and primary somatosensory cortex. The lateral corticospinal tract crosses over at the medulla, so it innervates contralateral distal limb muscles. The ventral corticospinal tract projects ipsilaterally and innervates the axial and proximal limb muscles. The corticobulbar tract, which terminates in the brainstem, innervates the motor neurons of the head and face muscles.

Describe the role of the cerebellum and basal ganglia in movement control.

The basal ganglia had a very complicated slide, but I think all we need to know is that it regulates motor control by concentrating information from different structures and feeding back to the motor cortex and SMA.

The cerebellum is important for comparing executed movements with motor commands (i.e. comparing what you actually did with what you intended to do), timing and coordination of movements, balance, muscle tone, and regulating eye movements. There are three main regions of the cerebellum: the spinocerebellum, the cerebrocerebellum, and the vestibulocerebellum. The spinocerebellum is important in motor execution and signals to the vestibulospinal and reticulospinal tracts. The cerebrocerebellum is important in motor planning. Finally, the vestibulocerebellum has roles in balance, and signals to the vestibular nuclei.

The Patient with an Infection

Last post covering content for the next test! Whoop-de-doop...

This lecture jumped around a bit, so I'm going to make my own headings and try and summarise the main points. Not sure how well I'll do, but I'll try.

What is a pathogen?

Pathogens are microbes that can cause disease. Traditionally, pathogens were distinguished from non-pathogens by virulence, which was defined as an ability to deliver "poison" and cause disease. The story is a bit more complicated than this, however, as host factors (e.g. immunosuppression, nutritional state, and previous exposure) and environmental factors may also affect the virulence of a pathogen. (I have described pathogen virulence factors here. If virulence factors are removed by gene technology or otherwise, pathogenicity is affected, but not viability.)

Pathogens, as I'm sure you should know by now, can cause an array of different diseases. It is important to figure out which pathogen type (and preferably which pathogen) a patient is infected with so that an appropriate treatment can be chosen. For example, antibiotics are ineffective on viruses and fungi. Usually, localised infections are due to bacteria or fungi and systemic infections are usually due to viruses, but this isn't always true. Meningococcal disease is pretty damn systemic, and that's caused by bacteria.

Of course, to get a disease, you must first be infected. I've touched on different routes of transmission here.

Meningococcal disease

This lecture focused quite a bit on meningococcal, so I guess I'll talk about it here. Outbreaks are usually in places where there is a lot of close contact with others, such as in university or military dormitories. There is also a region in Africa called the "meningitis belt," as the rate of incidence there is very high. Meningococcal is mainly transmitted by contact with respiratory secretions and saliva, which can result in colonisation (which lasts for months), or invasive disease. Infections mainly occur in the winter and early spring.

N. meningitidis, which causes meningococcal, has a few virulence factors that allow it to wreak havoc on the body. It has fimbriae, allowing it to adhere to the nasopharynx and hang around in there for a while. It also has a polysaccharide capsule, which prevents phagocytosis. Finally, it can release a potent endotoxin called outer membrane lipooligosaccharide (LOS), which binds to receptors on macrophages and neutrophils, triggering inflammatory and coagulation cascades. The characteristic "rash" sometimes seen in meningococcal patients is actually a result of coagulated blood under the skin.

The importance of taking a history

When dealing with a patient with an infection, it is important to take their history into account. Travel may increase the likelihood that a patient has come into contact with a certain disease (e.g. malaria and Dengue fever are more common in tropical areas). Mosquitoes may spread diseases such as Ross River virus and malaria. Other important exposures include contact with certain animals, consumption of certain foods and drinks, exposure to contaminated water, soil or dust (potting mix increases your risk of Legionella infection), sexual contact, and drug use.

Medical examination

In a medical exam, a doctor might look for signs of a "systemic inflammatory response" (i.e. high temperature, rapid pulse, rapid respiratory rate, and high blood pressure), as well as some more localised signs, such as rashes, heart murmurs, lung crepitations (crackling sounds made by inflamed lungs), abdominal tenderness, neck stiffness, and so on. There were a couple of slides on fever, but I've already touched on it here, so all I will say is that patients often shiver when they have a fever, and if they have extreme shivering ("rigors"), this is usually indicative of a serious infection. A blood test may also be ordered, with a full blood count to detect white blood cell levels, erythrocyte sedimentation rate (a non-specific indicator of inflammation), C-reactive protein (which I'm pretty sure is also a non-specific indicator of inflammation), and so on. Specimens may also be collected and sent off to the lab for further testing.

Viral Pathogenesis

Describe the various patterns of viral infection

The main patterns of viral infection are acute and persistent. In an acute infection, there is rapid production of virus particles, producing symptoms after an incubation period (which may be as short as a few days, or last for weeks or months). Symptoms tend to resolve relatively quickly, and immunity may result. In a persistent infection, the primary infection is not cleared by the immune system for some reason, so virus particles continue to be produced. Sometimes the virus will be detectable, while at other times it may "hide" by remaining latent in certain cells. Persistent infections may be problematic as they can be reactivated, may be associated with immunopathological diseases, and may even be associated with certain cancers.

Understand the different types of persistent infections and be able to give examples of viruses that pertain to each type

The different types of persistent infection are latent, chronic, and slow.

Latent infections

In a latent infection, after an initial acute infection, the virus remains latent in cells of the body. The virus may reactivate every now and again throughout a person's lifetime, which may or may not cause symptoms. As mentioned in previous posts, herpes simplex virus and varicella zoster virus are good examples of latent infections.

Another example of a latent infection is cytomegalovirus (CMV), which can remain dormant in CD34+ myeloid progenitor cells and CD14+ monocytes. CMV is usually asymptomatic, but can be shed and spread in the urine and saliva of healthy carriers. This can be problematic, as while CMV is usually asymptomatic, it can have nasty consequences for the immunosuppressed or for foetuses.

Yet another example of a latent infection is Epstein-Barr Virus (EBV), which can remain latent in B-cells. It usually infects epithelial cells, such as the mouth mucosa, which shed the virus for months after infection. Like CMV, it is often carried asymptomatically. Reactivation is usually caused by immunosuppression, but unlike CMV, it usually will not cause symptoms. EBV is, however, associated with some cancers (*cough*Burkitt's lymphoma*cough*), so don't get too complacent.

Chronic infections

In a chronic infection, the virus continues to be produced, though usually there are long periods with no symptoms. The virus, however, can still be shed in the blood, which may be problematic in cases of blood transfusions.

Hepatitis B is one example of a chronic infection. The virus replicates in the liver, and infectious virus particles (Dane particles) and Hep B surface antigen (HBsAg) circulate in the plasma. Usually, virions and HBsAg are cleared (so no chronic infection), but around 5-10% of those infected with Hep B will have a chronic infection. A small proportion of the chronically affected may also experience liver cirrhosis and cancer later on. As Hep B can be shed in the blood, blood donations are screened for this virus.

Lymphocytic choriomeningitis virus (LCMV) is a chronic infection that mainly affects rodents. (It can also infect humans, but only rarely.) It is transferred from mother to child. Infant mice with LCMV tend to be normal, but have persistent viraemia. Some antibodies may be produced, and if antigen-antibody complexes are deposited in the kidney, kidney disease may result. No cell-mediated immunity develops, and no cellular dysfunction is evident as a result of the disease.

Slow infections

Slow infections normally start with an acute infection with symptoms, which is followed by a long period in which the virus is kept at low levels by the immune system, and finally a phase where viral load continues to rise until death of the host. One of the main causes of slow infection are lentiviruses, which is a group of virus including HIV, SIV (simian immunodeficiency virus- affects monkeys) and FIV (feline immunodeficiency virus- affects cats). Lentiviruses, which can also exist as an integrated DNA provirus, replicate in lymphocytes and macrophages.

As I just mentioned, HIV is an example of a slow virus. The acute phase is usually mildly symptomatic, with some flu-like symptoms. Following the acute phase, the patient can remain asymptomatic for up to 10 years. Eventually, the virus comes back with a vengeance and kills off a lot of CD4 T-cells, compromising the immune system to the point where opportunistic infections can kill. Nasty.

The measles virus can also cause a slow infection. In rare cases, someone who has been infected with measles may get a complication called subacute sclerosing panencephalitis (SSPE) 1-10 years after measles infection. In SSPE, virus is replicated slowly in the central nervous system, and nucleocapsids are transmitted from cell to cell. High levels of neutralising antibody are produced, but because a lot of viral replication is still occurring within cells, the infection can still progress until death occurs.

For some reason, this lecture also included transmissible spongiform encephalopathies, which are brain diseases caused by prions (self-replicating proteins). Scrapie is a prion disease that affects sheep, and can be transmitted from ewe to lamb. It progresses to paralysis and death. Creutzfeldt-Jacob Disease (CJD) is a prion disease in humans that causes a pre-senile dementia. A variant form (vCJD) can be caused by ingesting beef infected with bovine spongiform encephalopathy. (This is also known as "Mad Cow Disease," and since it's hard to test for, it's the reason why many Brits can't donate blood in Australia.) Another transmissible spongiform encephalopathy, Kuru, is confined mainly to the New Guinea Highlands. It is spread by ritual cannibalism, but education campaigns have seen a decrease in Kuru infection.

Understand the pathogenesis of persistent infection

Persistent infections hang around because they have properties that allow them to hang around and/or are able to avoid the host defences. Let's take a look at their strategies.

• Non-immunogenic agents: Not all pathogens are immunogenic (i.e. they do not induce immune responses, like production of type I interferon, and/or are not susceptible to the actions of the immune system). That makes things rather tricky...
• Integrated genomes: Retroviral DNA can be integrated into the host genome, allowing a virus to remain part of the host genome indefinitely. Viruses may also exist as episomes (separate segments of DNA within the host cell), which also stops them from being destroyed by the host.
• Antigenic variation: Some viruses, particularly lentiviruses, can undergo mutations that change their cell surface antigens, making it difficult to form antibodies against them.
• Growth in protected sites: Viruses can grow in sites where the immune system is not very strong. For example, HSV and VZV reside in neurons, which don't usually express MHC-I. Some other infections grow in epithelial cells and are shed in secretions, which may not provoke an immune response.
• Growth in macrophages: Viral growth in macrophages also impairs some macrophage functions, including antigen presentation, phagocytosis, and cytokine production.
• Non-neutralising antibodies: Viruses can induce the formation of non-neutralising antibodies, which can form complexes with viral antigens, leading to immune complex diseases. Non-neutralising antibodies can also block the binding of C1 antibody, which usually binds to and modulates lysis of infected cells.
• Immunological tolerance: Many viruses only induce a very weak antibody response, which is not effective at wiping out the virus.
• Suppression of cell-mediated immunity: Viruses may reduce MHC-I expression on cell surfaces, replicate inside and impair the function of immune system cells (e.g. macrophages), or have other immunosuppressive effects.

Plasma Lipoproteins

A lot of this will be a recap of PHAR3303, which is alright with me, because it might make writing about this topic a bit less painful.

Overview of lipid metabolism

See previous post: Lipid and Lipoproteins: Structure, Function and Metabolism

The classes of lipids and lipoprotein

See previous post: Lipid and Lipoproteins: Structure, Function and Metabolism

The main types of lipids are fatty acids, glycerol, and cholesterol, all of which can be absorbed and used by cells. Fatty acids and glycerol can also become esterified to form triglycerides, and cholesterol can become esterified to form cholesterol ester. Triglycerides and cholesterol ester are storage forms that are good for transportation purposes, but they generally aren't usable by the cell.

Normal plasma cholesterol levels are <4mmol/L for total cholesterol, <2.5mmol/L for LDL cholesterol, and >1mmol/L for HDL cholesterol. The LDL/HDL ratio is usually less than 5.2. Normal plasma triglyceride levels are <1.5mmol/L.

The function of different apoproteins

I've covered most of these lipoproteins in an earlier post, but here's a quick overview anyway:

• Apo-AI: Found in HDL. Activates LCAT, which is necessary for reverse cholesterol transport.
• Apo-B100: Found in VLDL and LDL. Functions as a ligand for the LDL receptor.
• Apo-B48: Found in chylomicrons and chylomicron remnants. Similar to Apo-B100, but the receptor-binding domain is absent.
• Apo-CII: Found in HDL, chylomicrons, VLDL, and IDL. Acts as a cofactor for lipoprotein lipase, which breaks down triglycerides into fatty acids and glycerol.
• Apo-E: Found in HDL and HDL remnants. Like Apo-B100, it acts as a ligand for the LDL receptor.

Mechanisms of formation and metabolism of each class of lipoprotein

The main lipoproteins covered in this lecture were chylomicrons, which are synthesised in the enterocytes of the intestines, and VLDL, which is synthesised by hepatocytes in the liver. Chylomicrons and VLDL are synthesised in a similar fashion, so I'll discuss both of them at the same time.

After fatty acids and glycerol enter the cell, they reform to create triglycerides. At the same time, cholesterol is esterified in the endoplasmic reticulum via ACAT-2. Triglycerides and cholesterol ester are packaged into lipoproteins via microsomal transfer protein (MTP). The apoprotein ApoB-48 is added in the intestines (to make a chylomicron), but in the liver ApoB-100 is added instead (to form VLDL). Lipoproteins are transferred through the Golgi apparatus to the cell membrane. Chylomicrons are released into the lymph system as they are too large for capillaries, whereas VLDL is released directly into the circulation.

The LDL receptor pathway

LDL receptors are located in clathrin-coated pits of some cells. Once LDL binds, it is taken up into lysosomes, which break them down. Once free, the cholesterol from LDL begins to have some effects on the cell: it downregulates HMG CoA reductase (thus decreasing further synthesis of cholesterol by the cell), upregulates ACAT (thus increasing esterification and storage of cholesterol), and downregulates LDL receptors (thus decreasing further LDL uptake).

Calcium Homeostasis

Understand the importance & distribution of Ca2+ in body

I've already mentioned some of the functions of calcium here, but here are some more!

• Clotting- many clotting factors are activated by calcium
• Endocrine system- calcium is required for exocytosis of hormones (and other things)

Calcium levels are also important for regulating neuromuscular activity. When calcium levels are too high (hypercalcaemia), calcium binds to the activation gate of Na+ channels, making the membrane less permeable to sodium (and the cell less excitable). On the other hand, when calcium levels are too low, nerves and muscles become hyperexcitable. These phenomena are responsible for many of the symptoms of hyper- and hypocalcaemia.

99% of calcium is stored in the bone as hydroxyapatite. Around 1% is stored in cells (mainly in the mitochondria and endoplasmic reticulum). A very small amount (~0.1%) is in the extracellular fluid. The normal plasma calcium concentration is around 2.4mM or 9.4mg/dL. Of this, around 50% is free ionised calcium, around 41% is bound to proteins, and around 9% is bound to anions.

Describe the mechanisms maintaining plasma [Ca2+]

Calcium is regulated through the calciostat system, which makes use of calcium-sensing receptors (CaSR). Various hormones (which I will discuss later) affect calcium absorption, reabsorption (in the kidneys), and resorption (from bone).

Calcium is very poorly absorbed. Roughly 30% of calcium is considered to be "absorbed," but when you consider the calcium in secretions and calcium in cells that are being sloughed off, we really only end up absorbing and using around 10% of the calcium that we eat. Absorption of supplemental calcium is even worse than absorption of calcium in food.

In the kidneys, ionised and anion-bound calcium are filtered, and then around 90% of it is constitutively reabsorbed in the proximal tubule and ascending Loop of Henle. The remaining 10% may also be absorbed in the distal tubule and collecting duct, but only under the influence of appropriate hormonal signals.

There are two main ways in which bone can be reabsorbed. The rapid method is called "osteocytic osteolysis." When calcium in the bone fluid decreases, mineralised bone solubility increases, causing release of more calcium into the bone fluid. Furthermore, if parathyroid hormone is circulating, it can bind to parathyroid receptors on osteoblasts, causing an increase in membrane permeability to calcium. Thus, parathyroid hormone binding causes an increase in Ca2+ release into the extracellular fluid. The slow method of bone resorption occurs via osteoclasts. They have a ruffled edge that increases their surface area. HCl and acid phosphatase (which breaks down collagen fibres) are released from this ruffled edge, breaking down bone and releasing calcium.

Discuss the hormonal control

There are three main hormones that control calcium levels: parathyroid hormone, vitamin D3, and calcitonin.

Parathyroid hormone (PTH)

PTH is released from the chief cells of the parathyroid glands (not to be confused with the chief cells of the stomach!). These chief cells have CaSR (calcium-sensing receptors) that, when activated, decrease PTH production and secretion. When calcium levels drop, CaSR are no longer activated, and PTH production and secretion increases. PTH causes an increase in calcium reabsorption and bone erosion, both of which increase plasma calcium levels.

Vitamin D3

As you should know, vitamin D is produced from 7-dehydrocholesterol after activation by UV light and a series of hydroxylations. Vitamin D3 can be produced in either an active (1, 25 D3) form or an inactive (24, 25 D3) form. The active form is only produced when parathyroid hormone is present; thus, parathyroid hormone can also indirectly cause an increase in calcium absorption.

Vitamin D3 increases calcium reabsorption in the kidneys and calcium absorption in the intestines, increasing calcium concentrations. D3 also increases calcification of bone, which decreases plasma calcium levels, but the decrease in calcium due to this process is dwarfed in comparison to the increase in calcium via reabsorption and absorption.

Insufficient vitamin D3 can cause rickets and osteomalacia. Rickets type II is a rare type of rickets in which the vitamin D receptor is mutated.

Calcitonin

Calcitonin is released by parafollicular cells in the thyroid gland. It is released when calcium levels are high. In contrast to PTH and D3, calcitonin decreases calcium levels. It does this by increasing calcium excretion and inhibiting the erosion of bone.

Discuss hypo- and hyperparathyroidism

Hypoparathyroidism

In hypoparathyroidism, there is insufficient secretion of PTH. This may be due to an autoimmune disease or due to loss of the parathyroids during thyroid removal. Insufficient PTH can cause hypocalcaemia, which is defined as a calcium level of less than around 6-7mg/dL. (Remember, normal calcium levels are around 9.4mg/dL). Since hypocalcaemia causes hyperexcitability, symptoms include muscle tetany (which results in a distinctive "Trousseau sign"), fatigue, headaches, tingling, seizures, bronchospasm, and cardiac arrhythmias.

Hyperparathyroidism

Hyperparathyroidism can be primary (usually due to a tumour of the parathyroid gland) or secondary (usually due to hypocalcaemia, which in turn can be due to rickets or chronic renal disease). Hyperparathyroidism causes excessive PTH secretion and excessive demineralisation of bone, leading to hypercalcaemia (defined as a calcium level greater than 12-15mg/dL). As high calcium causes cells to become less excitable, symptoms include depression of the CNS and PNS, muscle weakness, constipation, kidney stones (possibly due to precipitation of calcium salts), and coma.

Know the Ca2+ requirements and sources of Ca2+

See earlier post: Calcium and Phosphorous

Organ Transplant: The Surgeon's Perspective

Another lecture without a lecture outline, so guess I'll have to wing it. There were also a lot of details in this lecture that I didn't quite get, such as variations on some of the surgical techniques, but I think I'll just cross my fingers and hope that that doesn't come up on the exam 0_o

Types of donors

Just like for bone graft donations, organ donors can be living or deceased. Obviously, not all organs can be taken from a living donor. (Well, I suppose you could take all of their organs, but then they wouldn't be living any more. Also that shit would never pass an ethics board.)

Donations from the deceased can be classified into two categories: DBD (Donation after Brain Death) and DCD (Donation after Cardiac Death). In DBD, the heart is still beating, so the organs maintain their perfusion. In DCD, the organs lose their perfusion, so they are not as high quality as organs donated from DBD. Usually only kidneys and lungs are taken from a DCD donor.

An important consideration is the ischaemia time, or the time that the organs have to go without blood perfusion after being removed. There are two types of ischaemia time: WIT (warm ischaemia time) and CIT (cold ischaemia time). Organs can be kept for longer if they are cold: for example, warm kidneys can only be kept for around 60-90min after removal, but if they are cooled down, they can be kept for longer than 24 hours. A cold heart can be kept for 6-8 hours and a cold liver can be kept for 12-16 hours. Part of the reason why DBD organs are of higher quality is because the WIT is basically zero: their heart is still beating when the donor passes away, and the functional circulation is directly replaced with a cool fluid, so their organs essentially go straight from perfusion to CIT.

Organ retrieval

Now for the real shitshow! (Not the surgery, that is- my writing. A lot of the details from here on in went over my head. Maybe it would have made more sense if I was a surgeon, but I'm not, and probably never will be. I value my sleep too much.)

When organs are retrieved, UW (University of Wisconsin) solution is inserted into the aorta and drained out through the inferior vena cava. UW solution helps to minimise cell metabolism and keep the cell membranes stable, which is good for preservation purposes. The gallbladder and bile duct are washed, and a liver biopsy might be done in order to assess viability (particularly if the donor appears to have fatty liver disease or something similar). During the removal process, several factors must be taken into consideration. One of these factors is variability in the hepatic artery (see here for the normal anatomy of arteries supplying the gastrointestinal tract). Some people may also have an accessory right hepatic artery from the superior mesenteric artery, and others may have an accessory left hepatic artery from the left gastric artery (which in turn comes from the coeliac artery).

After an organ is removed, it is packed in three bags. The first bag is filled with UW fluid, which helps to preserve the organ. The next bag is filled with ice water, but if the organ is going to be sent to its destination by air, just normal water is used (to prevent over-freezing). The third and final bag simply provides an extra layer of protection.

Transplantation

Now for the transplantation bit! This part of this post is going to be extremely lacking because he went into detail on surgical techniques, and I got kind of lost.

Obviously, blood loss is a concern in most types of surgery. Argon gas can be used to stop small areas from oozing. Machines can collect blood that are lost during the transplantation so that it can be re-infused. (This is normally only done after the new organ has been implanted, especially if the old organ was cancerous- you wouldn't want any risk of any of those cancerous cells re-infecting the patient.) Finally, traditional blood transfusions can be done. Only around 1/3 of liver transplant patients require these transfusions.

There are several ways in which all of the vessels can be joined up. In this post, I'm just going to talk about the vena cava and the bile duct, for no other reason than that those were the only two procedures that I kind of understood.

For the vena cava there are three main options: caval replacement, piggyback and side-to-side cavaplasty. In caval replacement, the inferior vena cava from the patient is replaced with the vena cava of the transplant. In a piggyback anastomosis, one end of the donor inferior vena cava is joined up with the patient's inferior vena cava, which remains intact. In side-to-side cavaplasty, the donor and recipient inferior vena cavas are opened on one side and joined together.

For the bile duct there are two main options: end-to-end and roux-en-Y (not sure whether or not this is the same roux-en-Y used for bariatric surgery). In roux-en-Y, the bile is drained directly into the small intestine. There's a nice picture here if you want a better idea.

Other types of liver transplant

Aside from transplanting a whole liver, there are other things you can do. In a split liver transplant, a single liver is used for two patients (usually one adult and one child). A reduced size liver transplant uses only part of a liver. Finally, a live donor liver transplant takes part of a live donor's liver (obviously not so much that they die- enough needs to be left to allow the donor's liver to regenerate).

Musculoskeletal tissue banking

Biological properties of musculoskeletal allograft

This lecture focused more on the "skeletal" grafts than the "musculo-" grafts. Bone grafts are often used in situations where there is bone loss, such as in joint replacement, infections and fractures. They can be derived from living donors (usually from femurs from hip replacement surgery- the femoral head is usually discarded) or from cadavers.

Osteoconduction vs osteoinduction
Interaction between growth factors and osteoblasts

Osteoconduction and osteoinduction are both desirable traits of a bone graft. Osteoconduction means that the bone will be able to grow through the scaffold provided by the graft, and osteoinduction means that the graft can promote bone growth. Osteoinduction can be either active or passive: active osteoinduction is due to growth factors (usually bone morphogenic proteins, or BMPs), and passive osteoinduction is due to other environmental or morphological factors. Another important trait for grafts is osteointegration, which is the ability of a graft to integrate into the recipient's bone.

Autograft vs allograft vs xenograft

An autograft uses a patient's own bone, which is obviously pretty ideal (non-immunogenic, will be osteoconductive, osteoinductive and osteogenic, and so on). The bone that is most likely to be used is the iliac crest. Autografts do have problems, however: the donor site might have problems, and longer surgery times might be needed. Autografts might not be suitable for some larger grafts, where structural strength is needed.

An allograft is a graft from another human. There are many types. Allografts are osteoconductive, but they are not osteogenic (which I think means that they don't undergo normal bone growth in this case) and only have limited osteoinduction capacity. There may also be some issues with immunogenicity.

Demineralised bone matrix (DBM) is a type of allograft that has been exposed to strong acids, removing the mineral parts (mainly calcium). It is not osteogenic, but is osteoconductive and has varying capacity for osteoinduction. Unfortunately, it is expensive and lacks structural integrity.

OP-1 implants, which are basically just recombinant BMP-7, have been trialled. Not much else was said about them during the lecture, however.

Other options that have been trialled are xenografts (grafts from different animals) and synthetic materials. Again, I don't have much more to add here.

Reducing bioburden: process controls & terminal irradiation
Appreciate the importance of the quality system 

It takes around 3-7 months to prepare a cadaver-derived graft for transplantation, and around 8-12 months to prepare a graft from a living donor. Many different process controls are implemented in order to ensure that the graft is as good as possible (you wouldn't want to accidentally graft a tumour into someone, for instance). Firstly, grafts are excluded if they contain malignancies or certain autoimmune diseases. Preparation is done in a Grade C cleanroom, which is kept clean via Hepa filters, particle counting, pressure gradients and environmental monitoring. Grafts are tested for microbes and irradiated to kill basically everything on them. (The high-dose irradiation also means that HLA matching isn't really necessary for bone grafts.)

Thermal Physiology II: Fever and Acclimation

This post is going to contain a tiny bit of the next lecture (Thermal Physiology III). The lectures all ran overtime to the point that the lecturer only got to talk about the third lecture for a grand total of five minutes :P

Describe and understand a standard heat acclimatisation procedure in humans

In heat acclimatisation procedures, a subject is placed in a hot room for a certain number of hours each day for a certain number of days in a row. Fun. (Not.)

Describe and understand what physiological changes occurs during the process of heat acclimatisation in humans

In the process of heat acclimatisation, sweat loss increases and contains fewer electrolytes (like sodium). This may be due to the effect of aldosterone on sodium reabsorption. Plasma volume also increases. As someone acclimatises to heat, their heart rate and rectal temperature in the hot environment decrease.

Describe and understand how heat flow is affected by insulation and temperature gradient
Describe and understand the inverse relationship between insulation and thermal conductance

Heat flow is related to insulation and temperature gradient according to the following equation:

Heat Flow = Temperature Gradient / Insulation

This can also be rearranged to give an equation in terms of conductance (which is the inverse of insulation):

Heat Flow = Temperature Gradient * Conductance

Describe and understand the various components of the heat balance diagram

There are several different curves on the heat balance diagram:

• Deep body temperature: Stays relatively constant at a range of environmental temperatures. Decreases if temperature is too low and increases if temperature is too high.
• Non-evaporative heat loss: Heat loss due to conduction, convection and radiation. Depends on the temperature gradient (if insulation is constant), so heat loss decreases as temperature increases. The slope of the line is not constant- it flattens out in the temperature range between maximum vasoconstriction and maximum vasodilation, before becoming steep again. (Maybe I should draw a diagram, but I really can't be bothered.)
• Heat production: Prior to the point of maximum vasoconstriction, heat production increases with decreasing temperature. After the point of maximum vasoconstriction, the curve flattens out as you are at your basal metabolism rate and can't decrease your heat production further.
• Evaporative heat loss: Heat loss due to sweating and some other factors, such as breathing. Stays relatively flat for a while. Increases slightly between the points of maximum vasoconstriction and maximum vasodilation, before increasing more sharply.

Now for some more terminology! The lower critical temperature is the temperature at which your arteries are maximally vasoconstricted. The upper critical temperature is the temperature at which your arteries are maximally dilated. The thermoneutral zone, also known as the Zone of Vasomotor Adjustment, is located between these two points.

Describe and understand the underlying mechanistic basis of heat stroke

"Heat stroke" is defined as a core body temperature of more than 41°C, but I'm not really sure about the mechanistic basis. I'm assuming that the main idea is that, when the amount of heat you are gaining exceeds the amount you are losing, your body temperature heats up over time until it gets to the point that your body just can't handle it any more (enzymes denature etc.)?

Describe and understand the limits to human heat tolerance
Describe and understand the prescriptive zone, how it is measured and what it means

The "prescriptive zone" is the point at which you can no longer thermoregulate. It is measured by putting subjects in a room with gradually increasing temperature or humidity and then finding the point at which the subjects' temperatures begin to increase. Several factors can influence the prescriptive zone- heat acclimatisation can increase the prescriptive zone, as can wind.

Understand the terms ‘torpor’ and ‘hibernation’

'Torpor' is a state in which heat production and metabolic rate drop. Hibernation is similar to torpor, but occurs for a longer period of time. Torpor is mainly found in small animals, some of which have to produce their own "antifreeze" to prevent their cells from freezing at sub-zero temperatures.

Describe and understand the relationship between surface area and body mass for animals of different sizes

As animals get larger, mass increases faster than surface area. Therefore, smaller animals will tend to have a relatively high surface area, and larger animals will tend to have a relatively low surface area. Since heat loss is proportional to surface area, smaller animals are more likely to struggle in the cold (as they are losing a lot of heat), and larger animals are more likely to struggle in the heat.

Describe the tissue known as brown adipose tissue and its role in non-shivering thermogenesis

Babies are unable to shiver, but they are able to produce heat via brown adipose tissue (a.k.a. "brown fat"). Brown adipose tissue has a lot of mitochondria that are capable of producing heat.

Describe and understand the role of UCP1 in non-shivering thermogenesis

UCP1 (uncoupling protein), also called "thermogenin," is found on the inner mitochondrial membrane in brown fat. UCP1 is essentially a H+ channel. Unlike ATP synthase, which is also an H+ channel, UCP1 does not produce ATP. Instead, UCP1 produces heat.

It was originally thought that adults don't have brown fat. This has been found to be untrue. Some adults do have brown fat, mainly in the supraclavicular and neck regions.

Describe and understand the mechanistic basis of fever, including the role of endogenous pyrogens, and how they operate to alter the thermoregulatory set-point

Fever is usually stimulated by some kind of invading microorganism. Various toxic products of microorganisms, such as lipopolysaccharide, are called exogenous pyrogens as they can stimulate fever. Exogenous pyrogens stimulate phagocytes to make and secrete endogenous pyrogens, such as IL-1β, IL-6, IFNβ, IFNγ and TFNα. It has been suggested that endogenous pyrogens cross the blood-brain barrier at the organism vasculosum of the lamina terminalis (OVLT), which is kind of like a "leakier" part of the blood-brain barrier.

After passing through the OVLT, endogenous pyrogens stimulate phospholipase A2, which cleaves phospholipids to form arachidonic acid. Arachidonic acid is then converted into prostaglandins via cyclooxygenase. (I've described these pathways in more detail here.) One of the more important prostaglandins in fever signalling is prostaglandin E2. Prostaglandin E2 changes the firing rate of cold-sensitive neurons, essentially tricking your body into thinking that it's cold so that thermoregulatory processes can kick in and raise your body temperature.

Interestingly enough, injecting exogenous pyrogen, endogenous pyrogen and prostaglandin E into the hypothalamus can all cause fever. However, the time it takes to cause fever is different. Exogenous pyrogen has the longest latency (i.e. delay before onset of fever), followed by endogenous pyrogen and then prostaglandin E2. In fact, prostaglandin E2 causes fever immediately after injection into the hypothalamus.

What's the point of fever? It's been suggested that fever might play a role in fighting infection. Yay...!

Describe and understand the mechanistic basis for some anti-pyretics

Most anti-pyretics work by blocking either cyclooxygenase or phospholipase A2. Paracetamol and NSAIDs (e.g. ibuprofen) block cyclooxygenase. Steroidal anti-inflammatory drugs (I assume these are just corticosteroids) block phospholipase A2.

Describe and understand how the various components of the heat balance equation change from rest to exercise

If you can't remember from my last post, the heat balance equation is as follows:

S = M ± Cond ± Conv ± Rad ± E - W

During exercise, our metabolic rate (M) increases. Therefore, to stop our temperature from increasing too much, we need to lose heat in some other way (e.g. increasing our evaporative heat loss (E) by sweating).

Describe and understand some of the arguments that the thermoregulatory relies on negative feedback regulation during exercise

During exercise, we make more heat as our metabolic rate increases. In early stages of exercise, our heat loss mechanisms (vasodilation and sweating) are still operating at their resting levels, which is insufficient for the increased metabolism during exercise. Therefore, body temperature rises, stimulating heat loss until heat loss is equal to heat gain. In other words, it's a negative feedback loop. Yay!

Describe and understand the effect of increased thermoregulatory demands on exercise performance

Pretty much all we got up to here is that increased muscle temperature does seem to increase performance, but if muscle temperature increases, body temperature also increases, which isn't necessarily good. There's also a battle between the muscles and the skin- the muscles want blood so they can do their job, and the skin wants blood so it can get rid of the excess heat. Overall, heat tends to reduce exercise performance. I think that's all we got up to in this lecture, so I'll end this post here.