The patient should not have had alcohol, tobacco, caffeine, or performed vigorous exercise within 30 minutes of the exam.
Ideally the patient should be sitting with feet on the floor and their back supported. The examination room should be quiet and the patient comfortable.
History of hypertension, slow or rapid pulse, and current medications should always be obtained.
Grasp the patient's wrist with your free (non-watch bearing) hand (patient's right with your right or patient's left with your left). There is no reason for the patient's arm to be in an awkward position, just imagine you're shaking hands.
Compress the radial artery with your index and middle fingers.
Note whether the pulse is regular or irregular:
Regular - evenly spaced beats, may vary slightly with respiration
Regularly Irregular - regular pattern overall with "skipped" beats
Irregularly Irregular - chaotic, no real pattern, very difficult to measure rate accurately
Count the pulse for 15 seconds and multiply by 4.
Count for a full minute if the pulse is irregular. [3]
A normal adult heart rate is between 60 and 100 beats per minute (see below for children).
A pulse greater than 100 beats/minute is defined to be tachycardia. Pulse less than 60 beats/minute is defined to be bradycardia. Tachycardia and bradycardia are not necessarily abnormal. Athletes tend to be bradycardic at rest (superior conditioning). Tachycardia is a normal response to stress or exercise.
Position the patient's arm so the anticubital fold is level with the heart. Support the patient's arm with your arm or a bedside table.
Center the bladder of the cuff over the brachial artery approximately 2 cm above the anticubital fold. Proper cuff size is essential to obtain an accurate reading. Be sure the index line falls between the size marks when you apply the cuff. Position the patient's arm so it is slightly flexed at the elbow. [4]
Palpate the radial pulse and inflate the cuff until the pulse disappears. This is a rough estimate of the systolic pressure. [5]
Place the stetescope over the brachial artery. [6]
Inflate the cuff to 30 mmHg above the estimated systolic pressure.
Release the pressure slowly, no greater than 5 mmHg per second.
The level at which you consistantly hear beats is the systolic pressure. [7]
Continue to lower the pressure until the sounds muffle and disappear. This is the diastolic pressure. [8]
Record the blood pressure as systolic over diastolic ("120/70" for example).
Higher blood pressures are normal during exertion or other stress. Systolic blood pressures below 80 may be a sign of serious illness or shock.
Blood pressure should be taken in both arms on the first encounter. If there is more than 10 mmHg difference between the two arms, use the arm with the higher reading for subsequent measurements.
It is frequently helpful to retake the blood pressure near the end of the visit. Earlier pressures may be higher due to the "white coat" effect.
For more information refer to A Guide to Physical Examination and History Taking, Sixth Edition by Barbara Bates, published by Lippincott in 1995.
Unlike pulse, respirations are very much under voluntary control. If you tell the patient you are counting their breaths, they may change their breathing pattern. You cannot tell someone to "breath normally," normal breathing is involuntary.
With an irregular pulse, the beats counted in any 15 second period may not represent the overall rate. The longer you measure, the more these variations are averaged out.
Do not rely on pressures obtained using a cuff that is too small or too large. This is frequently a problem with obese or muscular adults where the regular cuff is too small. The pressure recorded will most often be 10, 20, even 50 mmHg too high! Finding a large cuff may be inconvenient, but you will also "cure" a lot of high blood pressure.
Maximum Cuff Pressure - When the baseline blood pressure is already known or hypertension is not suspected, it is acceptable in adults to inflate the cuff to 200 mmHg and go directly to auscultating the blood pressure. Be aware that there could be an auscultory gap (a silent interval between the true systolic and diastolic pressures).
Bell or Diaphragm? - Even though the Korotkoff sounds are low frequency and should be heard better with the bell, it is often difficult to apply the bell properly in the anticubital fold. For this reason, it is common practice to use the diaphragm when taking blood pressure.
Systolic Pressure - In situations where ausculation is not possible, you can determine systolic blood pressure by palpation alone. Deflate the cuff until you feel the radial or brachial pulse return. The pressure by auscultation would be approximately 10 mmHg higher. Record the pressure indicating it was taken by palpation (60/palp).
Diastolic Pressure - If there is more than 10 mmHg difference between the muffling and the disappearance of the sounds, record all three numbers (120/80/45).
Hyperextend the middle finger of one hand and place the distal interphalangeal joint firmly against the patient's chest.
With the end (not the pad) of the opposite middle finger, use a quick flick of the wrist to strike first finger.
Categorize what you hear as normal, dull, or hyperresonant.
Practice your technique until you can consistantly produce a "normal" percussion note on your (presumably normal) partner before you work with patients.
Breath sounds are produced by turbulent air flow. They are categorized by the size of the airways that transmit them to the chest wall (and your stethoscope). The general rule is, the larger the airway, the louder and higher pitched the sound. Vesicular breath sounds are low pitched and normally heard over most lung fields. Tracheal breath sounds are heard over the trachea. Bronchovesicular and bronchial sounds are heard in between. Inspiration is normally longer than expiration (I > E). [2]
Breath sounds are decreased when normal lung is displaced by air (emphysema or pneumothorax) or fluid (pleural effusion). Breath sounds shift from vesicular to bronchial when there is is fluid in the lung itself (pneumonia). Extra sounds that originate in the lungs and airways are referred to as "adventitious" and are always abnormal (but not always significant). (See Table)
Adventitious (Extra) Lung Sounds
Crackles
These are high pitched, discontinuous sounds similar to the sound produced by rubbing your hair between your fingers. (Also known as Rales)
Wheezes
These are generally high pitched and "musical" in quality. Stridor is an inspiratory wheeze associated with upper airway obstruction (croup).
Rhonchi
These often have a "snoring" or "gurgling" quality. Any extra sound that is not a crackle or a wheeze is probably a rhonchi.
Peak flow meters are inexpensive, hand-held devices used to monitor pulmonary function in patients with asthma. The peak flow roughly correlates with the FEV1. [7] ++
Ask the patient to take a deep breath.
Then ask them to exhale as fast as they can through the peak flow meter.
Repeat the measurement 3 times and report the average.
These tests are only used in special situations. This part of the physical exam has largely been replaced by the chest x-ray. All these tests become abnormal when the lungs become filled with fluid (referred to as consolidation).
It has been said that "a peak flow meter is to asthma as a thermometer is to fever." Peak flow measurements are used to gauge severity of asthma attacks and track the disease over time. Ideally new readings are compared to the patient's current "personal best." Readings less than 80% of "best" may indicate a need for additional therapy. Readings less than 50% may indicate an emergency situation.
Increased fremitus indicates fluid in the lung. Decreased fremitus indicates sound transmission obstructed by chronic obstructive pulmonary disease (COPD), fluid outside the lung (pleural effusion), air outside the lung (pneumothorax), etc. #Whispered pectoriloquy is right up there with borborygmi on Dr. Rathe's list of favorite medical terms.
Ask the patient to touch your index finger and their nose alternately several times. Move your finger about as the patient performs this task.
Hold your finger still so that the patient can touch it with one arm and finger outstretched. Ask the patient to move their arm and return to your finger with their eyes closed.
Ask the patient to place one heel on the opposite knee and run it down the shin to the big toe. Repeat with the patient's eyes closed.
For more information refer to A Guide to Physical Examination and History Taking, Sixth Edition by Barbara Bates, published by Lippincott in 1995.
Visual acuity is reported as a pair of numbers (20/20) where the first number is how far the patient is from the chart and the second number is the distance from which the "normal" eye can read a line of letters. For example, 20/40 means that at 20 feet the patient can only read letters a "normal" person can read from twice that distance.
You may, instead of wiggling a finger, raise one or two fingers (unialterally or bilaterally) and have the patient state how many fingers (total, both sides) they see. To test for neglect, on some trials wiggle your right and left fingers simultaneously. The patient should see movement in both hands.
Additional Testing - Tests marked with (++) may be skipped unless an abnormality is suspected.
PERRLA is a common abbreviation that stands for "Pupils Equal Round Reactive to Light and Accommodation." The use of this term is so routine that it is often used incorrectly. If you did not specifically check the accommodation reaction use the term PERRL. Pupils with a diminished response to light but a normal response to accommodation (Argyll-Robertson Pupils) are a sign of neurosyphilis.
Nystagmus is a rhythmic oscillation of the eyes. Horizontal nystagmus is described as being either "leftward" or "rightward" based on the direction of the fast component.
Testing Pain Sensation - Use a new object for each patient. Break a wooden cotton swab to create a sharp end. The cotton end can be used for a dull stimulus. Do not go from patient to patient with a safety pin. Do not use non-disposable instruments such as those found in certain reflex hammers. Do not use very sharp items such as hypodermic needles.
Central vs Peripheral - With a unilateral central nervous system lesion (stroke), function is preserved over the upper part of the face (forehead, eyebrows, eyelids). With a peripheral nerve lesion (Bell's Palsy), the entire face is involved.
The hearing screening procedure presented by Bates on page 181 is more complex than necessary. The technique presented in this syllabus is preferred.
Deviation of the tongue or jaw is toward the side of the lesion.
Although it is often tested, grip strength is not a particularly good test in this context. Grip strength may be omitted if finger abduction and thumb opposition have been tested.
The "anti-gravity" muscles are difficult to assess adequately with manual testing. Useful alternatives include: walk on toes (plantarflexion); rise from a chair without using the arms (hip extensors and knee extensors); step up on a step, once with each leg (hip extensors and knee extensors).
Subjective light touch is a quick survey for "strange" or asymmetrical sensations only, not a formal test of dermatomes.
Prepared with assistance from Edward Valenstein, MD
Place your fingers behind the patient's neck and compress the carotid artery on one side with your thumb at or below the level of the cricoid cartilage. Press firmly but not to the point of discomfort. [3]
Assess the following:
The amplitude of the pulse.
The contour of the pulse wave.
Variations in amplitude from beat to beat or with respiration.
If the patient is late middle aged or older, you should auscultate for bruits. A bruit is often, but not always, a sign of arterial narrowing and risk of a stroke. ++ [4]
Place the bell of the stethoscope over each carotid artery in turn. You may use the diaphragm if the patient's neck is highly contoured.
Ask the patient to stop breathing momentarily.
Listen for a blowing or rushing sound--a bruit. Do not be confused by heart sounds or murmurs transmitted from the chest.
The patient should not have eaten, smoked, taken caffeine, or engaged in vigorous exercise within the last 30 minutes. The room should be quiet and the patient comfortable.
Position the patient's arm so the anticubital fold is level with the heart.
Center the bladder of the cuff over the brachial artery approximately 2 cm above the anticubital fold. Proper cuff size is essential to obtain an accurate reading. Be sure the index line falls between the size marks when you apply the cuff. Position the patient's arm so it is slightly flexed at the elbow.
Palpate the radial pulse and inflate the cuff until the pulse disappears. This is a rough estimate of the systolic pressure. [6]
Place the stetescope over the brachial artery. [5]
Inflate the cuff 20 to 30 mmHg above the estimated systolic pressure.
Release the pressure slowly, no greater than 5 mmHg per second.
The level at which you consistantly hear beats is the systolic pressure. [7]
Continue to lower the pressure until the sounds muffle and disappear. This is the diastolic pressure. [8]
Record the blood pressure as systolic over diastolic (120/70).
Blood pressure should be taken in both arms on the first encounter. [9]
Position the patient supine with the head of the table elevated 30 degrees. ++
Use tangential, side lighting to observe for venous pulsations in the neck.
Look for a rapid, double (sometimes triple) wave with each heart beat. Use light pressure just above the sternal end of the clavicle to eliminate the pulsations and rule out a carotid origin.
Adjust the angle of table elevation to bring out the venous pulsation.
Identify the highest point of pulsation. Using a horizontal line from this point, measure vertically from the sternal angle. [10]
This measurement should be less than 4 cm in a normal healthy adult.
Position the patient supine with the head of the table slightly elevated.
Always examine from the patient's right side.
Inspect for precordial movement. Tangential lighting will make movements more visible.
Palpate for precordial activity in general. You may feel "extras" such as thrills or exaggerated ventricular impulses.
Palpate for the point of maximal impulse (PMI or apical pulse). It is normally located in the 4th or 5th intercostal space just medial to the midclavicular line and is less than the size of a quarter.
Note the location, size, and quality of the impulse.
For more information refer to A Guide to Physical Examination and History Taking, Sixth Edition by Barbara Bates, published by Lippincott in 1995.
With an irregular pulse, the beats counted in any 30 second period may not represent the overall rate. The longer you measure, the more these variations are averaged out.
Avoid compressing both sides a the same time. This could cut off the blood supply to the brain and cause syncope. Avoid compressing the carotid sinus higher up in the neck. This could lead to bradycardia and depressed blood pressure.
Additional Testing - Tests marked with (++) may be skipped unless an abnormality is suspected.
Bell or Diaphragm? - Even though Korotkoff sounds are low frequency and should be heard better with the bell, it is often difficult to apply the bell properly to the anticubital fold. For this reason, it is common practice to use the diaphragm when taking the blood pressure.
Maximum Cuff Pressure - When the baseline blood pressure is already known or hypertension is not suspected, it is acceptable in adults to inflate the cuff to 200 mmHg and go directly to auscultating the blood pressure. Be aware that there could be an auscultory gap (a silent interval between the true systolic and diastolic pressures).
Systolic Pressure - In situations where ausculation is not possible, you can determine systolic blood pressure by palpation alone. Deflate the cuff until you feel the radial or brachial pulse return. The pressure by auscultation would be approximately 10 mmHg higher. Record the pressure indicating it was taken by palpation (60/palp).
Diastolic Pressure - If there is more than 10 mmHg difference between the muffling and the disappearance of the sounds, record all three numbers (120/80/45).
Pressure Differences - If there is more than 10 mmHg difference between the two arms, use the arm with the higher reading for subsequent measurements.
Sternal Angle - The sternal angle is taken to be 5cm above the right atrium. A jugular pulse 10cm above the sternal angle equates to a central venous pressure of 15cm of water.
Left Sternal Border - The left 3rd, 4th, and 5th interspaces are considered the tricuspid area and are referred to as the Lower Left Sternal Border or LLSB.
Also, if you are a Biochemistry Major and took BCHM 317 last semester, please take the following 3 question survey before the start of the next class: Survey: OXIDATION/PHOSPHORYLATION REDUNDANCY
Learning Goals/Objectives for Chapter 9A: After class and this reading, students will be able to
list energy sources used to move ions/molecules from low to high concentrations across a concentration gradient;
explain how ATP is used to drive the thermodynamically uphill movement of Na and K ions by the Na?K ATPase
We have previously discussed how chemical potential energy in the form of reduced organic molecules can be transduced into the chemical potential energy of ATP. This ATP can be used to drive reductive biosynthesis and movement (from individual cells to whole organisms). ATP has two other significant uses in the cell.
Active Transport: Molecules must often move across membranes against a concentration gradient - from low to high chemical potential - in a process characterized by a positive DG. As protons could be "pumped" across the inner mitochondrial membrane against a concentration gradient, powered by the DG associated with electron transport (passing electrons from NADH to dioxygen), other species can cross membranes against a concentration gradient - a process called active transport - if coupled to ATP hydrolysis or the collapse of another gradient. This active transport is differentiated from facilitated diffusion we studied earlier, which occurred down a concentration gradient across the membrane. Many such species must be transported into the cell or into intracellular organelles against a concentration gradient!
Signal Transduction: All cells must know how to respond to their environment. They must be able to divide, grow, secrete, synthesize, degrade, differentiate, cease growth, and even die when the appropriate signal is given. This signal invariably is a molecule which binds to a receptor, typically on the cell surface. (Exceptions include light transduction in retinal cells when the signal is a photon, and lipophilic hormones which pass through the membrane.) Binding is followed by shape changes in transmembrane protein receptors which effectively transmits the signal into the cytoplasm. We will discuss three main types of signal transduction pathways:
nerve conduction, in which a presynaptic neuron releases a neurotransmitter causing a postsynaptic neuron to "fire";
signaling at the cell surface which leads to activation of kinases within the cytoplasm;
apotosis or programmed cell death
We will discuss signal transduction in the final three sections.
Energy Requirements for Active Transport.
For active transport to occur, a membrane receptor is required which recognizes the ligand to be transported. Of major interest to us, however, is the energy source used to drive the transport against a concentration gradient. The biological world has adapted to use almost any source of energy available.
Energy released by oxidation: We have already encountered the active transport of protons driven by oxidative processes. In electron transport in respiring mitochondria, NADH is oxidized as it passes electrons to a series of mobile electron carriers (ubiquione, cytochrome C, and eventually dioxygen) using Complex 1, 3 and 4 in the inner membrane of the mitochondria. Somehow the energy lost in this thermodynamically favored process was coupled to conformational changes in the complex which caused protons to be ejected from the matrix into the inner membrane space. One can imagine a series of conformation-sensitive pKa changes in various side chains in the complexes which lead in concert to the vectorially discharge of protons.
ATP hydrolysis: One would expect that this ubiquitous carrier of free energy would by used to drive active transport. In fact, this is one of the predominant roles of ATP in the biological world. 70% of all ATP turnover in the brain is used for the creation and maintenance of a Na and K ion gradient across nerve cell membranes using the membrane protein Na+/K+ ATPase.
Light: Photosynthetic bacteria have a membrane protein called bacteriorhodopsin which contains retinal, a conjugated polyene derived from beta-carotene. It is analogous to the visual pigment protein rhodopsin in retinal cells. Absorption of light by the retinal induces a conformation changes in the retinal and protein, which leads to vectorial discharge of protons ;
Collapse of an ion gradient: The favorable collapse of an ion gradient can be used to drive the transport of a different species against a concentration gradient. We have already observed that collapse of a proton gradient across the inner mitochondria membrane (through FoF1ATPase) can drive the thermodynamically unfavored synthesis of ATP. Collapse of a proton gradient provides a proton-motive force which can drive the active transport of sugars. Likewise a sodium-motive force can drive active transport of metal ions. Since the energy to make the initial ion gradients usually comes from ATP hydrolysis, ATP indirectly powers the transport of the other species against a gradient.
Often times, transport of one species is coupled to transport of another. If the species are charged, a net change in charge across the membrane may occur. Several terms are used to describe various types of transport:
symport - two species are cotransported in the same direction by the same transport protein
antiport - two species are cotransported in opposite directions by the same transport protein
electrogenic - a net electrical imbalance is generated across the membrane by symport or antiport of charged species
electroneutral - no net electrical imbalance is generated across the membrane by symport or antiport of charged species
Figure:
Examples of Transport: Metal Ions
Na/K - These ions are both transported by the Na/K ATPase. This protein keeps the K+in and Na+out high compared to their respective concentrations on the other side of the membrane. The protein exists in two essential conformations, E1 and E2, depending on the phosphorylation state of the protein. ATP and 3 Na+ bind to the cytoplasmic domain of the enzyme in the E1 conformation. In the presence of Na ions, the bound ATP is cleaved in a nucleophilic atack by an Asp side chain of the protein. (Hence, the protein is a Na+-activated ATPase. The phosphorylated enzyme changes conformation to the E2 form in which Na+ ions are now on the outside of the cell membrane, from which they dissociate. The phosphorylated protein in conformation E2 now binds 2 K+ ions on the outside, which activates hydrolysis of the Asp-PO3 mixed anhydride link. The dephosphorylated protein is more stable in the E1 conformation to which it changes as it bring K+ ions into the cell. This is an example of an electrogenic antiporter. Transport proteins that use this mechanism of transport are designated as P types, since ATP cleavage is required and PO43- is covalenty transferred to an Asp residue from the ATP. P-Type transporters are inhibited by vanadate (VO43-), a transition state analog of phosphate. Note: Transport mediated by P type membrane proteins can, in the lab, be used to drive ATP synthesis.
Detailed kinetic analysis of ATP and vanadate interactions show there are a low affinity and high affinity site for each on Na/K ATPase. The high affinity vandate site appears to be the same as the low affinity ATP site, which suggest that vandate binds tightly to the E2 form of the enzyme. The low affinity vandate site appears to be the same site (based on competition assays) as the ATP site, which is probably the E1 form. Hence vandate binds preferentially to the E2 form would inhibit the transition to the E1 form. Vanadate also inhibits phosphatases, enymes that cleaves phosphorylated Ser, Thr, and Tyr - phosphoesters in proteins. This supports the notion that vanadate binds preferentially to the E2 form, which has a phosphoanhydride link (Asp-O-phosphate) that is hydrolyzed, promoting the conversion of E2 back to E1. Vanadate is probably at transition state analog inhibitor in that it can readily adopt a trigonal bipyramidal structure, mimicking the transition state for cleavage of the tetrahedral anhydride bonds of ATP and Asp-O-PO4.
K - In addition to the above mechanism, K ions can be transported with protons in an electroneutral antiport mechanism by a K+/H+-ATPase found in stomach cells, which gives rise to a low pH in the lumen of the stomach.
Ca - Calcium levels are very low in cells. Transient increases are more likely to be detected in a signal transduction pathways than a transient decrease in high basal or constituitive cytoplasmic levels. Ca2+-ATPase, homologous to the Na/K-ATPase, removes Ca2+ from the cytoplasm to either the outside of the cells or into internal organelles. In addition a Na+-Ca2+ exchange protein (an antiporter) transports calcium ions out of the cell using a sodium-motive potential. Transport of calcium ions
There are also other types. F-type are similar to the F0F1ATPases and can transport protons against a concentration gradient powered by ATP breakdown. Notice that this is the opposite role for this enzyme that we discussed in mitochondrial oxidative phosphorylation. V-type (vacuolar) are found in the membranes of acidic organelles (like lysosomes) and acidic vesicles within neurons, where neurotransmitters are stored.
Examples of Transport: Sugars
Lactose - Lactose can be transported into E. Coli against a concentration gradient using galactoside permease, one of the proteins encoded by the lac operon. This protein uses a proton-motive force to pump lactose into the cell. The proton gradient is created by an electron transport complex in the membrane which is inhibited by cyanide, reminiscent of the cytochrome C oxidase complex in oxphos.
Driven by oxidation - The proton gradient formed during aerobic oxidation and photosynthesis in mitochondria and chloroplast, respectively, is paid for by free energy decreases associated with oxidation of organic molecules.
Driven by ATP cleavage - As mentioned above, protons are transported into the the lumen of the stomach by a K+-H+ ATPase.
Driven by light - Photosynthetic bacteria have a membrane protein called bacteriorhodopsin which contains retinal, a conjugated polyene derived from beta-carotene. The retinal is covalently attached to the protein through a Schiff base linkage to an epsilon amino group of Lys (much as pyridoxal phosphate is in PLP-dependent enzymes). Bacteriorhodopsin is analogous to the visual pigment protein rhodopsin in retinal cells. Absorption of light by the retinal induces a conformational changes in the all trans-retinal, which causes an associated conformational change in bacteriorhodopsin. The initial state (BR) changes through a series of intermediates (K, L, M, N, and O). Various side chains and the protonated N of the Schiff base of retinal change their relative positions with respect to each other, which leads to changes in protonation states of the side chains and ultimately vectorial discharge of protons through the membrane. As the M state forms, H+ is moved to the extracellular side of the membrane (as shown below). Later a H+ is taken up on the cytoplasmic side (at the Schiff base of the retinal link) leading to reformation of the BR state. Experiments have been done to trap the protein in some of these intermediate states. In one (Leuke et al, 1999), a mutant (Asp 96 to Asparagine or D96N) trappped the protein in a state, MN, that occurs after a H+ has been moved to the extracellular side but before a compensatory H+ has been taken up on the cytoplasmic face. The mutation hinders the reuptake of the proton.
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) - This is a member of a family of an ATP-Binding Cassette or ABC transporter proteins. The membrane protein has 12 transmembrane helices. In contrast to other ion transporters which transport a discrete number of ions (3 sodium and 2 potassium ions, for example), this changes conformation to form an open pore through which chloride ions flow. This protein is defective in Cystic Fibrosis.
Multidrug Resistance Transporter - MDR - This is another example of an ATP-Binding Cassette or ABC transporter. It acts in a somewhat promiscuous fashion in pumping nonpolar toxic molecules out of the cell. This would seem quite beneficial to the organism, unless the toxic molecule is a chemotherapeutic drug used to kill a tumor cell.
Phospholipid Flippase or Transbilayer amphipath transporter (TAT) - This is a member of the P-Type ATPase family which instead of moving ions across the membrane flips amino lipids (like PE) across leaflets in the bilayer. In an early chapter we noted that flip-flop diffusion in liposomes was slow compared to that in cells, suggesting that the flip-flop diffusion was catalyzed in the cell. Catalysis requires ATP cleavage and produces two conformations of the protein. During the conformational change of the protein, a phospholipid appears to bind to the protein and is flipped to the other side of the membrane.
The disposition of phosphatidylserine, a negatively charged phospholipid, between membrane leaflets is especially interesting and import. Almost all the PS is localized in the inner leaflet. Cells in which PS is found in the outer leaflet are target for program cell death (apoptosis). PS in the outer leaflet can also promote blood clotting as clotting factors are recruited to the surface. It appears that a P-type ATPase is required. Using gene silencing by RNA interference in C. Elegans, Darland-Ranson found that onespecific P-type ATPase, TAT-1 out of 6 found in the organisms had PS flippase activity, which would retain PS in the inner leaflet. Cells with PS in the outer leaflet were often targets of phagocytosis, suggesting the phagocytes have receptors that recognize PS. Cells with PS receptors may also bind and internalize virus, which have membrane leaflets acquired from infected cells as the virus buds off from the cells. Such cells might have PS in their outer leaflets since the infected cells may be in the process of dying through apoptosis, which would increase PS in the outer leaflet.
As mentioned earlier, one of the biggest problems in medical drug development is the productions of drugs that can diffuse across the cell membrane. This requires that the drug be sufficiently nonpolar while at the same time being sufficiently polar to have reasonable aqueous solubility, allowing blood transport. Another approach to getting drugs across the membrane is to modify them to bind to transporters whose normal function is to move solutes against a concentration gradient across a lipid bilyaer. The extent of modification of the drug depends on how close the structure of the drug is in comparison to the normal ligand for the transporter. This approach has been used by the biotech company XenoPort, to develop drugs that can be more readily absorbed by the small intestine, which has many active transporters designed to move nutrients into cells.
Maximum Cuff Pressure - When the baseline blood pressure is already known or hypertension is not suspected, it is acceptable in adults to inflate the cuff to 200 mmHg and go directly to auscultating the blood pressure. Be aware that there could be an auscultory gap (a silent interval between the true systolic and diastolic pressures).
Test the Three Divisions for Pain Sensation 
Pre-Class Questions: 
