Category Archives: Cell biology and Genetics

– Cell cycle
– Cancer
– Bone remodeling.
– How blood glucose is regulated?

Water and Sodium Balance, Hyper- and Hyponatremia

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A human body contains 50 to 70% water, of which about 2 thirds is located inside the cells, the other one third is in the extracellular fluid and blood plasma. Water can move freely between different compartments in the body, but its direction is determined by which compartment has more solutes, or higher osmolality. As a rule, water moves from the more diluted solution to the more concentrated solution – from lower to higher osmolality.
Sodium, being the major extracellular solute, is the principal determinant of plasma osmolality and the most important regulator of fluid balance. A normal blood sodium level is kept between 135 and 145 mmol/L. Hyponatremia occurs when blood sodium falls below 135, while hypernatremia is when it exceeds 145.
Clinical manifestations of sodium disorders reflect disturbances in water movement in the most sensitive organ of the body – the brain. In hypernatremia, high blood sodium levels draw water out of the brain cells, causing dehydration and shrinkage. Whereas in hyponatremia, low concentrations of plasma sodium drive water into brain cells, making them swell, causing edema. Both situations produce neurologic symptoms, which can range from headache, confusion, to seizures, coma or even death.
Hypernatremia most often occurs because of inadequate water intake, or excessive water loss or excretion. Water intake is regulated by thirst. When a decreased body fluid volume or an increased plasma osmolality is detected, the brain perceives it as thirst and produces water-seeking behavior. Impaired thirst mechanism is a common cause of hypernatremia in the elderly.
The body loses water primarily by excreting it in urine. Water excretion by the kidneys is mainly regulated by vasopressin, a hypothalamic hormone that causes the kidneys to retain water in response to low blood volume or high plasma osmolality. Impaired vasopressin release, renal dysfunction, and use of certain diuretics, are common causes of excessive water loss through the kidneys.
Fluid loss through the digestive tract is normally negligible, but can be substantial in vomiting or diarrhea. Sweat loss though skin can be significant in extreme heat or during excessive exercise.
Chronic hypernatremia is treated with oral hypotonic fluids, while acute or severe hypernatremia may require intravenous administration along with constant monitoring to avoid overcorrection. The underlying cause must also be addressed.
For hyponatremia, treatment depends on the body fluid volume:
– In low volume, or hypovolemic hyponatremia, both sodium and water levels decrease, but sodium loss is relatively greater. This commonly occurs due to loss of sodium-containing fluids, as in vomiting and diarrhea, especially when loses are replaced with plain water. This type is managed by rehydration with isotonic fluids.
– In high volume, or hypervolemic hyponatremia, both sodium and water levels increase, with a relatively greater increase in body water. This often results from fluid retention in conditions such as heart failure, liver cirrhosis, or kidney failure; and is usually treated with diuresis.
– In normal volume, or euvolemic hyponatremia, sodium level is normal, but there is an increase in total body water. This can be caused by excessive water intake combined with renal insufficiency, or syndrome of inappropriate ADH secretion, which causes the kidneys to retain more water. This type is managed by restricting free water intake and addressing the underlying cause.
Premenopausal women are more susceptible to acute hyponatremia with severe brain edema, perhaps because female hormones increase vasopressin level, and inhibit the brain sodium-potassium pump, which pumps sodium out of the cell and helps maintain normal brain volume.
Acute or symptomatic hyponatremia is an emergency and should be treated with intravenous hypertonic sodium chloride, but sodium levels must be closely monitored to avoid overly rapid correction.

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Overview of the immune system, with animation.

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The immune system is the body’s defense system. It protects the body from disease-causing organisms, called pathogens. The protection has several layers.
First, invading pathogens meet with a number of surface barriers, which consist of physical, chemical, and biological obstacles designed to keep them out. The primary physical barrier is the skin, which covers the entire body. Body systems that are open to outside environment, such as the respiratory, digestive, urinary and reproductive system, each have their own mechanisms to prevent entrance of microbes: mucous membranes trap them, sneezing or coughing reflex expels them, while urine mechanically flushes them out.
Chemical barriers include stomach acid and various antimicrobial substances in sweat, saliva, tears and other body fluids.
The skin and mucous membranes are also heavily inhabited by the body’s normal flora, which competes with pathogens for nutrition and space, providing biological barriers.
If an organism manages to get past the surface barriers, for example, via a splinter that pierces through the skin, it will meet with the innate component of the immune system, which mounts an immediate, but non-specific response. If this fails to contain the infection, another layer of defense, called the adaptive, or acquired, immune response comes into play. The adaptive response takes longer to be activated, but is more effective as it specifically targets the invading pathogen. It also leaves the body with a “memory” of the pathogen, so it can react faster the next time the same pathogen attacks.
The major players of the immune system are the white blood cells, or leukocytes. All leukocytes derive from hematopoietic stem cells in the bone marrow. Each of them has different roles in the immune response.
The first response of the innate immune system is inflammation. Resident macrophages, which constantly patrol body tissues, ingest the pathogen and release inflammatory chemicals, called cytokines, which attract other immune cells to the site of injury. Basophils, eosinophils and mast cells release their own cytokines, amplifying inflammation. Cytokines dilate blood vessels, increasing blood flow and are responsible for clinical signs of inflammation such as redness and swelling. They act on endothelial cells of blood vessels and serve as chemical cues for migration of neutrophils – the major phagocytes involved in first-line defense. Activated endothelial cells attach to neutrophils in the flow, slowing them down, before getting them to squeeze through the vessel wall. Neutrophils engulf bacteria and destroy them with enzymes or toxic peroxides. They may also release highly reactive oxygen species in a phenomenon known as oxidative burst, which kills pathogens faster and more efficiently. The neutrophils themselves, however, also die in the process, their debris forming pus on the injury site.
The adaptive immune response starts with the so-called “antigen-presenting cells”, of which dendritic cells are most effective. Resident dendritic cells on the site of infection swallow up pathogens, cut them into pieces, called antigens, and display them on their surface. These dendritic cells are then picked up by lymphatic capillaries and travel to lymph nodes, where they present the antigens to a matching T-cell. The pathogen itself may also travel to a lymph node where it may encounter a matching B-cell. The match-finding process underlies the specificity of adaptive immune response. T-cells and B-cells exist in billions of variations, each carries a unique surface protein, which acts like a key. Among these billions of keys, only the ones that can bind to, or unlock, the invading pathogen, are activated. Activated T-cells and B-cells undergo differentiation and proliferation, called clonal expansion. This process produces memory cells, ready for future infections by the same pathogen; and effector cells, which include activated cytotoxic T-cells and plasma B cells producing antibodies; both of these are specific to the pathogen. Antibodies and cytotoxic T-cells then leave the lymph node for the bloodstream to be delivered to the site of infection. Antibodies attach to pathogens and either target them for destruction or neutralize them. Cytotoxic T-cells release toxins to kill infected host cells.

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The Endocrine System, Overview with Animation

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The endocrine system is one of the two systems that are responsible for communication and integration between various body tissues, the other being the nervous system. Endocrine communication is achieved by means of chemical messengers called hormones. Hormones are produced in endocrine glands and secreted into the bloodstream to reach body tissues. A hormone can travel wherever the blood goes, but it can only affect cells that have receptors for it. These are called target cells. There are 2 major types of hormones: steroid hormones derived from cholesterol and are lipid-soluble; and non-steroid hormones derived from peptides or amino-acids and are water-soluble. Lipid-soluble steroid hormones can cross the cell membrane to bind to their receptors inside the cell, either in the cytoplasm or nucleus. Steroid hormone receptors are typically transcription factors. Upon forming, the hormone/receptor complex binds to specific DNA sequences to regulate gene expression, and thus mediating cellular response. On the other hand, water-soluble non-steroid hormones are unable to cross the lipid membrane and therefore must bind to receptors located on the surface of the cell. The binding triggers a cascade of events that leads to production of cAMP, a second messenger that is responsible for cellular response to hormone. It does so by changing enzyme activity or ion channel permeability.
Major endocrine glands include: the hypothalamus, pituitary gland, pineal gland, thyroid and parathyroid glands, thymus, adrenal gland, islets of the pancreas, and testes in men or ovaries in women. The endocrine system also includes hormone-secreting cells from other organs such as kidneys and intestine.
Except for the hypothalamus and the pituitary, different endocrine glands are involved in different, more or less independent, processes. For example, the pancreas produces insulin and glucagon that keep blood sugar levels in check; the parathyroid glands produce hormones that regulate calcium and phosphorus; thyroid hormones control metabolic rates; while the ovaries and testes are involved in reproductive functions. On the other hand, the hypothalamus and pituitary gland play a more central, integrative role. The hypothalamus is also part of the brain. It secretes several hormones, called neuro-hormones, which control the production of other hormones by the pituitary. Thus, the hypothalamus links the nervous system to the endocrine system. The pituitary is known as the master gland because it controls the functions of many other endocrine glands. (See “Hypothalamus and Pituitary Gland video for details!)
A major role of the endocrine system is to maintain the body’s stable internal conditions, or homeostasis, such as blood sugar levels or serum calcium levels. To do this, it utilizes negative feedback mechanisms, which work very much like a thermostat: the heater is on when the temperature is low, off when it’s high. For example, when blood glucose level is high, such as after a meal, glucose induces insulin release from the pancreas. Insulin helps body cells consume glucose, clearing it from the blood. Low blood glucose can no longer act on the pancreas, which now stops releasing insulin. Another example is the regulation of thyroid hormones levels which are induced by a pituitary hormone called thyroid-stimulating hormone, TSH. TSH, in turn, is under control of thyrotropin-releasing hormone, TRH, from the hypothalamus. When thyroid hormone levels are too high, they suppress the secretion of TSH and TRH, consequently inhibiting their own production.

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Unsaturated versus Saturated versus Trans Fats, with Animation

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Contrary to popular belief, not all fats cause heart diseases and are bad. In fact, most fats, in adequate amounts, are required for normal bodily functions, especially brain functions. There are also good fats that actually decrease the risks for cardiovascular diseases.

A fat molecule is composed of a glycerol head and three fatty acid tails, each of which is a long hydrocarbon chain – a carbon skeleton bound to hydrogen atoms. When all the carbons are fully bound to hydrogens, the fatty acid is said to be saturated – all the bonds between carbon atoms are single, and the hydrocarbon chain has a straight shape. A fat molecule made entirely of saturated fatty acids is a saturated fat. Due to their straight tails, saturated fats are compact and solid at room temperature.

On the other hand, when the hydrocarbon chain has fewer hydrogens, it is said to be unsaturated. Instead of binding to a maximum number of hydrogens, some carbon atoms bind to each other via a double bond. The presence of double bonds may bend the hydrocarbon chain, creating gaps between molecules, making them less compact. As a result, unsaturated fats are usually liquid at room temperature. A fat molecule that contains only one double bond is a monounsaturated fat, while one that has multiple double bonds is polyunsaturated.

Dietary fats provide fatty acids for the synthesis of the cell membrane – a vital component of all animal cells. The gaps in unsaturated fatty acids provide membrane fluidity, facilitating membrane transport and cellular signaling. While both types of fats are needed for an optimal composition of the cell membrane, too much saturated fat, which is commonly the case in a typical American diet, would make the membrane rigid and hinder cellular responsiveness. Membrane fluidity is most important in the nervous system, where neuronal response requires extremely fast cellular communication.  A certain ratio of unsaturated to saturated fatty acids is also required for the formation of myelin – the insulating material that wraps around axons of neurons and speeds up the conduction of electrical signals.

The body is capable of synthesizing all the fatty acids it needs, with the exception of polyunsaturated fatty acids omega-3 and omega-6, which must be obtained from the diet. These are known as essential fatty acids.

In general, unsaturated fats are healthier than saturated fats. Unsaturated fats decrease the risks for heart disease by reducing the amount of bad cholesterol, LDL, and increasing the good cholesterol, HDL; while saturated fats increase both good and bad cholesterol. But not all unsaturated fats are equal. In fact, a type of unsaturated fat, known as trans-fat, is the unhealthiest of all!

A double bond can give rise to 2 possible configurations: cis and trans. Cis is when the 2 hydrogen atoms are on the same side of the bond, while trans is when they are on the opposite sides. A cis double bond bends the fatty acid molecule, while the somewhat more symmetric trans configuration does not. A trans-fat is therefore similar in structure to a saturated fat. More importantly, trans-fats rarely occur in nature so the body does not have the necessary enzymes to break them down. Diets rich in trans-fats increase the bad cholesterol LDL and reduce the good cholesterol HDL, having the most detrimental effect on blood vessels.

Trans-fats are found mainly in partially hydrogenated oil products, such as margarine. Because unsaturated fats are less stable and spoil faster, food manufacturers add hydrogens to make them more saturated through a process known as partial hydrogenation. This process not only prolongs shelf-life of vegetable oils, but also turns them into solid, or semi-solid products, which are preferred by commercial bakers for their low cost and wide range of different textures. Unfortunately, partial hydrogenation also converts some of the cis double bonds into trans configuration, producing trans-fats. The FDA has officially banned production of partially hydrogenated oils in June 2018, but products made earlier may still be in use until January 2020.

 

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High Cholesterol and Familial Hypercholesterolemia, with Animation

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Cholesterol is an essential component of all animal cells, but TOO MUCH cholesterol IN THE BLOOD is a high-risk factor for cardiovascular diseases such as heart attacks and strokes.
Cholesterol levels are measured in a blood test known as lipid panel or lipid profile. This test typically reports: total cholesterol; LOW-density lipoprotein, LDL, also known as “bad” cholesterol; HIGH-density lipoprotein, HDL, or “good” cholesterol; and triglycerides. A desirable profile includes LESS than 200mg/dL of TOTAL cholesterol, with LESS than 100mg/dL of LDL and MORE than 40mg/dL of HDL.
The body obtains cholesterol in 2 ways: from foods of animal origin, and its own endogenous production. Usually, cholesterol levels are kept in check by a negative feedback control. LOW levels of INTRACELLULAR cholesterol INDUCE its own production, while HIGH cholesterol levels INHIBIT it.
It is noteworthy, however, that this regulation applies to the concentration of cholesterol INSIDE the CELLS, NOT in the BLOOD. The HIGH prevalence of HIGH BLOOD cholesterol worldwide suggests that this control mechanism is NOT sufficient to maintain healthy cholesterol levels when challenged by a number of factors, including poor diet, lack of exercise, smoking, obesity, diabetes, and aging.
In addition, some people have an INHERITED condition called “familial hypercholesterolemia”, FH, that causes very HIGH levels of LDL, the “bad“ cholesterol, at a young age. Left untreated, patients are likely to have heart attacks in their 40s or 50s. LDL is basically a vehicle that transports cholesterol from the liver to peripheral cells so it can be used in the cell membrane. Peripheral cells TAKE UP LDL by endocytosis, using their LDL receptor, which binds to a protein ligand on LDL surface. Most cases of FH are caused by a MUTATION in the LDL receptor gene. A defective LDL receptor REDUCES LDL uptake, leaving MORE LDL in the circulation while the cells are DEFICIENT in cholesterol. LOW INTRAcellular cholesterol levels induce FURTHER production of endogenous cholesterol in the liver, eventually causing even HIGHER levels of circulating LDL. One copy of the mutated gene is enough to cause high cholesterol. The condition is therefore inherited in an autosomal DOMINANT manner. A parent with an altered gene has a 50% chance of passing it to a child. If both parents have FH, each child has a 50% chance of having FH, a 25% chance of NOT having FH, and a 25% chance of having TWO copies of the mutated gene, called HOMOZYGOUS FH. Without treatment, homozygous FH patients may have heart attacks in their 20s and may not survive past the age of 30.
Treatments for high cholesterol must start with life style changes such as healthy diets and physical exercise. On top of that, some people may require medications to lower cholesterol. These drugs INHIBIT cholesterol production, intestinal absorption, or reabsorption in the form of bile. Homozygous FH patients usually require more DRASTIC treatment measures which include a procedure called LDL APHERESIS. In this procedure, the blood is diverted through a FILTRATION device where LDL is REMOVED before the remaining plasma and blood cells are returned to the body. The procedure is repeated weekly or biweekly.

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Blood Types, Blood Group Systems and Transfusion Rule, with Animation

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A blood type refers to the PRESENCE or ABSENCE of a certain marker, or ANTIGEN, on the surface of a person’s red blood cells. For example, in the ABO system, presence of A or B antigen gives type A or B, presence of both antigens gives type AB, while their ABSENCE gives type O.
Blood typing is critical for blood transfusion, as there are very SPECIFIC ways in which blood types must be MATCHED between the donor and recipient for a safe transfusion. The rule is simple: patients should NOT be given antigens that their own blood does NOT have. This is because the recipient’s immune system may recognize any “NEW” antigen as “FOREIGN” and develop antibodies to target it for destruction. Depending on the scale of the triggered immune response, the reaction can be serious or fatal.
Applying the rule, a type A patient, who is NEGATIVE for B antigen, can only receive blood from type A and type O donors, whose blood does NOT contain B antigen. A type AB patient, having both antigens, can receive blood from anyone, while a type O person, being NEGATIVE for both A and B, can only receive from type O donors, but can give blood to anyone.
Another important system is the Rh system, for which, D antigen, or Rh factor, is best known. The blood type for this antigen can be either Rh-positive or Rh-negative. By the same rule, a Rh-negative patient canNOT receive blood from a Rh-positive donor, while the reverse direction is fine.
Each of the 4 types of the ABO system can be Rh-positive or negative. This gives 8 possible combinations – the 8 basic blood types everyone knows about.
But ABO and Rh are only a FRACTION of the 35 currently known blood group systems, many of which can cause serious reactions during transfusion if mismatched. Altogether there are HUNDREDS of antigens, giving rise to a gigantic number of possible blood types. A fully specified blood type should describe the COMPLETE SET of antigens that a person has. In theory, this list must be determined for both donor and recipient before a transfusion can take place. In reality, however, most people only need to care about their ABO type and Rh factor.
The ABO and Rh systems are the most important in blood transfusion for 2 reasons. First, most people can produce ROBUST antibodies against A, B and D antigens, which may NOT be the case for other antigens. In fact, anti-A and anti-B antibodies are usually developed during the first year of life. Second, the 8 basic blood types are distributed in comparable proportions that make mismatching a likely event. Most other antigens occur at such frequencies that ONLY a VERY SMALL subset of patients is potentially at risk. For example, if 99.99% of a population is positive for a certain antigen and only 0.01% is negative, only that tiny fraction of negative patients is at risk regarding that antigen. To account for possible INcompatibility OUTSIDE ABO and Rh, an ADDITIONAL test is usually made before transfusion. A blood sample from the patient is mixed with a sample of donor blood and the mixture is examined for CLUMPS. No clumping means a compatible match.

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Membrane Transport, with animation

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All animal cells are enclosed in a plasma membrane, which consists of 2 layers of phospholipids. The hydrophobic nature of the cell membrane makes it intrinsically permeable to small NON-polar and uncharged polar molecules, but NON-permeable to large polar molecules and CHARGED particles. Charged particles, such as ions, must use special channels to move through the membrane.
Transport of a molecule can be passive or active. PASSIVE transport does NOT require energy input because it moves the molecules “DOWNHILL”, for example, from HIGHER to LOWER concentration. ACTIVE transport, on the other hand, moves the molecules AGAINST their gradients and therefore requires ENERGY expenditure.
Ion channels permit PASSIVE transport of ions. These are transmembrane proteins that form PORES for ions to pass through. Most ion channels are SPECIFIC for a certain type of ion.
Ion channels can be classified by how they change their OPEN-CLOSED state in RESPONSE to different factors of the environment. Common types of ion channels include:
– LEAK channels: these channels are almost always OPEN allowing more or less steady flow of ions; examples are potassium and sodium leak channels in neurons.
– LIGAND-gated ion channels: these channels OPEN upon BINDING of a LIGAND. They are most commonly found at synapses, where neurons communicate via chemical messages, or neurotransmitters. An example is the GABA receptor, a chloride channel located on POST-synaptic neurons. It OPENS upon binding to GABA, a neurotransmitter released by the PRE-synaptic neuron, and allows chloride ions to flow into the cell.
– VOLTAGE-gated ion channels: these channels are REGULATED by membrane voltage. They OPEN at some values of the membrane potential and CLOSE at others. These are the channels that underlie ACTION POTENTIALS in neurons and cardiac muscles.
ACTIVE transport of ions is carried out by ion transporters, or ion PUMPS. These are transmembrane proteins that PUMP ions AGAINST their concentration gradient using cellular ENERGY, such as ATP. Most notable example is the sodium-potassium pump which maintains the resting potential in neurons by pumping two potassium IN and three sodium OUT of the cell.
Another type of ion transporters, known as SECONDARY transporters, do NOT use ATP directly. Instead, they move ONE ion DOWN its concentration gradient and use THAT ENERGY to POWER the transport of a SECOND ion. Symporters transport the two ions in the same direction, while antiporters pump the coupled molecule in the OPPOSITE direction.

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Membrane Potential, Equilibrium Potential and Resting Potential, with Animation

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Membrane potential, or membrane voltage, refers to the DIFFERENCE of electric charges across a cell membrane. Most cells have a NEGATIVE transmembrane potential. Because membrane potential is defined RELATIVE to the exterior of the cell, the negative sign means the cell has MORE negative charges on the INSIDE.

There are 2 basic rules governing the movement of ions:

– they move from HIGHER to LOWER concentration, just like any other molecules;

– being CHARGE-bearing particles, ions also move AWAY from LIKE charges, and TOWARD OPPOSITE charges.

In the case of the cell membrane, there is a THIRD factor that controls ion movement: the PERMEABILITY of the membrane to different ions. Permeability is achieved by OPENING or CLOSING passageways for specific ions, called ION CHANNELS. Permeability can change when the cell adopts a DIFFERENT physiological state.

Consider this example: 2 solutions of different concentrations of sodium chloride are separated by a membrane. If the membrane is EQUALLY permeable to BOTH sodium and chloride, both ions will diffuse from higher to lower concentration and the 2 solutions will eventually have the same concentration. Note that the electric charges remain the same on both sides and membrane potential is zero.

Now let’s assume that the membrane is permeable ONLY to the positively-charged sodium ions, letting them flow down the concentration gradient, while BLOCKING the negatively-charged chloride ions from crossing to the other side. This would result in one solution becoming INCREASINGLY positive and the other INCREASINGLY negative. Since opposite charges attract and like charges repel, positive sodium ions are now under influence of TWO forces: DIFFUSION force drives them in one direction, while ELECTROSTATIC force drives them in the OPPOSITE direction. The equilibrium is reached when these 2 forces COMPLETELY counteract, at which point the NET movement of sodium is ZERO. Note that there is NOW a DIFFERENCE of electric charge across the membrane; there is ALSO a CONCENTRATION gradient of sodium. The two gradients are driving sodium in OPPOSITE directions with the EXACT SAME force. The voltage established at this point is called the EQUILIBRIUM potential for sodium. It’s the voltage required to MAINTAIN this particular concentration gradient and can be calculated as a function thereof.

A typical RESTING neuron maintains UNequal distributions of different ions across the cell membrane. These gradients are used to calculate their equilibrium potentials.  The positive and negative signs represent the DIRECTION of membrane potential. Because sodium gradient is directed INTO the cell, its equilibrium potential must be POSITIVE to drive sodium OUT. Potassium has the REVERSE concentration gradient, hence NEGATIVE equilibrium potential. Chloride has the same INWARD concentration direction as sodium, but because it’s a negative charge, it requires a NEGATIVE environment inside the cell to push it OUT.

The resting membrane potential of a neuron is about -70mV. Notice that ONLY chloride has the equilibrium potential near this value. This means chloride is IN equilibrium in resting neurons, while sodium and potassium are NOT. This is because there is an ACTIVE transport to keep sodium and potassium OUT of equilibrium. This is carried out by the sodium-potassium PUMP which constantly brings potassium IN and pumps sodium OUT of the cell. The resulting resting potential, while costly to maintain, is essential to generation of action potentials when the cell is stimulated.

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HIV and AIDS infection stages, HIV life cycle, Transmission, Diagnosis and Treatment, with Animation

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HIV, for human immunodeficiency virus, is a virus that attacks the immune system, weakening the body’s ability to fight infections. Progressive destruction of the immune system eventually leads to its failures, a state known as “acquired immunodeficiency syndrome”, or AIDS, when the body is INcapable of defending itself from common infections.

HIV targets a specific group of cells called CD4+ cells. CD4 is a receptor expressed on the surface of many immune cells, including T helper cells, macrophages and dendritic cells, where it is essential for cell communication and hence normal function of the immune system. HIV hijacks this receptor to gain access to the cells. Apart from CD4 receptor, another factor, called a co-receptor, is also required for HIV entry and infection. Several co-receptors have been identified in different cell types, with CXCR4 and CCR5 being the most common. CXCR4 is expressed on many T-cells, but usually not on macrophages, and is used by T-tropic strains of HIV. CCR5 is expressed on macrophages, some T-cells, and is used by M-tropic strains. Some HIV strains use CCR5 to infect initially but evolve to use CXCR4 later during disease progression. Viruses that can use both co-receptors are call dual-tropic. Some people are born with a deletion in CCR5 and are substantially RESISTANT to HIV infection.

HIV life cycle starts with attachment of a HIV envelope protein, gp120, to CD4 receptor and co-receptor, followed by fusion of HIV with host cell. The virus then injects its content, HIV RNA and several enzymes, into the cell. One of these enzymes, known as “reverse transcriptase”, is used to convert HIV RNA into DNA, an important step that would allow the virus to integrate into host cell DNA. Once in the nucleus, HIV enzyme INTEGRASE inserts the viral DNA into the host DNA. At this point the virus may adopt either LATENT or ACTIVE infection.

In active infection, HIV uses the host machinery to produce multiple copies of its RNA and proteins, which are then assembled into new virus particles, ready to infect more CD4 cells.

In latent infection, the virus remains integrated in host DNA, and may lie dormant for years, forming a latent HIV reservoir, which can REactivate and infect again at a later time.

HIV is transmitted through infected body fluids, most commonly via sexual contacts, shared contaminated needles, and mother to child during childbirth or through breastfeeding. It is not transmitted through air or casual contacts.

Diagnosis is by detection of viral protein, RNA, proviral DNA , or antibody produced against HIV.

There are three stages of HIV infection:

The ACUTE stage generally develops within a couple of weeks after a person is infected with HIV. During this time, patients may experience flu-like symptoms. HIV multiplies RAPIDLY resulting in HIGH viral load in the blood and INcreased risks of transmission.

The CHRONIC stage, also called clinical latency, is usually Asymptomatic. HIV continues to multiply but at much SLOWER speeds. Patients may not have any symptoms, but they can still spread HIV to others. Without treatment, the disease usually progresses to AIDS within 2 to 10 years.

AIDS is the final stage of HIV infection. As the immune system is failing, the body can’t fight off common diseases, and opportunistic infections take hold. AIDS is diagnosed when CD4 cell count is LOWER than 200 per microliter, or if certain opportunistic infections are present.

There is currently no cure but treatment with anti-retroviral therapy can SLOW DOWN progression to AIDS and reduce transmission risks. Anti-retroviral drugs are classified based on their ability to interfere with certain stage of HIV life cycle. Accordingly, there are: entry and fusion inhibitors, reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors. These drugs, however, can NOT reach the LATENT virus, which hides out safely in healthy T-cells but may reactivate and infect again. This is the major reason why HIV infection is not curable with current available treatments.

 

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Acid-Base Balance Regulation, with Animation

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pH is an indicator of acidity. The body’s blood pH is strictly regulated within a narrow range between 7.35 and 7.45. This is because even a minor change in acidity may have devastating effects on protein stability and biochemical processes.

Normal cellular metabolism constantly produces and excretes carbon dioxide into the blood. Carbon dioxide combines with water to make carbonic acid which dissociates into hydrogen ions and bicarbonate.

CO2 + H2O =  H2CO3 =  H+ + HCO3−

This is an equilibrium, meaning all the components of the left and right sides co-exist at all times, and the concentration of any component is determined by that of others at any given moment. The rule of thumb is: an increase in concentration of ANY component on ONE side will shift the equation to the OTHER side, leading to INCREASED concentrations of all components on THAT side, and vice versa. This equilibrium is central to understand acid-base regulation. CONTINUED carbon dioxide production by all cells of the body drives the equilibrium to the right to generate more hydrogen ions. Because pH is basically a function of hydrogen ion concentration, more hydrogen means higher acidity and lower pH. Normal metabolism, therefore, constantly makes the blood more acidic. The body must react to keep the blood pH within the normal limits. This is achieved by 2 mechanisms:

  • Elimination of carbon dioxide through exhalation. The amount of carbon dioxide exhaled by the lungs is regulated in response to changes in acidity. A decrease in pH is sensed by central or arterial chemoreceptors and leads to deeper, faster breathing; more carbon dioxide is exhaled, less hydrogen is made, blood acidity decreases and blood pH returns to normal. Pulmonary regulation is fast, usually effective within minutes to hours.
  • Excretion of hydrogen ions and reabsorption of bicarbonate through the kidneys. The kidneys control blood pH by adjusting the amount of excreted acids and reabsorbed bicarbonate. Renal regulation is slower; it usually takes days to respond to pH disturbances.

Renal regulation: Although all of the plasma bicarbonate is filtered in the glomerulus during the first step of urine formation, virtually ALL of it is REabsorbed BACK into the blood. Most of this reabsorption happens in the proximal tubule. The amount of reabsorbed bicarbonate in the proximal tubule is regulated, via a number of mechanisms, in response to changes in blood pH. It increases during acid loads and decreases during alkali loads. While the proximal tubule basically RETURNS FILTERED bicarbonate back to the blood, the downstream collecting duct generates NEW bicarbonate by ACTIVELY SECRETING acids. As protons are depleted from the distal tubular cells, the equation shifts to the right, producing MORE bicarbonate which then exits into the blood. Hydrogen ions secreted into the lumen combine with urinary buffers, mainly filtered phosphate, and ammonia, to be excreted in urine. The ammonia buffering system is particularly important because unlike phosphate, which is filtered in FIXED amounts from the plasma and can be depleted during high acid loads, ammonia production is regulated in response to changes in acidity and its concentration may increase several folds when necessary. Blood pH is the main regulator of acid excretion, but potassium, chloride concentrations and several hormones also play important roles.

Pathologic changes may cause acid-base disturbances. Acidosis refers to a process that causes increased acidity, while alkalosis refers to one that causes increased alkalinity. It’s not uncommon for a patient to have several processes going on at once, some of them in opposite directions. The resulting plasma pH may be normal; too acidic, called acidemia; or too basic, called alkalemia.

Acidosis may result from INadequate function of the lungs which causes arterial carbon dioxide to accumulate. This is RESPIRATORY acidosis. On the other hand, METABOLIC acidosis may result from excessive production of metabolic acids, DEcreased ability of the kidneys to excrete acids, ingestion of acids, or loss of alkali. Metabolic acidosis is characterized by primary DEcrease in plasma bicarbonate.

Alkalosis can also be either respiratory or metabolic. Respiratory alkalosis is caused by INcreased ventilation resulting in excessive exhalation of carbon dioxide. Metabolic alkalosis can result from excess loss of acids through the kidneys or gastrointestinal tract, bicarbonate retention, or ingestion of alkali. Metabolic alkalosis is characterized by primary increase in plasma bicarbonate.

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