-
How should you address a patient?
Use last names unless otherwise instructed
-
When should you wash your hands?
Upon entering the patient's room, prior to shaking their hands
-
What are the 6 (7) components of the medical history?
- Chief Complaint (CC)
- (Other Active problems)
- Hx of Present Illness
- Past Medical Hx
- Family Hx
- Social Hx
- Review of Systems
-
How should the chief complaint be recorded?
In the patient's own words
-
When should other active problems be discussed?
Right after the CC and again after the HPI
-
Should you ever agenda set with the patient?
Yes, pick about 3 problems to talk about--prioritize and negotiate with the patient
-
What kind of questions should you ask during the history of present illness?
- Location: Where is it?
- Duration/Freq: When did it start?
- Severity: How bad is it?
- Quality: What is it like?
- Timing: When does it happen?
- Associated Symptoms: What else?
- Aggrevating/alleviating factors: What makes it better/what makes it worse?
-
Which part of the medical interview consists of the patient's story of what happened?
History of Present Illness
-
Where should serious illnesses and hospitalizations from the patient's childhood be recorded?
Past medical history
-
What does the family history include?
The patient's immediate family and anyone who lives with them--looking for inheritable disease and illnesses affecting the family
-
Your patient tells you they don't eat meat because of religious beliefs. Where should this information be recorded?
Social History
-
What is the goal of the review of systems?
To uncover additional information about other medical problems and the present illness
-
What does ETHNIC stand for?
- Explanation: What do you think might be causing this?
- Treatment: Others they have tried/what do you want from me?
- Healers: Who have you sought advice from (social network)?
- Negotiate: Resolve with a mutually agreed upon plan
- Intervention: Letting the patient use safe alternative treatments
- Collagboration: with the pt and their social network, especially if working with a mental disorder
-
Definition: Health Insurance
(in theory) a pool of dollars for a pool of people
-
Are people more likely to be uninsured for a short period of time or a long period of time?
Short
-
In 2007, how many people were uninsured in America?
45 million
-
Are the uninsured more likely to be employed or unemployed?
Employed
-
How much have premiums increased since 2000?
87%; premiums are increasing much faster than wages
-
Definition: Medicaid
insurance for children, women, and the very poor
-
Definition: Medicare
Insurance for the elderly (>65) and the permanently disabled
-
What does the term access to care include?
health insurance, geographical, cultural, and language barriers
-
Definition: Access to Quality care
the access to care that affects important health outcomes (mortality, QOL, etc.); this shifts with time and is likely to become more patient centered in the future
-
What are the 4 access-related programs currently available?
COBRA, HIPPA, SOBRA, EMTALA
-
What does COBRA do?
former employees can keep their insurance about 18 months after leaving or being let go
-
What does HIPPA do?
individual must be offerred at least 2 plans from each insurer
-
What does SOBRA do?
Medicaid for emergencies (eg. preggo women)
-
What does EMTALA do?
says that the ER must accept all patients
-
What does the term safety net include?
FQHC, hospitals, charity-funded clinics and government programs
-
Which is better, addressing the growing access to care problem on a small scale, or on a large scale?
- On a small scale it's rewarding (eg. pts and missions)
- On a large scale it's frustrating and complex
-
When learning about a new disease, should you focus more on the underlying mechanisms or the actual symptoms and clinical presentations?
Focus on the underlying mechanisms so that you can predict the symptoms
-
VINDICATES is a way of thinking about the etiology of a disease and what caused it. What does this acronym stand for?
- Vascular
- Infectious
- Neoplastic (cancer)
- Drugs or toxins
- Inflammatory/Idiopathic
- Congenital (gene abnormalities)
- Autoimmune disorder
- Trauma
- Endocrine/Metabolic
- Something else/supernatural/supertentorial
-
Definition: Pathogenesis
Physiological response of cells and tissues to trauma or disease
-
Definition: Idiopathic
the cause is unknown
-
Definition: Pathognomic
A definitive/absolute cause of the disease
-
What is the goal of pathology?
To track the progression of changes in a disease to further understand so that they might be prevented in the future
-
What is the central dogma of pathology?
Cellular dysfunction-->organ dysfunction-->clinical disease
-
Who is the father of modern pathology?
Rudolf Virchow
-
Definition: hypertrophy
increase in size of cell in response to energy
-
Why does a cell increase in size during hypertrophy?
due to the syntehsis of more structural components within the cell (proteins and myofilaments)
-
Is hypertrophy always bad?
No, can be pathological (hypertrophy of heart insystematic hypertension), but it can be good too (exercise--most common stilus is increased workload)
-
Histologically, what does a hypertrophied cell look like?
The nucleus becomes abnormally large, not centered and darkened; takes on a boxcar-like shape
-
Definition: hyperplasia
Increase in the absolute number of cells in response to stimulus or persistent injury
-
Is hyperplasia always bad?
No, example of the enlargment of breasts during pregnancy
-
Histologically, what does hyperplasia look like?
tremendous proliferation of the glands; looks very similar to cancer
-
Definition: Atrophy
Shrinkage in the size of a cell (opposite of hypertrophy); may result in loss of function due to pressure, disuse (cast on leg), denervation, ischemia, or chronic injury
-
Why does atrophy occur?
due to decreased protein synthesis (b/c of reduced metabolic activity) and increased proteind degredation in cells (via ubiquitin-proteasome pathway)
-
Definition: Metaplasia
A reversible, induced change in the type of epithelium; commonly seen in smokers
-
What is the most common form of cancer in the respiratory tract and why?
Squamous cell carcinoma- the cells have gone through metaplasia and been altered to form squamous cells (abnormal in the resp. tract)
-
Why does metaplasia occur?
Stem cells or undifferentiated mesenchymal cells present are reprogrammed
-
Definition: dysplasia
disordered growth following chronic injury resulting in cells sloughing off more easily
-
Where is dysplasia most commonyl seen?
in squamous epithelial cells
-
Which of the 5 types of cell adaptations covered is pre-cancerous?
- Only dysplasia is pre-cancerous
- (metaplasia, hypertophy, hyperplasia, and atrophy are not)
-
Dysplasia results in a loss of what?
loss of uniformity as well as architectural orientation, which is why it's precancerous
-
Histologically, what does dysplasia look like?
A carcinoma; the nuclei are not well-oriented,d arker, and there are more of them
-
Which of the 5 cell adaptations covered can be both physiologic and pathologic?
Atrophy, hyperplasia, and hypertrophy
-
What is the difference between necrosis and apoptosis?
Apoptosis is programmed cell death of individual cells; necrosis is wide-spread, massive cell death
-
What are the 2 key components of connective tissue?
cells and extracellular matrix
-
What makes up the ECM?
fibers (collagen and elastin) and Ground Subtance (GAGs and associated protein cores)
-
Where can connective tissue be found?
In supporting tissues, basement membranes, cartilage, and bone
-
Definition: basement membranes
Thin sheets of ECM underlying all endothelial cells and epithelium
-
What type of stain must be used to see basement membranes?
PAS (dyes the membrane purple)
-
What are the 5 major components of the basement membranes?
Type IV collagen, heparing sulfate proteoglycan, laminin, entactin, and fibronectin
-
Which 2 layers of the basement membrane make up the basal lamina?
The lamina lucida and the lamina densa
-
The lamina lucida and the lamina densa are synthesized by what?
Epithelial cells
-
What is the primary molecule comrpising the lamina lucida?
laminin
-
What is the structure of the laminin that makes up the lamina lucida (rara)?
- it is composed of 3 peptides: alpha (heparin binding site), gamma (proteoglycan binding site, entactin attachment site, integrin (cell surface receptor) binding sites), and beta (proteoglycan binding site, heparin sulfate bdingin site, integrin (CSR) binding site)
- This gives it the ability to bind to several different molecules and to itself to form the network that is the primary component of lamina lucida
-
To which chain of the laminin molecule would heparing sulfate bind?
the alpha and beta chains
-
To which chain of the laminin molecule would entactin bind?
the gamma chain
-
To which chain of the laminin moelcule would proteoglycans bind?
The gamma and beta chains
-
Cells can itneract with laminin because of the binding sites on which chains?
The gamma and beta chains
-
What is the primary molecule comprising the lamina densa?
type IV collagen
-
What are the 3 main domains of Type IV collagen?
The non-collagenous domain 7S (n-terminal), non-collagenous domain NC1 (c-terminal), and the triple helical collagenous domain in the center which is composed of 3 peptides
-
Why does collagen Type IV not form fibers and sheets like the other types?
Because the non-collagenous domains are not cleaved off, as they are in the other types. This prevents interactions between collagenous domains
-
What type of interactions occur between type IV collagen to give it the characteristic chicken wire appearance?
- Anti-parallel connections (7S domain connects to 4 collagens) and
- Head to head connections (NC1 domains connect 2 collagens
-
What are the 3 layers of the basement membrane?
Lamina lucida (rara), lamina densa, and lamina reticularis
-
Where is the lamina reticularis synthesized?
in the underlying connective tissue (mostly by fibroblasts)
-
A defect in a particular fibroblast would most directly affect which of the 3 basement membrane layers?
The lamina reticularis would be synthesized incorrectly, or not at all
-
Which of the three layers of the BM is the most difficult to identify on an EM?
the lamina reticularis
-
What is the primary molecule comprising the lamina reticularis?
reticular fibers which are formed by collagen III
-
Where is the glomerular basement membrane located?
in the kidneys
-
What is the primary function of the glomerular basement membrane?
To serve as a filtration barrier
-
Is the ECM underlying the Glomerular referred to as basal lamina or basement membrane?
Although it is composed of only the lamina densa and the lamina lucida, it is still referred to as basemement membrane
-
How is the membrane of the glomerular formed?
fusion of epithlial and endothelial cells
-
What is the effect of diabetes on the glomerular and why?
thickening of the membrane due to inability to process glucose-->excess glucose in the blood-->AAs in tissue interact with glucose to form highly reactive O2 intermediates-->react with proteins in the BM to form advanced glycated ends (AGE)-->bind to RAGE-->signals a change in gene activity to create more BM
-
What is the main problem with AGE?
They are degraded slower than normal proteins, resulting in a buildup and decreased formation of normal proteins
-
What does AGE stand for?
advanced glycated ends; formed from interactions between AAs in the tissue and excess glucose
-
How are the lamina lucida and the lamina densa connected?
Entactin binds the collagen via the C-termini domains an the laminin via the entactin binding sites on the beta chain
-
How are epithelial cells connected to the lamina lucida (rara)?
Integrins bind to the long arms of the beta and gamma chains on laminin and acts like velcro; these integrins then bind to attachment proteins that are connected to the actin cytoskeleton of the cell
-
Can epithelial cells move on top of the basement membrane?
The connection between the attachment proteins and the integrins allows teh cell some movement
-
What is the biochemistry behind junctional epidermolysis bullosa?
the skin sloughs off because of mutations in integrins or laminin chains; there is detachment of the epithelium from the BM; almost always perinatally lethal
-
What is bullosa pemphigoid?
An autoimmue disorder in which hemidesmosomes are targeted by the body (specifically by BP180 and BP230); inflammation occurs at dermal-epidermal junctions; benign; affects older people
-
What is pemphigus vulgaris?
an autoimmune disorder in which the desmosomes are targeted (specifically by desmoglein); skin sloughs off because things holding the cells side by side ripa apart; this is a disorder with the epidermal-epidermal junction
-
Would you be more likely to find oral ulcers in pemphigus vulgaris ro bullous pemphigoid?
pemphigus vulgaris
-
Which is more benign, pemphigus vulgaris ro bullous pemphigoid?
bullous pemphigoid
-
What is the difference between junctional epidermolysis and bullous pemphigoid?
- Junctional epidermolysis is a defect with the integrins or laminin chains, whereas bullous pemphigoid is a defect with the hemidesmosomes
- Subtle difference, similar clinical presentation
-
Where is fibronectin found in the basement membrane?
at the C-terminal (NC1) end of collage; this is a dimer formed by disulfide bonds on the collagen
-
What is the function of fibronectin in the BM?
contains a collagen binding domain and a cell binding domain (through the integrins)
-
Where are proteoglycans found in the BM?
they bind to the laminin network; specifically, the GAG side cahin (heparin sulfate) binds to alpha and beta chains of laminin
-
What is the function of the proteoglycans in the BM?
The GAGs have long and highly negative arms that function to sequester growth factors from the ECM
-
What is the primary function of adipose tissue?
To store fat in the form of triglycerides
-
Adipose tissue is an example of what major grouping of tissue?
Connective tissue
-
Which type of adipose tissue is found in higher prevalence in adults?
White adipose tissue (WAT)
-
What are the 3 functions of white adipose tissue?
- insulation (conducts heat only 1/3 as readily as other tissues)
- shock absorption (surrounds all major organs)
- energy storage (buffer for energy imbalances)
-
Why is white adipose tissue such an efficient mechanism of energy storage?
- Because the carbons of fatty acids form high energy bonds (contain about 9 cal/gram)
- Also because the triglycerides are stored with very little water
-
Where are you most likely to find brown adipose tissue (BAT)?
in fetuses and infants; diminshes after the first decade
-
Which type of adipose tissue is mroe metabolically active?
Brown adipose tissue
-
What are the primary functions of brown adipose tissue?
- important in regulating body temp (generates heat via thermogenesis)
- direct release of energy as heat (lipids do this instead of being used as a substrate)
-
How do the lipids of BAT release energy directly?
They utilize the uncoupling protein (UCP-1) of mitochondria to transfer protons from outside to inside without the production of ATP
-
Definition: Adipocytes
loose association of lipid-filled cells that comprises the major bulk of adipose tissue in all adult mammals
-
Which type of adipose tissue is more richly vascularized?
BAT although each adipocyte of WAT is in contact with at least one capillary
-
Can adipocyte tissue undergo hyperplasia?
No, the number of adipocytes increases through development and then remains constant through life; the size of each adipocyte can change
-
How does mature adipose tissue develop?
fibroblast-like precursor cells (mesenchymal cells) differentiate into preadipocytes with the expression of PPAR. These preadipocytes contain insulin growth factor-1 (IGF-1) and begin to synthesize lipoprotein lipse (LPL) and accumulate small fat droplets in the presence of insuling. These can then differentiate into WAT or BAT
-
Definition: Unilocular
single lipid droplet that pushes the cell nucleus and mitochondria against the plasma membrane; gives the cell a characteristic signet shape; predominantly in the WAT
-
Definition: Multilocular
Containing many smaller droplets of lipids; predominantly in the BAT
-
Definition: Lipogenesis
the depsoition of fat
-
How does lipogenesis work?
in adipose tissue, triglycerides are hydrolyzed to glycerol and free FAs by lipoprotein lipase; these free FAs are then taken up adipocytes in a concentration dependent manner by a transport protein; FAs combine with CoA to form a thioester and are re-esterized to form triglycerides
-
What is the primary source of glucose in lipogenesis?
Glucerol
-
What is the role of insulin in the storage of fatty acids?
- enhances storage and blocks mobilization and oxidation of FAs by stimulating lipoprotein lipoase formation
- Also required for transport of glucose
-
Definition: Lipolysis
decomposition and release of FAs from the adipose tissue
-
How does lipolysis work?
the multi-enzyme complex HSL (hormone sensitive lipase) hydrolyzes triglyceride into free FAs and glycerol
-
How does insulin affect lipolysis?
It inhibits through the inhibition of the hormone sensitive lipase (HSL) enzyme
-
Universally, what must your BMI be greater than to be considered overweight?
25
-
Unviersally, what must your BMI be greater than to be considered obese?
30
-
In 2005, approximately how many adults were overweight?
1.6 billion
-
In 2005, aprroximately how many adults were obese?
400 million
-
Collagen is a linear peptide. Why?
A glycine present at every third AA produces this structure
-
What 3 amino acids is collagen rich in?
Glycine, proline, hydroxyproline
-
How is collagen synthesized?
- all collagens are syntehsized with 2 non-collagenous domains--to produce the collagen fibrils, non-collagenous domains must be removed
- They are synthesized as individual chains called procollagen which contain registration peptides within the cell. These are then secreted to the ECM where procollagen peptidases cleave the non-helical registration peptides to produce insoluble tropocollagen; aggregation of tropocollagns form collagen fibrils and covalent cross-linking between these reinforces the fibrillar structure
-
What is the function of the registration peptides on procollagenous molecules?
help assemble and regulate the procollagen into the triple helical molecule
-
What causes the characteristic banding pattern seen on collagen under the EM?
the overlap of tropocollagen
-
When collagen fibrils aggregate to form collagen fibers, what is the approximate size of these fibers?
Similar to the size of a fibroblast
-
What is the most abundant type of collagen found in the body?
type I
-
What type of connective tissue do tendons consist of?
irregular connective tissue composed primarily of type I collagen
-
What is the functin of loose connective tissue?
to support tubes especially in the linin gof the GI, GU, and respiratory tract; contains a lot of Type I and ground substance
-
What is the structure of type II collagen?
networks of fibrils, not fibers
-
Where is type II collagen primarily found?
in the cartilage (but most abundantly in the hyaline and elastic)
-
What is the structural difference between type I collagen and type III collagen?
Type III forms reticular fibers which are very different from the collagen fibers found in type I
-
Where are you most likely to find collagen type III?
In the lamina reticularis
-
What is the primary function of collagen type III?
forms the supporting framework for many highly cellular organs such as the spleen and lvier
-
What is the structural organization of collagen type IV?
forms networks with no fibers or fibrils because the non-collagenous parts are not cleaved off
-
Where are you most likely to find collagen type IV?
In the basement membrane
-
What is the primary function of elastic fibers?
To provide elasticity and stretching to tissues
-
How does elastic fiber add elasticity?
the cross-linking between individual elastin molecules
-
Are elastic fibers present as fibers or sheets?
Both; most commonly fibers, but elastic sheets are found in the walls of large blood vessels
-
What are elastic fibers composed of?
tropoelastin, fibrillin I, fibrillin II, and microfibril associated protein (MAGP)
-
What is the primary function of fibrillin I in the elastic fibers?
to provide the force and structural support
-
What is the primary function of fibrillin II in the elastic fibers?
to regulate the assembly of said fiber
-
How are elastic fibers synthesiezed and assembled?
- Primarily synthesized by fibroblasts and smooth muscle cells
- Proelastin is formed in the RER from desmosine and isodesmosine; all components of the elastic fiber are then secreted to the ECM (proelastin secreted by the GA); coassembly of MAGp and tropoealstin to produce the immature elastic fibers; these bundle together to form mature elastic fibers
-
Where does synthesis and assmebly of the elastic fiebrs take place?
Synthesis of the components occurs in the cell (RER); components are secreted to the ECM where they are assembled
-
What is the deficiency associated with Marfan's syndrome?
Fibrillin I is deficient. Because of this, elastic fibers cannot be synthesized because there's no structural support
-
What is the reason for early death associated with Marfan's syndrome?
mitral valve prolapse (flap goes down into ventricle instead of coming up like in normal patients; basically, the seal is no good) and aortic dissection
-
What type of autosomal disorder is Marfan's syndrome?
Autosomal dominant (but the good gene still can't produce enough)
-
What is the typical clinical presentation of a patient with Marfan's?
Chest deformity, tall, long arms, arachnodetyly
-
What is the function of matrix metalloproteinases (MMPs)?
- degrade ECM proteins to help cells
- involved in embryonic development, tissue morphogenesis, wound repair, inflammaotry diseases and cancer
-
What are matrix metalloproteinases (MMPs) dependent on for their catalytic activity?
metal ions
-
Where do MMPs come from?
Epithelial cells or cells moving in and out of the ECM
-
MMPs are highly potent. How are they regulated?
- Proteolytic activation
- Proteolytic processing and inactivation
- Protein inhibition (by tissue inhibitors of MMPs called TIMPs)
- ECM localization (bound by stuff in ECM to keep it there)
- Cell surface localization (by receptors)
- Endocytosis and Intracellular degredation
-
How are MMPs related to cancer?
They are overexpressed in tumor cells to degrade the basement membrane and other structural proteins in teh underlying connective tissue
-
Resident and Transient cells are two types of what?
Connective tissue cells
-
Fibroblasts and adipocytes are two types of what?
Resident cells, which are a type of connective tissue cell
-
What is the function of fibroblasts?
To synthesize proteoglycans, collagen, and elastin
-
What are reticular cells?
Fibroblasts that syntehsize type III collagen in bone marrow and lymphoid organs
-
Definition: Chondroblast
fibroblast equivalent in cartlage--synthesize type II collagen
-
Definition: Osteoblasts
fibroblast equivalent in bone--synthesizes type I collagen
-
Definition: Odontoblasts
fibroblast equivalent in teeth (dentin)--synthesizes type I collagen
-
Where is type IV collagen synthesized?
in epithelial cells
-
Histologically, what do fibroblasts look like?
Usually the only thing you can see is the nucleus because the cytoplasm is squeezed long and tight to make connections with other cells
-
What are the 5 different types of transient cells discussed?
Macrophages, lymphocytes, plasma cells, mast cells, and eosinophils
-
What is the function of a macrophage?
to phagocytose anything foreign in the ECM; literally "big-eater"
-
What color does trypan dye turn macrophages and why?
dark blue because of the phagocytic vesicles inside
-
Where are lymphocytes most abundant?
in the GI tract
-
A lymphocyte can differentiate into what?
A plasma cell
-
Are lymphocytes fairly active?
No, almost quiescent
-
What is diapedesis and how does it relate to lymphocytes?
- It is the mechanism by which lymphocytes move through the connective tissue
- Cells interact with receptors (selectin) on endothelial cells weakly. Lymphocyte rolls along the surface until it interacts tightly with integrin and then passes in between the cells into the ECM
-
Why does a plasma cell have an abundant amount of ER and GA?
It actively synthesizes antibodies (proteins or immunoglobulins)
-
Histologically, where is the nucleus of a plasma cell located?
- Off to the edge
- Characteristic cartwheel configuration is created by the distribution of heterochromatin
-
Which type of transient cell is most directly involevd in an allergic reseponse?
Mast cells
-
How do mast cells function?
When an antigen cross-links 2 IgE antibodies on the surface of the mast cell, a movement of cystolic Ca2+ is initiated; this triggers the release of granules storing histmine, proteases, and proteoglycans; cytokines are also synthesized and released into the local environment
-
How do anti-histamines work?
The block the effect of the histamines released from the the mast cell, but they do not interfere with the release of it
-
Which type of transient cell is the first line of defense in a parasitic infection?
An eosinophil
-
Eosinophils contain granules that are involved ini fighting infections. What do these granules contain, and what are the functions of the contents?
- Eosinophil peroxidase (binds to microorganisms and helps macrophages kill them)
- Major basic protein (MBP) (binds and disrupts parasitic membranes)
- Eosinophil cationic protein (works with MBP to fragment parasites)
-
What occurs during normal wound healing?
a fibrin clot is laid out to stop the bleeding; cytokines recruit macrophages and fibroblasts via diapedesis; these cells are attracted to the ligand EN-RAGE; the recruited fibroblasts degrade excess MMPs and synthesize collagen to heal the wound
-
What occurs during diabetic wound healing?
AGE (the highly reactive proteins) are everywhere; these compete to make tissue like glue so that the fibroblasts can't get to the wound site; as a result, the connective tissue is further destroyed (by MMPs), the wound won't heal, and it just keeps getting worse and worse
-
What does fimbrin do?
Involved in the tight packing of actin fibers (parallel bundles)
-
What does alpha-actinin do?
Involved in the loose packing of actin fibers (contractile bundles)
-
What is the difference between a GTP cap and a Cap Z?
The GTP cap is used to stabilize microtubules while the Cap Z is used to stabilize actin filaments
-
When a cell moves, there are finger-like projections and webs in between them. What are the actuals names for each of these?
Filopodia and lamellopodia (respectively)
-
Filopodia and Lamellopodia are both types of what?
Actin filaments
-
Myosin I, myosin II, kinesin, and dynein are all types of what?
cytoplasmic motors
-
Dietary glucose is transported into the intestinal epithelial cells along with 2 Na+ molecules via wich transporter?
Na+, glucose transporter
-
What is the function of Na+, K+-ATPase?
Moves 3 Na+ molecules into the blood and 2 K+ molecules into the intestinal epithelial using the energy from hydrolyzing ATP
-
The potassium channel of cells allows for what?
The diffusion of K+ out of the cell
-
What is the function of the GLUT2 (Glucose transporter 2)?
to move glucose from the intestinal epithelial cells into the blood
-
What are some of the characteristics of GLUT 1-4?
- They use passive facilitated diffusion
- They have bi-directional transport because glucose is travelling tothe lowest concentration (passive)
- They require a sugar gradient
- Stereoselective for Glucose
-
Slight differences in the primary sequence of isoforms may allow for differences in what?
- Substrate specificity
- Substrate Km
- Tissue distribution
- Regulation
-
GLUT2 is a high capacity, low affinity transporter. What does this mean?
- High glucose concentrations within the cell won't saturate GLUT2 and it keeps operating
- Takes a long time to reach saturation of transporter
-
Glucose transporters 5-7 are stereoselective for what?
fructose
-
Upon insulin stimulation and/or muscle contraction, what happens to GLUT4?
It is translocated to plamsa membrane
-
The Na+, glucose transporter is what type of transporter?
a secondary active transporter, meaning that it uses Na+ transport (with gradient) to drive glucose transport (against gradient)
-
The binding of glucose and 2Na+ to the Na+, glucose transporter causes a conformational change in the transporter that moves the glucose and sodium to the interior of the cell. How many steps are involved in this process?
It's a 6 step process
-
Potassium and sodium have two of the highest gradients throughout the body. What are their respective gradients?
- Intracellular: plasma concentration
- Na+ 10:142
- K+ 140:4
-
What are the three membrane protein classes?
Pore, channel, and pump/transporter
-
Definition: Pore Membrane protein
both ends of passage are open always
-
Definition: Channel Membrane protein
- both ends of channel are open during passage (fast process)
- Channel opening can be regulated
- Ion channels have smaller pore sizes
-
Definition: Pump/Transporter membrane protein
only one end is open during passage at any time; analagous to an air lock; binding causes a conformational change
-
What is the difference between a pump and a transporter?
A pump has slow movement of ions against a gradient and requires ATP; a transporter also has slow movement of ions, but it is driven by a gradient and may or may not require ATP
-
Given that the name of a membrane protein is glucose transporter, what can you infere?
The transporter works with a gradient and experiences a conformational change upon binding
-
How many tissue specific isoforms of the glucose transporter (GLUT) are there?
12
-
What do we know about the structure of a glucose transporter?
It contains 12 transmembrane alpha-helices (don't know a lot)
-
Where would you be most likely to find the GLUT2 transporter?
In the liver, kidneys, islets, and small intestine
-
What is the Km (Kd for our purposes) of GLUT2?
17 mM, signifies that it does not ever get saturated as the normal circulating glucose concentration is 3.6 to 5.6 mM
-
What is the function of GLUT2?
To move glucose from the cell to the blood
-
What happens to the islets when glucose begins going from the blood to the cells?
It releases insulin in a 1:1 ratio
-
What is the Km of the GLUT1 transporter?
3-7 mM; this is involved in basal glucose uptake and transport across blood tissue barriers
-
What is the Km of GLUT3?
1.4 mM; found in the brain and nerve cells; needs to be low because brain has high demand for glucose, don't want to lose it in the blood
-
The GLUT4 is regulated by what?
Insulin and muscle contraction (which is why it's important to exercise); involved in translocation from vesicle to plasma membrane
-
Which glucose transporter is reduced in adipose tissue of diabetic animals?
GLUT4 and mRNA are reduced in adipose tissue of diabetic animals
-
How many different SGLT (sodium glucose transporters) are there?
At least 6 isoforms
-
Sodium glucose transporter (SGLT1) is present where?
in the kidney and intestines (in the epithelial cells); it functions to reabsorb glucose into the kidneys and intestine
-
Where can you find SGLT2?
in the kidney; it has a low affinity and high selectivity for glucose
-
Which direction do SGLTs run?
They prefer to move glucose into the cell, but they can be bi-directional
-
If no glucose is absorbed from the gut into the cell, what happens to water?
There is more water in the lumen of the gut because glucose isn't absorbed out of the gut and water prefers to stay where glucose is
-
What would you do for a patient with glucose/galactose malabsorption: Intestinal SGLT1?
They cannot absorb glucose into the cell from the gut properly. Give them fructose as a dietary alternative
-
Familial renal glucosuria: Kidney SGLT2 is a disorder where glucose is not taken up from the urine properly. Patients are constantly thirsty. Why?
Sodium is not taken up and builds up in high concentration in the urine. More water goes there (produces more urine, polyurea) and the patient is frequently thirsty. Large amounts of glucose are also excreted although there is no change in blood glucose levels
-
Oral rehydration therapy is often used to combat bacterial-caused diarrhea. The patient ingests concentrated glucose/Na+ solution (such as Pedialyte). How does this work?
It drives the SGLT into action and more sodium and glucose is moved into the cells. Consequently, more water is also moved into the cells
-
Transport systems are often coupled to what?
Ion gradients
-
Why is it difficult to measure the effect of knocking out one membrane protein?
Because the transporters work together and knocking out one will likely affect several others
-
What is a resting ion channel?
always open
-
What is a voltage-gated ion channel?
It responds to changes in membrane potentials
-
What is a ligan-gated ion channel?
It responds to extracellular neurotransitters
-
What is a signal-gated ion channel?
It responds to intracellular signal transduction events
-
How do ion transporters that are voltage-gated typically work?
They have arms in the center that move and cause a conformational change when there is a change in electricl potential
-
Which transporter is most directly responsible for building the Na+/K+ gradient?
Sodium potassium ATPase
-
Which membrane transporter is arguably the most important in the body (according to Swint-Kruse)?
Sodium, potassium ATPase; it uses 1/3 of cell's ATP to maintain this gradient
-
What inhibits the Na+, K+ ATPase?
cardiac glycosides like digoxin; leads to slower, stronger heart contractions
-
What are the three classes of ATPases?
- P-Type ATPase (ion transport including Na+ K+)
- F and V-type ATPase (sets up the H+ gradient in metabolism)
- ABC superfamily (transports ions, peptides, lipids, and drugs)
-
How many different ATP binding cassette (ABC) transporters are there in humans?
48
-
How many domains does an ABC transporter have?
4, 2, or 1 polypeptide subunits with 2 TM domains (not conserved, specificity for different ligands) and 2 nucleotide binding domains (bind ATP to cause conformational change, Walker A is a good example of this)
-
How many steps do all types of ABC transporters have to transport a molecule?
4 (steps 1 and 4 are the same....so maybe just 3)
-
What do most of the residues that makeup the p-glycoprotein have in common?
They are hydrophobic
-
What is the most probable explanation for the evolution of MDR transporters?
An MDR transporter is a multi-drug resistant protein. It probably evolved to protect the cell against toxins that freely diffuse in; these nonspecifically transport lipophilic, planar molecules out of the cell
-
What family of membrane proteins do MDR transporters belong to?
All families, not just ABC
-
What is the primary active transporter?
ABC superfamily
-
The p-glycoprotein is a member of which common grouping of transmembrane proteins?
MDR (multidrug resistant) or ABC (ATP binding cassette)
-
When Keq is greater than 1, what can we say about the solution at equilibrium?
It is mostly composed of product
-
When Keq is much less than 1, what can we say about the solution at equilibrium?
It is mostly reactant
-
What does free energy do?
Drives the reaction to proceed toward equilibrium
-
What is the equation for free energy?
- deltaG=deltaH-TdeltaS
- G=H-TS
-
What does the numeric value of G tell you about the reaction?
- It tells youthe direction the reaction will occur.
- Negative reactions proceed forward and are spontaneous.
- Positive are not spontaneous and likely will not happen
-
What is the difference between delta G and delta G not?
Delta G determines what actually happens whil delta G not refers to the standard state
-
What is the equation for delta G not when delta G is zero at equilibrium?
delta G not=-RTln(Keq)
-
When reactants A and B form C and D, what is the height of energy in the reaction called?
The transition state or the activation energy, enzymes work by lowering the energy of activation
-
For a given reaction, what do K1 and K2 tell you?
- K1 is the rate of the forward reaction, K2 is the rate of the reverse
- The velocity of the forward reaction=K1[A][B]
- The velocity of the reverse reaction=K2[C][D]
-
What are the factors that affect the observed rates (velocity)?
energy, encounter, and orientation
-
Definition: transient phase
The brief period when the reaction has just started
-
Definition: steady state
- a situation where all state variables are constant, but equilibrium has not yet been reached
- Our bodies are in steady state because we do not reach equilibrium because of constant replenishing of reactants and removal of products
-
What are the general properties of catalysts?
- Highly specific
- Unchanged in the reaction
- Only required in trace amounts (because not used up)
- No change in Keq
- Only change rate constants
- Allow for a controlled release of energy
- Charged side chains often predict pH sensitivity
-
How many enzyme substrate complexes are there in a given reaction?
Depends on the number of products and reactants. For 2 react, 2 prod, there are 4 enzyme substrate complexes (EA, EAB, ECD, EC) and each one represents a transition state (though none of these transition states are equal to the uncatalyzed transition state activation energy
-
How do reactions that are not spontaneous occur in our bodies?
They are coupled to favorable reactions
-
What does it mean to say that free energy is a state function?
- It is independent of the pathway it took to get to the final product
- Cares only about the distance of the energy between the first reactant and the final product
-
What is the best way to stain peroxisomes and why?
Use diaminobenzidene plus H2O2 because it forms an electron dense precipitant in the peroxisome
-
What the three major functions of the peroxisome?
- Ether lipid synthesis
- beta-oxidation of fatty acids
- alpha-oxidation of fatty acids
-
Patients with mutations in the peroxisome often have what clinical symptoms?
Demylination in the brain
-
A patient with excess peroxisome will likely have what "benefits"?
The ability to digest more fat
-
Where are peroxisome proteins formed?
in the ER
-
To be transported into the peroxisome, what must a protein do?
- A protein must have the starting sequence of serine-lysine-leucine; if this sequence is present, it will bind to complex 5 which transports it inside the peroxisome where the pH change causes the protein to release and 5 to come back out
- This starting code is called the peroxisome transport signal 1 (at the C-terminal)
-
What is a PPAR?
- Peroxisome proliferating activating receptor
- incerases the number of peroxisomes by increasing the number of times they divide
- PPAR binds to free fatty acids and DNA to signal proteins to make more peroxisomes
- Activation of a PPAR leads to burning more fatty acids and less glucose
-
In normal humans, what effects the activity of PPAR?
- Exercise increases
- Age decreases
- Short term fasting increases
- Long term fasting decreases
-
Patients with muations in PPAR are at a higher risk of developing what?
Type II diabetes
-
What is the defect in X-linked Adrenoleukodystrophy?
- the ABCD gene (ATP dependent protein that pumps fatty acids into peroxisome)
- This is a spectum disorder
- Patients can't pump fatty acids into peroxisomes, so they build up in the blood and cytosol and knockout the adrenal glands; also leads to problems with myelin formation and retardation
- TMNT: diet control
-
How are mitochondria organized in the cell?
- In long chains
- Have an inner membrane, outer membrane, intermembrane space, and matrix (which is broken up by stacks of inner membrane)
-
What are christae?
the extensively folded flat structures of the inner membrane within the mitochondria
-
Where does the proton gradient occur in the mitochondria?
in the space between the inner and outer membrane. Formed by the electron transport chain
-
How does the ATPase form ATP from the proton gradient?
The energy from the electrochemical gradient turns the rotor handle and phosphorylates ADP
-
Approximately how many proteins does the mitochondria contain?
~1000
-
Whom do you get your mitochondrial DNA from?
La momma mia
-
Which organelle is most likely to have evolved form bacteria?
the mitochondria
-
Which organelle best fits the description of garbage disposal?
Lysosome
-
What proton pump is responsible for the extreme acidity of the lysosome?
V-type ATPase
-
Which acid hydrolases are included in the lysosome?
- nucleases, proteases, glycosidases, lipases, phosphatases, sulfatases, phspholipases
- All function best at low pH (inactive when transpored through cytosol because pH is 7.0)
-
What is the function of an early endosome?
- receives incoming endocytic vesicles
- Sorts for recycling and degredation
-
What is the developmental process of a lysosome?
Early endosome (formed from pinched off membrane)-->late endosome-->lysosome
-
What is the function of the late endosome?
Contains intraluminal vesicles (ILV) which ubiquinate proteins that are not destined to be recycled and targets them for the lysosome
-
Where is cargo from the late endosome sent?
The lysosome to be degraded
-
A protein with a manose-6-phosphate signal will be shipped where?
To the lysosome
-
Bacterium that enter the cell are destroyed where?
In the lysosome
-
Definition: Lysosome
acidic vesicles in the cytoplasm that are full of hydrolytic enzymes; functions to hydrolyze macromolecules to monomers and recycle subunits
-
How many different lysosomal storage diseases are currently known?
- 40
- diseases typically result from lack of a particular enzyme in the lysosome; lysosome can't break down a particular component and it builds up over time; symptoms vary depending on which component it is; worst is I cell disease
-
What is the biochemistry behind I-cell disease?
Manose-6-phosphate shuttle does not work and garbage and debris cannot be shuttled into the lysosome. This is the worst of the lysosomal diseases because none of the enzymes within can work and debris builds up. Results in demylination and death within the first few months
-
What are the 6 classes of enzymes?
Oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases
-
What is the function of a oxidoreductase (eg. peroxidase, oxidase, reductase, hydrolase, oxygenase) and what are the common coenzymes?
- Reduces one compound to oxidize the other (redox reactions)
- NADH, NADPH, FADH2
-
What is the function of a transferase (eg. glycosyltransferase, glycogen synthase, transaminase, kinase)?
Transfers a component from one substrate to another
-
What is the function of a hydrolase (eg. protease, esterase, phosphatase, peptidase, urease)
- Splits water to carry out some type of chemistry
- H2O will ALWAYS be involved
-
What is the function of a lyase (decarboxylase, aldolase)?
Cleaves C-C, C-O, C-S, and C-N bonds by means other than oxidation or hydrolysis
-
What is the function of an isomerase (epimerase, mutase, racemase)?
Only rearrangement of the atoms, none added or lost
-
What is the function of a ligase (synthetase)?
- forms C-C, C-S, C-O, and C-N bonds using the energy from ATP hydrolysis; doesn't transfer the phosphate, just uses the energy
- ATP or GTP will ALWAYS be involved
-
What does a kinase do?
A kinase is a transferase, so it transfers one chemical group to another compound; specifically, it transfers phosphate groups from ATP
-
What role do metal ions serve as ligands?
structural and co-factor
-
Can vitamins be co-factors?
Yup
-
What is the function of ATP?
Carries phosphoryl group (very high energy bond) for protein phosphorylation
-
What is the function of NAD(P)H?
Shuttles electrons for redox of biological fuels, helps produce ATP
-
What is the function of FADH2?
Shuttles electrons for the redox of biological fuels (more powerful than NAD); always bound to a protein
-
How does Coenzyme A act as a co-factor?
Carries an acyl group
-
How does thiamine pyrophosphate act as a co-factor?
Carries an aldehyde for decarboxylation
-
How does biotin function as a co-factor?
Carries a CO2 for carboxylation
-
How does tetrahydrofolate function as a co-factor?
in amino acid metabolism, it carries one carbon unit to another carbon or a sulfur
-
How does S-adenosylmethionine function as a co-factor?
Carries a methyl to oxygen or nitrogen
-
How does pyridoxal phosphate function as a co-factor?
In amino acid metabolism, it forms a Sciff base with many amine compounds, forming a key intermediate in AA metabolism
-
Proteases are the most famous hydrolases. What do they do?
Cleave peptide bonds, found everywhere, classified by which amino acid side chains or metals are located in their active site
-
Chymotrypsin is an example of what?
A serine protease. There is a serine residue in it's active site. It works by forming an acyl enzyme (covalent intermediate) and then hydrolyzing the acyl enzyme
-
How do active sites work? (4 ways)
- Bind more tightly to the intermediate than to the reactants or products
- Strain the reactant to look more like the transition state
- Trap 2 reactants close to each other
- Orient the two reactants so the proper regions are juxtaposed
-
What does the Michaelis-Menton equation assume?
- that the enzyme is saturated [S]>>>>[E]
- that the reaction is in steady state
- and because it measures only the early (linear) times, that the reaction is irreversible
-
Michaelis-Menton rate of formation
k1[E][S] = (k2 + k3)[ES]
-
If the enzyme is saturated, according to the Michaelis-Menton equation, what is Vmax?
Vmax=k3[ES]
Where k3 is the rate from ES to E + P
-
If we are considering steady state reactions only, which rate can be negated from the Michaelis-Menton equation?
- k4
- the rate from E + P to ES
-
What is the equation for the Michaelis-Menton constant (Km)?
- Km= (k2 + k3)/k1
- additionally, Km=[S]([Et]-[ES])/[ES]
-
What is the common form of the Michaelis Menton equation?
Vnot= (Vmax*[S])/(Km +[S])
-
What is the significance of the Michaelis-menton equation?
At half Vmax, Km = [S]
-
According to Michaelis-Menton, what happens to the velocity if [S] is much greater than Km?
Velocity is maximal
-
According to Michaelis-Menton, what happens to the velocity when [S] is much less than Km?
The velocity decreases to a minimum
-
What do each of the points on the lineweaver burke plot signify?
- X-intercept= -1/Km
- Y-intercept= 1/Vmax
- Slope is Km/Vmax
- Where x-axis= 1/[S] and y-axis=1/(Vnot)
-
What are the 7 different ways enzymes can be regulated?
- Isozymes
- Enzyme concentration
- Covalent modification
- Cooperativity/Allosteric Regulation
- Linked enzymatic Reactions
- Substrate/co-factor availability
- Inhibition
-
How do isozymes regulate enzymatic activity?
Isozymes are slightly different forms of the same enzyme with the similar function. Different isozymes have different enzymatic activity in different tissues due to specificity of the active site
-
How do you regulate enzyme concentration?
changes in gene expression and enzyme degredation
-
What are 2 common examples of covalent modification to regulate enzymatic activity?
Phosphorylation and proteolysis
-
What is a good example of linked enzymatic reactions that regulate enzyme activity?
metabolic pathways
-
A ligand that readily dissociates from an enzyme, but decreases enzyme function when associated is an example of what?
reversible enzyme inhibition
-
A ligand that does not dissociate before the protein degrades or the patient dies is an example of what kind of enzyme inhibition?
Irreversible enzyme inhibition
-
What is a naturally occuring irreversible enzyme inhibitor?
Serpin and heavy metals (non-specific binding to side chains that mimics other co-factors; tmnt is chelation)
-
In terms of the Lineweaver burke plot, what is the difference between competitive and non-competitive inhibitors?
- Competitive inhibitors alter the x-intercept, or the 1/km
- Non-competitive inhibitors alters the slope, or Km/Vmax because X binds to both free enzyme and the ES
-
What do uncompetitive inhibitors bind to?
only ES complexes
-
What do non-competitive inhibitors bind to?
free enzymes and ES complexes
-
What does a non-competitive inhibitor of an enzyme alter in the Michaelis-Menton equation?
it decreases Vmax
-
If substrate concentration is increased in non-competitive inhibition, what will happen?
Nothing, the degree of inhibition is based solely on the concentration of the enzyme
-
If substrate concentration is increased in competitive inhibition, what will happen?
Km will increase because the inhibitor competes with the substrate to get to the active site; more enzyme will be in the ES complex because more substrate is present
-
Where do noncompetitive inhibitors bind to the enzyme?
In locations remote from the active site
-
In competitive inhibition, Km increases with increasing inhibitor concentration while Vmax remains the same. Why is this?
Competitive inhibitors resemble the structure of the substrate, so increasing the inhibitor concentration increases the time it takes for half the enzyme to be bound. Vmax remains unchanged because increasing the substrate concentration allows the substrate to overcome the inhibition and reach Vmax.
-
Patients sufferring from Zellweger Syndrome have decreased synthesis of plasmalogen in the hepatocytes, normal energy production, normal exocytosis, normal lysosomal enzyme synthesis. Which orgnalle is most likely to be affected in this disorder and how?
The peroxisome. Peroxisomes are the sole site of plasmalogen synthesis (which is a glycerol-based phospholipid).
-
Where is DNA located within the mitochondria?
the matrix
-
What is the deficiency in Tay-Sachs disease?
Tay-Sachs disease is a lysosomal storage disease. Hexosaminidase A is deficient, resulting in the buildup of GM2 ganglioside and leading to mental retardation, blindness, and mortality. The best treatment would be to stimulate hexosaminidase production
-
Which component of the basment membrane is most likely to functionin adherence of the epithelia to the basement membrane?
laminin of the lamina lucida
-
Which compound is most likely to be the insoluble scaffolding of the basement membrane?
Type IV collagen
-
Which moleclue is most directly responsible for the filtration characteristics through the basement membrane?
The highly charged GAGs
-
The basolateral membrane is definitively characterized by the presence of what?
The presence of Na+, K+-ATPase
-
Hormonal receptors are found on which surfaces of the epithelial cells?
apical and lateral
-
Exocytosis, endocytosis, and ion transport all occur across which surface(s) of the epithelial membrane?
the apical and the basolateral
-
A glycocalyx, consisting of oligosaccharides linked to glycoproteins, glycolipids, and proteoglycans, covers which surface(s) of the epithelial membrane?
The apical
-
The mechanochemical enzyme that can be found on the surfaces of cellular organelles where it mediates movement toward the plus end of microtubules is what?
Kinesin
-
Compared to skeletal muscle cells, what is absent in smooth-muscle cells?
Troponin
-
What are the 6 different types of junctions seen between cells?
- zonula occludens
- zonula adherens
- macula adherens (desmosomes)
- Gap junctions
- Hemidesmosomes
- Focal Adhesions
-
A tight juncion that seals the gap between epithelial cells is called what?
zonula occludens
-
A junction that connects actin filament bundles in one cell wtih that in the next (cytoplasmic connections) is called what?
zonula adherens
-
The junctions that connects intermediate filaments in one cell to those in the next are called what (cytoplasmic connection)?
Desmosomes (macula adherens)
-
A junction that allows the passage of small water-soluble molecules from cell to cell is called what?
A gap junction
-
The junction that anchors intermediate filaments in a cell to the extracellular matrix is called the what?
Hemidesmosome
-
The molecule between the desmosomes that actually connects the intermediate filaments is called the what?
Cadherins
-
What are the 3 families of cell adhesion molecules?
Cadherins, immunoglobulin family of CAMs, and integrins
-
What are the 2 primary functions of the cell adhesion molecules?
- Structurally link the cell to the outside
- Cell signalling complexes
-
Which cell adhesion molecule is calcium dependent?
Cadherins
-
What are the three types of binding cell adhesion molecules can utilize?
homophilic, heterophilic, and extracellular matrix linkages
-
Which junction is the tightest and prevents tracer ions from coming through?
The zonula occludens
-
What are the 2 junctional adhesion molecules used in the zonula occludens (tight junctions)?
occludin (utilizes ZO-1 as the main intracellular plaque protein) and claudin (utilizes ZO-2)
-
In cholera infection, the bacteria releases a specific toxin called ZOT that disrupts cell-cell adhesions. Specifically, which adhesion does this disrupt?
The Zonula Occludens toxin disrupts the Zonula Occludens
-
What is the major component of linkage in the zonula adherens?
Cadherin
-
What is the main intracellular plaque protein used by the cadherins of the zonula adherens?
Vinculin
-
Which junction best fits the description, spot weld?
Desmosomes
-
What is the major protein involved in the links created by the desmosomes?
Cadherins
-
What is the major intracellular plaque protein used by the cadherins in the desmosomes?
Desmoplakin
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