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Triplet repeat mutations
- causative mutation occurs in a long repeating sequence of three nucleotides
- amplification of a specific sets of three nucleotides within the gene disrupts its function
Types of triplet repeat mutations
- Fragile X syndrome (loss of function)
- Huntington disease (gain of function)
- myotonic dystrophy
Fragile X syndrome
- type of triplet repeat mutation
- mutation in the FMR1 gene (loss of function of this gene)
- second most common genetic cause of mental retardation after Down syndrome
- long face, large mandible, large everted ears, large testicles (macroorchism)
- an example of a trinucleotide expansion condition, and a very common form of inherited moderate intellectual disability. The FMR1 (fragile X mental retardation 1) gene may be involved in transporting mRNA from nucleus to cytoplasm. The expansion repeat triggers hypermethylation, and loss of FMR1 gene expression in the brain leads to abnormal synapse connections.
- Fragile X due to the affect on X chromosome – shutting down translation getting hyper methylation - Methylated DNA is less transcriptionally active
- Most commonly inherited form of intellectual disability
- disease occurring with more severity and at an earlier age of onset and with more severity with each passing generation, may be seen in an increase in the size of the trinucleotide expansion
- refers to the phenomenon whereby clinical features of fragile X syndrome worsen with each successive generation, as if the mutation becomes increasingly deleterious as it is transmitted from a man to his grandsons and great-grandsons. Females less affected because of the Barr body.
transcriptional silencing of the maternal allele
transcriptional silencing of the paternal allele
- silencing of a gene
- certain genes are differentially "inactivated" during paternal and maternal gametogenesis
- trait that is expressed differently when allele is inherited from mother vs. father.
- transcriptional silencing of the paternal or maternal copies of certain genes during gametogenesis. For such genes only one functional copy exists in the individual. Loss of the functional allele (not imprinted) by deletions gives rise to diseases.
- type of genomic imprinting
- mental retardation, short stature, hypotonia, obesity, small hands and feet, hypogonadism
- deletion affects paternally derived chromosome 15
- type of genomic imprinting
- mental retardation, ataxic gait, seizures, inappropriate laughter (happy puppet syndrome)
- deletion affects maternally derived chromosome 15
study of inheritance
Single gene disorders
- inherited in Mendelian fashion
- eg: cystic fibrosis, PKU, sickle cell, Huntington's disease
- including small rearrangements, small deletions, or altered chromosome number (aneuploidy)
- eg: Turner's syndrome, Down syndrome, Klinefelter syndrome
Having a chromosome number that is not a multiple of the haploid number for the species.
- with environmental influences on genetic inheritance
- disease is expressed when a threshold is reached
- eg: hypothyroidism, Alzheimer's, breast/ovarian cancer, colon cancer, schizophrenia
base and sugar
base, sugar, phosphate
nucleotides are linked in a
5’ -> 3’ direction
nucleotide bases are
pyrimidines (cytosine, thymine [and uracil in RNA]) and purines (adenine, guanine)
created by the C bonding to G and A to T via hydrogen bonding
DNA is condensed via winding around proteins (histones) into chromatin that is condensed during cell division into chromosomes
- petite for the short arm of the chromosome
- depends on location of centromere
- for the long arm of the chromosome because q comes after p
- depends on location of centromere
full set of chromosomes = 23x2=46
half set of chromosome 23 (one of each)
repeating nucleotide sequences located at the end of chromosomes
- used to dye the chromosomes in a karyotype
- highlights G-banding as the Giesma dye preferentially attaches to A-T rich areas
basic unit of heredity, consisting of exons and introns
TATA box is part of the promotor and initiates transcription
any nucleotide sequence encoded by a gene that remains present within the final mature RNA product of that gene after introns have been removed by RNA splicing
any nucleotide sequence within a gene that is removed by RNA splicing while the final mature RNA product of a gene is being generated
sequence of a protein is determined by the triplets of codons
sequence of three adjacent nucleotides constituting the genetic code that determines the insertion of a specific amino acid in a polypeptide chain during protein synthesis or the signal to stop protein synthesis.
- 64 combinations
- (a codon is a set of 3 bases with 4 options for each = 4 x 4 x 4)
- 20 total amino acids allows for "wobble" in the third piece of the codon to code for the same amino acid
- is the amino acid chemically similar following a mutation
- eg: valine being replaced with glutamic acid WRT sickle cell anemia, if it was replaced with another non-polar amino acid the effect might not be as drastic.
- heritable changes but no change with DNA sequence
- aka Methylation: adding a methyl group to the cytosine or guanine nucleotide
e.g., with differential promoter or enhancer involvement, as with steroid hormone-receptor complexes
e.g., affecting mRNA or ribosomal activities; the role of micro RNAs (miRNAs) has become increasingly appreciated (2006 Nobel Prize).
e.g., protein folding in the rough endoplasmic reticulum or glycosylation in the Golgi apparatus, as discussed with Dr. Rosen with respect to the CFTR in cystic fibrosis.
variants of the same gene that exist at the same spot or locus of a chromosome. The coexistence of multiple alleles is genetic polymorphism.
coexistence of multiple alleles
(copy number variants) with DNA segments of >1000 bp length
- (single nucleotide polymorphisms)
- typically bi-allelic, very common
- genetic variation in a DNA sequence that occurs when a single nucleotide in a genome is altered; SNPs are usually considered to be point mutations that have been evolutionarily successful enough to recur in a significant proportion of the population of a species
Silent (synonymous) mutation
- change in intron - gets thrown out anyway
- "wobble" in the third codon position (amino acid does not change)
- type of SNP
- amino acid has changed
- eg sickle cell anemia
- type of SNP
- creation of abnormal stop codon
- eg: CF, having 30 chain vs a 5000 chain
- alteration of the reading frame of the codons
- frame has shifted due to an addition or deletion of a nucleotide, changes everything after it (downstream)
Trinucleotide expansions (repeats)
- amplification of C-G containing codons that can amplify in length from generation to generation (adding extra glycines, 1 or 2 maybe no impact, but 100+ could be bad)
- eg: Fragile-X
mobile DNA sequences that can move in the genome. Most human transposons are inactive as transposons, but remain part of gene regulation. For variation
densely packed with DNA that is inactivated, e.g., by C-G methylation.
X chromosome inactivation
forming a Barr body is a well-known example of heterochromatin formation. Methylated DNA is less transcriptionally active
- (from heterozygous parents, A allele dominant):
- 1:2:1 for homozygous dominant, heterozygous, homozygous recessive
- what we see
- (from heterozygous parents, A allele dominant):
- 3:1 dominant, recessive
person of interest in a pedigree/genogram
get more recessive alleles from these - relating to or denoting people descended from the same ancestor. "consanguineous marriages"
in small populations, culturally or geographically isolated, in the autosomal recessive with pseudodominance
only comes from the mother because it’s part of the egg at conception
The frequency, under given environmental conditions, with which a specific phenotype is expressed by those individuals with a specific genotype.
the strength of the effect of a gene on the phenotype
- person should be a carrier but they’re not
- Referring to the presence of a gene that is not phenotypically expressed in all members of a family with the gene
possessing cells of two or more different genetic make ups, e.g., a mutation following early mitotic divisions, or patterns of X-inactivation. The level of mosaicism may affect the phenotype.
Germ line mosaicism
risk factor for sporadic traits.
inactive heterochromatin (X chromosome in women)
- The process of cell division in sexually reproducing organisms that reduces the number of chromosomes in reproductive cells from diploid to haploid, leading to the production of gametes in animals and spores in plants.
- Useful for variation due to crossing over and the 2 stages of cell division
- All the chromosomes
- lymphocytes are interrupted during mitosis to view each stage
the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells
autosomal dominant inheritance
- only one copy of allele required for disease. Individuals with a single copy of an autosomal dominant trait have a 50% chance of transferring the trait allele to offspring.
- Every generation, no gender predilection
- person with expression of the phenotype
trait expressed where no prior family history exists, e.g., spontaneous mutation, which occurs for many of the autosomal dominant conditions.
autosomal recessive inheritance
- two copies of alleles required for disease, with one allele supplied from each parent.
- One copy of allele makes an individual heterozygous and hence an asymptomatic carrier.
- Two carrier parents have a 50% chance of carrier offspring and 25% chance of offspring with disease.
- Skips generations with carriers
- If incidence in general population is 1/X, what is the chance of someone being a carrier of the recessive allele?
- eg: CF, sickle cell anemia, Tay-Sachs disease, PKU
- Chance is sqrt(X)/2
- p2 + 2pq + q2 = 1 with respect to alleles p and q
- where p + q =1 as well
Sickle cell anemia
- an example of a missense mutation that leads to a hemoglobin that polymerizes abnormally under low oxygen tensions.
- Autosomal recessive
- Single gene disorder
- Alterations in phenylalanine metabolism can lead to PKU (phenylketonuria) and severe intellectual disability. It is a condition tested for at birth, as a special diet can prevent the condition. Scandinavian populations may carry this allele at higher rates than others.
- Tyrosine is basis for melanin (very fair skinned – Scandanavian – musty odor from build up of metabolites). Not getting the phenylalanine hydroxylase to convert to tryosine.
- Too much Phenylalanine can lead to neural damage.
- When tested positive – life long diet of low phenylalanine.
X-linked recessive disorder
all males inheriting the allele will get the disease; women will need two recessive alleles in order to inherit the illness. There are also (rare) X-linked dominant disorders that will not be discussed.
factor VIII deficiency
- factor IX deficiency
- Queen Victoria
- (maternal inheritance)
- Given their cytoplasmic location, mitochondria are inherited from the mother, so a pattern of all offspring affected from an affected mother would be the pattern of expression. Note that some individuals in a pedigree are deliberately labeled as “gray” to indicate that they are not fully affected.
- (egg contains mitochondria, sperm does not)
- daughters then transmit this DNA further, sons do not
- affect organs most dependent on oxidative phosphorylation (skeletal muscle, heart, brain)
abnormal chromosome number, which may include trisomy or monosomy.
loss of chromosome segment
addition of chromosome segment
rearrangement within one chromosome
the transfer of one part of a chromosome to another part of the same or a different chromosome, resulting in rearrangement of the genes
translocation of one part of a chromosome between two acrocentric chromosomes with a fusion near the centromere and subsequent loss of the short arms.
- Trisomy 21
- mental retardation, congenital heart defects, epicanthic folds and flat facial profile
- a possible chromosomal error that occurs, particularly as seen in anaphase I.
- leads to a gamete with 2 of same chromosome or gamete with none of one chromosome. Can get Downs with double of chromosome 21 from one parent. Can get Turner's syndrome (XO - monosome) with a blank sex chromosome from one parent.
22q11.2 deletion syndrome
- (DiGeorge syndrome)
- microdeletion affecting pharyngeal arches, often with cardiac (and neurologic) involvement in addition to the third and fourth pharyngeal issues of potential effects on thymus and parathyroid glands, e.g., 46,XX,del(22)(q11.2). A gene in this region (TBX1) is involved in neural crest migration.
Fluorescence in situ hybridization
- (chronic myelogenous leukemia)
- somatic translocation of Philadelphia chromosome rearrangements on chromosomes 9 and 22 and subsequent enhanced oncogene expression, e.g., 46, XY,t(9;22)(q34;q11). The ABL proto-oncogene encodes a tyrosine kinase, which can trigger a number of intracellular activities. Imatinib (Gleevac®) selectively inhibits that tyrosine kinase
- myelogenous = originating in or produced by the bone marrow
- (or multifactorial inheritance)
- disease results from a combination of interacting genetic and nongenetic factors.
- (gene chips)
- structured to identify SNPs from computer examination of the results.
- the sequencing of the human genome and the availability of microarrays to identify SNPs has allowed the established of genome-wide association studies (GWAS) to identify SNPs (from a particular population) that associate with identifiable/observable traits. These are often done as case-control studies looking for statistical association of SNPs with disease, with the hope that a particular SNP (or other marker) may be located close to a disease gene.
- Risks of type I error from multiple comparisons
Several issues that arise from GWAS:
- these studies are hypothesis-free, in that the whole genome is searched and not in one particular region or possible biological pathway
- case-control matchups are used, e.g., one will need to stratify appropriately for ethnic background
- type I statistical errors are certainly possible, as multiple comparisons are made (and so need to address with appropriate statistical modeling)
- hypothesis-free (i.e., not targeting specific areas) ways of screening the whole genome for SNPs associated with clinical presentations
- (hereditary nonpolyposis colon cancer; Lynch syndrome)
- Autosomal dominant
- DNA mismatch repair
- Possible intervention: early endoscopy, possible long term aspirin prophylaxsis
Alpha-1 antitrypsin deficiency
- Autosomal recessive
- Protease inhibitor
- Possible intervention: avoidance of smoking or occupational lung exposures
- Autosomal dominant
- fibrillin, connective tissue protein
- Possible interventions:
- Echocardiographic screening
- Prophylactic beta adrenergic blockade
- failure of the cardiac sphincter of the esophagus to relax, resulting in difficulty swallowing
- high sphincter tone due to myenteric inhibition
- do a Barium swallow study
- part of gut lining
- lined with epithelial cells (simple columnar), a lamina propria of loose connective tissue, and muscularis mucosae.
- The muscularis mucosae is innervated by submucosal (Meissner's) plexus.
- part of gut lining
- dense connective tissue, with supporting blood and lymph vessels. Location of Meissner’s plexus. For secretions
- part of gut lining
- made up of 2 layers, circular and longitudinal. Innervated by the myenteric (Auerbach's) nerve plexus. For motility
- (aka visceral peritoneum)
- part of gut lining
The gut is regulated by part of the autonomic nervous system and is made up of two components: the extrinsic nervous system and intrinsic (enteric) nervous system.
The extrinsic nervous system of the gut
is under sympathetic (inhibitory with respect to the GI tract by sympathetic ganglia) or parasympathetic (stimulatory by pelvic splanchnic nerve) control.
The vagus nerve supplies what part of the gut?
the upper GI tract and ascending colon and will carry afferent (75%) sensory and efferent (25%) motor fibers.
The pelvic splanchnic nerves supply what part of the gut?
the anal canal and the transverse, descending, and sigmoid colon.
- contain both afferent and efferent components and stimulate smooth muscle relaxation and release of digestive secretions via the vagus nerve.
- Presence of food stretching the esophagus can simulate secretions/peristalsis
The intrinsic (enteric) nervous system
- controls contractile, secretory, and endocrine functions of the GI tract independent of autonomic control. It is made up of two plexuses; the myenteric plexus (aka Auerbach’s plexus) and the submucosal plexus (aka Meissner’s plexus).
- The enteric nervous system functions autonomously (can work on its own), but also receives modulation from the PNS and SNS.
peptides released from endocrine cells of GI tract into systemic circulation. (e.g. gastrin, cholecystokinin, secretin, glucose dependent insulinotropic peptide).
peptides secreted by endocrine cells of GI tract and act locally. (e.g. somatostatin.)
peptides synthesized by neurons of the GI tract and act locally. (e.g. ACh, NE, VIP, substance P). (vasoactive intestinal polypeptide)
- secreted by G cells of stomach and stimulate parietal cells to make HCl and intrinsic factor
- made by the pyloric (antral) glands of the stomach
- secreted by I cells of small intestine and stimulate gallbladder contraction and pancreatic enzyme secretion (of amylase, lypase, trypsin) as well as slows gastric emptying
- Release of CCK activates the zymogens
secreted by S cells of small intestine and stimulate ductal cells of pancreatic to secrete water and bicarbonate (HCO3)
Glucose dependent insulinotropic peptide (GIP)
secreted by small intestine; inhibits acid secretion, and enhances insulin response to oral glucose
for B12 absorption
- smooth muscle is organized in large sheets with gap junctions so it contracts as one unit
- phasic or tonic contractions
maintained at a constant tone (i.e. sphincter muscles)
periodic and are followed by a relaxation period (i.e. peristalsis)
pacemaker for GI smooth muscle
- interstitial cells of Cajal
- slow wave contraction
- malfunction of the lower esophageal sphincter or increase in intra-abdominal pressure
- can lead to erosion of esophagus by stomach acids
fundus, body, antrum.
that stores food, initiates protein digestion, kills bacteria with gastric acid, and dispenses food into small intestine as chyme.
- in the medulla
- responds to various sensory receptors
Reverse peristalsis in the small intestine →deep breath →downward contraction of diaphragm → forceful contraction of abdominal muscles →lower esophageal sphincter relaxes → gastric contents are expelled through esophagus.
Obstruction at the pylorus
would cause acid vomitus
obstruction below the duodenum
would cause neutral or basic vomitus.
Methods of stimulating vomit reflex
- Direct irritation/distension of stomach
- Central stimulation of vomiting chemoreceptors in the 4th ventricle
- Motion stimulation of vestibular receptors
- Central stimulation of vomiting center by psychological factors
pill place under eye lid, induces vomiting, used in pets
functions of the small intestine
continued digestion and absorption, and propulsion to large intestine.
villi of the small intestine
increase surface area eightfold to enhance absorption, especially within the proximal intestine.
duodenum is usually protected from acidic chyme by
- buffering from:
- alkaline pancreatic juice containing bicarbonate
- alkaline mucus secretion from Brunner's glands in the duodenal submucosa
Crypt of Lieberkuhn
- gland within epithelial lining of the intestine. Contains immune cells and goblet cells in addition to enterocytes which absorb water and nutrients. High turnover of epithelial cells due to the exposure of acidic contents.
- Chemo affects these – N/V, risk of mutation in fast growing cells - cancer
specialized columnar epithelial cells which secrete mucus
segmentation vs. peristaltic contractions
- coordinated by enteric nervous system
- Segmentation helps with mechanical digestion, separates and then recombines it
- Peristaltic moves the chyme along, triggered by presence of chyme in the lumen
peristaltic contraction of the small intestine
the presence of chyme within the lumen will trigger ascending/excitatory pathway to stimulate depolarization of slow waves and contraction of the muscularis layer behind the bolus, while the descending/inhibitory pathway will cause hyperpolarization within the muscle and relaxation in front of the bolus.
Tinea coli and peristalsis
act like purse strings when they contract, get the haustra out-pouches and reabsorption of water in process
- amylase (ptyalin) to help begin carbohydrate digestion
- lingual lipase to begin lipid digestion
- electrolytes such as calcium and fluoride (to help maintain enamel) or bicarbonate (to help buffer regurgitated stomach contents)
- antimicrobial agents such as lysozyme
- Salivary glands
- made up of an acinus and a duct.
- secretion by both parasympathetic (IP3 second messenger) and sympathetic but predominately parasympathetic
- anticholinergic effect on parasympathetic pathway of salivary gland stimulation
- inhibits salivation by blocking the muscarinic receptor
Acinar cells of salivary glands
secrete initial isotonic saliva and utilize myoepithelial cells to eject saliva into mouth
Ductal cells of salivary glands
- modify saliva into hypotonic solution
- The ductal cells use the Na+/K+ ATPase on the basal (non lumen) side to set up concentration gradients that then allow the net absorption of NaCl.
oxyntic (body) glands
- (glands of stomach)
- mucous neck cells for mucus
- parietal cells for HCl, also for intrinsic factor (for B12 absorption)
- chief cells for pepsinogen activated by HCl to become pepsin to digest protein
- enterochromaffin-like cells (ECL cells) for histamine to stimulate H+ production also
reduces acid production in the stomach
pyloric (antral) glands have:
- (glands of stomach)
- mucous cells
- G cells for gastrin – secreted into systemic circulation, stimulate parietal cells to make HCl and intrinsic factor
- Expend large amounts of ATP in order to secrete HCl into the lumen at levels necessary to drop the stomach pH to such low levels (1-2).
- Parietal cells are also full of carbonic anhydrase.
- Also make the glycoprotein intrinsic factor necessary for vitamin B12 absorption at the ileum. Inability to absorb vitamin B12 leads to pernicious anemia because it can't be transported to the bone marrow for RBC production.
The net summary of parietal cell activity is a luminal secretion of HCl and absorption of NaHCO3 into the extracellular fluid, i.e., bloodstream
Proton pump inhibitors
omeprazole (Prilosec) and prevacid are a common treatment for GERD. They act by inhibiting the K+/H+ ATPase and decrease the amount of H+ secreted into the stomach.
Acidity can be stimulated by
- acetylcholine via PLC/IP3 second messenger system.
- gastrin via PLC/IP3 system.
- histamine (via H2 receptors) from ECL cells via adenyl cylcase/cAMP second messenger system.
Acidity is inhibited by
somatostatin and prostaglandins.
a peptide hormone secreted by stomach/intestine/pancreatic cells.
paracrine peptides found in most organs. NSAIDs inhibit prostaglandins, hence their association with increased risk for peptic ulcer disease. So NSAIDs increase H+ production, so increased risk of reflux
cephalic phase of gastric secretions
(vagal nerve stimulation) 30%
gastric phase of gastric secretions
(positive feedback from stomach once food reaches stomach) 60%
intestinal phase of gastric secretions
(stimulation of hormones when chyme reaches intestine, a smaller proportion) 10%
Protective factors of the gastric lining
- the mucus cells produce an adherent mucus that is bicarbonate rich
- prostaglandins and somatostatin to inhibit H+ production
- tight junctions between the gastric epithelial cells help to prevent acid diffusion
- Gastrin stimulates growth of mucosa
- growth factors stimulate rapid epithelial cell turnover
Damaging factors of the gastric lining
- Direct effects of H+ and pepsin
- H.pylori gram negative rod
- NSAIDS-inhibit prostaglandins
- Stress-triggers inflammatory response and increases histamine which triggers production of H+ ions
- Smoking-stimulates vasoconstriction, delays healing of everything
- Alcohol-stimulates gastric secretion of H+
erosion of mucus membrane of stomach/duodenum which occurs with loss of protective mucous barrier and/or excessive H+ and pepsin secretion.
- unique in its ability to survive in acidic environments. This is partly due to the enzyme urease which converts urea to ammonia (NH3 ) to neutralize gastric acid. The cytotoxins released by H. pylori break down the protective mucous barrier.
- Do a urease breath test
- gastrin-producing tumor seen with excessive acid secretion from high levels of gastrin.
- Called gastrinoma or incidentaloma
Exocrine function of Pancreas
- contains secretory units of acini which secrete digestive enzymes (amylase, lipase, and trypsin) and ductal cells that produce a bicarbonate-rich juice for buffering the chyme delivered to the duodenum.
- The exocrine pancreas is under parasympathetic (stimulatory) and symptathetic (inhibitory) activity.
Most pancreatic enzymes are produced as inactive zymogens (cuts down on risk of self-digestion of pancreas). Zymogen is how it’s stored.
Endocrine function of Pancreas
- pancreatic islets of Langerhans that secrete insulin, glucagon, and somatostatin
enzyme for digestion of carbohyrates/starches
enzyme for digestion of fats
- enzyme for digestion of protein
- enterokinase changes trypsinogen to trypsin
- In acute pancreatitis trypsin is activated and triggers activation of other pancreatic enzymes which are directly responsible for cellular destruction and clinical consequences.
the zymogen (inactive) which is changed to pepsin in the stomach by HCl.
changes trypsinogen to trypsin
end result is net secretion of bicarbonate from ductal cells into pancreatic ductal juice and net absorption of H+ into pancreatic venous blood
- depends on pancreas
- people with insufficency need to take pancreatic enzymes to digest lipids or avoid fatty foods
Pancreatic secretion regulation
Enzymatic and aqueous portions of the secretion are regulated via different pathways with stimulation of enzymatic secretion through PLC/IP3 second messenger system and stimulation of aqueous secretion through adenyl cyclase/cAMP system.
Parasympathetic Nervous System
- Long preganglionic neurons and short postganglionic neurons
- The preganglionic neurons are cholinergic and release acetylcholine (ACh) which then binds to nicotinic receptors on the postganglionic neurons which are also cholinergic and again release ACh. The ACh then binds to the muscarinic receptors on the target cells
Sympathetic Nervous System
- Short preganglionic neurons and long postganglionic neurons
- The preganglionic neurons are cholinergic and release acetylcholine (ACh) which then binds to nicotinic receptors on the postganglionic neurons which are adrenergic and release norepinephrine (NE). The NE then binds to the Beta receptors on the target cells.
Phospholipase C is a class of enzymes that cleave phospholipids just before the phosphate group
- (Inositol 1,4,5-triphosphate)
- also known as a second messenger
The inappropriate activation of pancreatic enzymes can lead to acute pancreatitis where there is potentially fatal autodigestion of the pancreas and surrounding tissues. Autodigestion is breakdown of tissues – bad day
Common causes of acute pancreatitis
- ductal obstruction, trauma, infection, and toxicity. All of these lead to inflammation, proteolysis (break down of proteins in cells), necrosis, and hemorrhage.
- Trypsin is activated and triggers activation of other pancreatic enzymes which are directly responsible for cellular destruction and clinical consequences.
- largest internal organ
- receives arterial blood from the hepatic artery
- receives venous blood through the portal vein system which is rich in nutrients and pancreatic enzymes
- functional cell of the liver
- make bile, canuliculi collect the bile, they are like bile vessels that then dump into the bile duct
- surrounded by sinusoids, which are highly fenestrated capillaries where blood from the portal system and hepatic artery mix, allowing for efficient filtration. Kupffer cells are also found within sinusoids and are responsible for removal of bacteria and aged/damaged RBCs. Bile canaliculi exist within the hepatic plates.
- carries blood from GI, pancreas, spleen
- lots of nutrients
carries lots of oxygen
Sinusoids of liver
- surround the hepatocytes
- where blood from portal system and hepatic artery mix
- empty to central veins and then to hepatic vein
- contain Kupffer cells which remove bacteria and old/damaged RBCs
Spleen and Kupffer cells
remove old/damaged RBCs
network of bile vessels that collect the bile from the hepatocytes and then dump it into the bile duct
Functions of the liver include
- Regulation of carbohydrate, lipid, and protein metabolism.
- Synthesis of proteins such as albumin (for oncotic pressure), clotting factors, and binding proteins.
- Glucose is taken up into SER to be stored as glycogen where it is easily degraded back to glucose.
- Regulation of cholesterol production and excretion
- Bile acid production and secretion
- Bilirubin production and excretion (broken down Hgb)
- "First pass" filtration of portal blood (everything that goes through gut goes into portal circulation)
- Endocrine functions
- Vitamin and iron storage (B12, ferritin)
The majority (90%) of bile acids are recirculated from small intestine, the other 10% are synthesized in the SER of the hepatocyte.
- cholesterol derivatives, principally made up of cholic acid and chenodeoxycholic acid. The liver conjugates bile acids to form bile salts. Their function is digestion and absorption of lipids in the small intestine. Bile is stored and concentrated in the gallbladder.
- Bile is constantly recycled via enterohepatic recirculation especially at the ileum.
Released from liver
bile salts, cholesterol, bile pigments, phospholipids. All secreted as bile through bile duct, stored in gall bladder
- Where bile is stored and concentrated
- Presence of chyme makes the gall bladder contract to release bile, through sphincter of Oddi which emulsifies the fats (lipids) to break them up.
RBCs usually live ...
~120 days, then get broken down.
- in the blood, then it is conjugated in the liver. Conjugation makes it (green) soluable in water so the body can excrete it.
- a breakdown product of the heme ring of hemoglobin during red blood cell degradation. The bilirubin is carried to the blood (bound to albumin), then extracted by the liver.
- The liver can conjugate some of the free bilirubin with glucuronic acid to from a water-soluble conjugated bilirubin that can be secreted into bile in the small intestine.
- conjugated bilirubin
- can be modified by the intestinal flora to colorless urobilinogen, which upon further oxidation can give color to feces or urine.
- a yellow staining of tissues produced by high levels of bilirubin in the plasma. Jaundice occurs by increased production of bilirubin by hemolysis, or by decreased removal of bilirubin by liver damage or obstruction
occurs as a result of hepatic dysfunction such as obstruction (elevated conjugated bilirubin)
occurs from extrahepatic conditions such as hemolytic disease (elevated unconjugated bilirubin).
hemolysis – get too much unconjugated (indirect) bilirubin, Gilbert’s syndrome
hepatitis, cirrhosis – increased levels of both
obstruction - get too much conjugated (direct) bilirubin
Jaundice in babies
due to increased levels of bilirubin being made, need a few days to make removal happen, put baby under lights (blue and UV light helps break down bilirubin)
Phase I reactions
include oxidation, reduction, and hydrolysis catalyzed by cytochrome P450 monooxygenase. (Enzymes from psychopharm)
Phase II reactions
involve active metabolites from phase I reactions that are conjugated with substances like glutathione, amino acids, and sulfate to inactive metabolites.
Substances that induce Phase I reactions
(cytochrome P450) will speed up the enzymatic process and hence decrease the duration of action of other drugs that utilize this system. (e.g. chronic ethanol use leading to subtherapeutic levels of antiseizure medications).
Substances that inhibit Phase I reactions
(cytochrome P450) will slow down the enzymatic process and increase the duration of action of other drugs that utilize this system, potentially creating drug toxicity. (warfarin increased if pt given amiodarone)
- irreversible fibrotic and nodular destruction of hepatocytes.
- Caused by EtOH, fatty liver disease, hepatitis, get further necrosis due to abnormal blood flow
- Can get portal hypertension – esophageal varices
Plasma proteins and coagulation factors
- Produced by the liver
- Plasma albumin and most of the plasma proteins and coagulation factors are produced by liver. Albumin is 70% of total plasma protein and accounts for most of the colloid osmotic (oncotic) pressure.
- Portal hypertension (increased interstitial fluid)
- Increased lymph formation (can’t keep up with the increased interstitial fluid from the portal hypertension)
- Loss of capillary oncotic albumins (hypoalbuminemia)
- Systemic manifestations of cirrhosis:
- Coma due to accumulation of toxins – encephatopathy 2° toxins
- Jaundice from bilirubin
- Spider nevi – increased levels of estrogen (associated with dilated/enlarged arteries close to skin) blanching.
- Increased levels of estrogen – get man boobs, testicular atrophy due to increased conversion of androgens to estrogens due to liver failure
- Ascities – portal hypertension, decreased albumin, increased lymph
- Anemia – liver stores B12 & folic acid, so that’s abnormal and decreased RBCs made
- Hemorrhage – decreased clotting factors
- Splenomegaly – portal hypertension causes back up and congestion into spleen
- Thrombocytopenia – due to enlarged spleen, reduces platlets
- must be broken down from polysaccharides and disaccharides into monosaccharides (glucose, fructose, and galactose) to be absorbed in the small intestine.
- Starts in the mouth with alpha-amylase
- Pancreatic amylase and brush border help with breakdown
- result of broken down carbohydrate
- can then be co-transported with Na+ or by facilitated diffusion into intestinal cells.
- Sports drinks have Na+ to help with transport of glucose/galactose for energy
- Fructose doesn’t do co-transport
- Monosaccharides move from the lumen (apical membrane) into the epithelial cell of the small intestine and out the basolateral membrane into portal circulation
- begins in the stomach with pepsin. In the brush border of the small intestine, trypsinogen is converted to trypsin in the presence of enterokinase to begin the bulk of protein digestion.
- Different proteases are specialized for different parts of the amino acid sequences to produce amino acids, dipeptides, and tripeptides.
- Then absorbed through the epithelial cells, with the help of H+ from the stomach, into portal circulation.
- Proteins don’t have to be broken down to smallest parts (as carbohydrates do)
- made by chief cells
- Pepsinogin activated by HCl to become Pepsin.
blood lipids; broken down into monoglycerides and FFA (free fatty acids)
lipids synthesized by the liver; component of cell membrane and precursor to steroid hormones, bile, and vitamin D
- lipid molecule that makes up PL bilayer of cell membranes
- Phospholipids are broken down to lysolecithin and FFA
dietary form of cholesterol; broken down to cholesterol and FFA (free fatty acids)
- structure formed by phospholipids in an aqueous solution; how small lipids are transported through the small intestine
- Lipids are emulsified with bile and then packaged into micelles with the hydrophobic lipids at the core and the hydrophilic bile salts lining the exterior to allow for entry into the epithelial cells.
structure consisting of cholesterol esters, triglycerides, and phospholipids; how lipids are transported from the intestine to the rest of the body through the portal vein or thoracic duct/lymphatics
lymphatic capillaries within intestinal villi
composed of triglycerides, cholesterol, and phospholipids.
begins in the mouth with small contributions from lingual and gastric lipase. The churning action of the stomach breaks lipids into small droplets to increase their surface area and then slowly releases them into the small intestine, allowing ample time for release of pancreatic lipase. Lipids are emulsified with bile and then packaged into micelles with the hydrophobic lipids at the core and the hydrophilic bile salts lining the exterior to allow for entry into the epithelial cells.
broken down to monoglycerides and FFA
Water soluble vitamins
e.g. B vitamins (except B12) and vitamin C are absorbed by cotransport.
Fat soluble vitamins
(A,D,E, and K) are absorbed with lipids. (as micelles)
binds to intrinsic factor in the small intestine, binds to a receptor in the terminal ileum, binds to transcobalamin (TCII) in the cytosol, and is transported to the bone marrow for RBC production or the liver for storage.
- heme iron-bound to hemoglobin or myoglobin in meats
- Organic iron enters the enterocyte and is reduced to Fe2+
- free iron-from vegetables or recycled hemoglobin
- inorganic iron is reduced to Fe2+ in the luminal membrane before being transported through.
Fifteen to thirty percent of iron is stored as ferritin in the liver, while the remainder is bound to transferrin and transported through the blood to bone marrow where it is used for hemoglobin and RBC production.
Excessive iron storage
- seen in hemochromatosis.
- This can lead to liver cirrhosis and liver cancer, cardiomegaly, and issues with endocrine glands (pancreatic and testicular failure)
- Donate blood regularly to help with this.
Diarrhea and hypokalemia
Excess potassium loss during diarrhea can therefore lead to a metabolic acidosis and hypokalemia.
- enterotoxin stimulates active NaCl transport out of the cell via increased cAMP activity, with water following
- Abnormal stimulation of adenylyl cyclase may result in secretory diarrhea
- (gluten sensitivity)
- autoimmune damage to the intestinal lining, with villus atrophy
increased osmolality of luminal contents, with undigested lactose (get abnormal stool)
vomiting, swallowing, breathing, blood pressure, balance/posture, coughing
breathing, balance/posture, relay info from cerebellum to cerebral cortex
relay of info visual and auditory
sensory to and motor from the cortex, only sense that doesn’t pass through thalamus is smell
temperature regulation, water balance, regulates hormones (control over pituitary)
- the area of the body associated with the stimulated sensory neuron.
- Receptive fields may vary in size, e.g., two-point discrimination between a fingertip and the back of the neck.
- Small receptive field is more precise
helps to sharpen the localization of the stimulus.
occurs when a constant stimulus is applied for a prolonged period of time and the frequency of action potentials begins to decline.
- rapidly adapting
- Pacinian corpuscles vibration, vibration on skin, detect the on and the off but not necessarily the sensation through out
- slowly adapting
- Merkel’s receptors on the skin (mechanoreceptors) sensitive to pressure
- Ruffini's corpuscles are sensitive to stretch
- useful for vibration
- Tonic/slowly adapting
- useful for stretch
- Tonic/slowly adapting
- on the skin (mechanoreceptors) sensitive to pressure
proportion of rods to cones
- function in darkness
- Many rods will converge onto one bipolar cell, allowing better sensitivity in low light.
- Peripherally - only need 1 photon to activate
- have higher acuity in light
- Just a few cones will converge onto one bipolar cell, allowing better acuity when there is bright light.
- Cone cells that vary in their sensitivity to different wavelengths of light account for color discrimination.
- Cones are in the fovea – needs 100’s of photons of light
Acuity is highest in the fovea; as cones are located in the fovea and rods are located in the periphery.
- optic pathway
- from the retinal ganglion to the CNS includes the optic nerve, optic chiasm, optic track, the geniculate body of the thalamus, and the visual cortex via the geniculocalcarine tract.
directing of sound
conveying of sound from tympanic membrane and middle ear bones
conversion of sound to action potentials (neurosensory loss happens here)
- Sound waves are directed toward the tympanic membrane, causing it to vibrate.
- The vibration of the tympanic membrane causes the ossicles to vibrate and the stapes is pushed into the oval window causing displacement of fluid in the cochlea.
- The basilar membrane of the Organ of Corti bends with hair cells, triggering the mechanically-gated cation channels to open/close
- This triggers either a release of glutamate (excitatory) or a decrease in the release of glutamate (inhibitory).
- Changes in glutamate stimulate afferent cochlear nerves.
- The basilar membrane is narrow and stiff at the base nearest to the oval window and stapes vs. wide and compliant at the apex.
- High frequencies heard at base (narrow and stiff)
- Low frequencies heard at apex (wide and compliant)
progressive, symmetric, age-related hearing loss. typically high-pitched tones are lost first, suggesting changes at the base, although the condition is considered to be multifactorial in origin
- sensed by the utricle and saccule to sense linear acceleration
- sensed by the semicircular canals
Benign paroxysmal positional vertigo
a common disorder of the inner ear and characterized by a spinning sensation generated by abnormal stimulation of the semicircular canals.
The utricle and saccule contain a mixture of mucopolysaccharides and calcium carbonate which act similarly to the cupula within semicircular canals to help exaggerate the force of the bending on the hair cells when the head is tilted.
olfactory receptor cells
receptors linked with G proteins. There are actively dividing basal cells that replace the olfactory cells. G protein adenylyl cyclase -> cAMP -> depolarization -> olfactory tract
Much of the pathway involves the limbic system and does not pass through the thalamus, hence smell as generating emotions and memories.
Much of what we know as "flavor" is actually sensed through smell, hence the blandness of food during a cold.
- inability to smell scents
- can follow head injuries that damage the olfactory nerves or infections that damage the cells, and will contribute to ageusia because of the contribution of smell to taste.
loss of taste function
- specialized epithelial cells acting as chemoreceptors.
- Sweet, sour, bitter, salty, umami
Taste buds sense five primary stimuli:
- salty (through Na+ or similar cations)
- sour (through H+ ions)
- bitter, sweet, umami (through receptors associated with G proteins)
would run through CN VII (first 2/3 of tongue) and CN IX (last 1/3 of tongue, pharynx) to the brainstem, and then project via the thalamus to the taste cortex.
Alpha motor neurons
- innervate the extrafusal muscle fibers (typical contractile ones). These alpha motor neurons will supply a motor unit—small in eyes, large in a thigh muscle.
- Gamma motor neurons
- innervate the intrafusal fibers (more specialized sensory fibers) for appropriate levels of muscle tone.
- The muscle spindle fibers are set with a sensory middle area, and slightly contractile regions at each end.
- There are two types of intrafusal fibers in muscle spindles: nuclear bag fibers and nuclear chain fibers.
- Fast-conducting group Ia neurons will carry the signal from both, and slower group II neurons will carry the signal from the nuclear chain fibers.
- As the spindle fibers are stretched, they can give:
- static response: absolute length of the muscle (more from the nuclear chain fibers, carried by group II neurons) length change
- dynamic response: rate of length change (more from the nuclear bag fibers, carried by the group Ia neurons) velocity of contraction
- Coactivation of alpha and gamma motor neurons
- will allow the spindle fibers to "keep pace" with the more typical muscle fibers around them, and so able to monitor level of muscle contraction.
Nuclear bag fibers
are fewer and larger, nuclei in the center
Nuclear chain fibers
there are more, they’re smaller and the nuclei are in a chain
muscle stretch reflex
- (or myotactic reflex) as generated by passive stretching and subsequent contraction of a muscle. This is useful for an antigravity (i.e., standing erect) response, but we know it best as reflex (deep tendon reflex) testing.
- Muscle stretch activates group Ia afferent fibers in the muscle spindle.
- Ia fibers synapse in spinal cord and activate alpha-motoneurons.
- Alpha motoneurons stimulate contraction of the muscle
- Gamma motoneurons stimulate contraction of muscle spindle
- Muscle spindle shortens and decreases the stimulus to Ia fibers (like negative feedback)
- At the same time, information from the spinal cord causes contraction of synergistic muscles and relaxation of antagonistic muscles.
Golgi tendon organs
- within tendons are sensitive to muscle tension and will initiate an inhibitory relaxation via Ib afferent neurons to the muscle if tension is sufficiently high.
- (opposite of stretch reflex) so when you tap the patella tendon and the quads contract, you need the hamstrings to relax (protective reflex)
Static stretching v ballistic stretching
- Slow stretch – stimulates the Golgi tendon (static)
- Bouncing stretch – stimulates the stretch reflex (ballistic) could cause damage to muscle – early aerobics videos
- (Crossed-extension reflex)
- is another protective reflex where the muscle will contract in response to a harmful stimulus. The reflex stimulates flexion on affected side and extension on the contralateral side
- Step on a nail – contralateral muscles help to shift your weight to opposite foot to relieve weight on foot with the nail
- Touch a hot stove – flex to move away, relax the extensor muscles
Summary of muscle stretch reflex
- One synapse
- Stimulus is stretch of the muscle
- Ia sensory afferent fibers are activated
- Response is contraction of the muscle
- (knee jerk)
Summary of Golgi tendon reflex
- Two synapses
- Stimulus is contraction of the muscle
- Ib sensory afferent fibers are activated
- Response is relaxation of the muscle
- (clasp knife)
Summary of Flexor-withdrawal reflex
- Many synapses
- Stimulus is pain/temperature
- II, III, IV sensory afferent fibers are activated
- Response is flexion on ipsilateral side and extension on contralateral side
- (touching a hot stove)
- coordinate muscle function by comparing information about intended movements (from their motor contex input) with the actual movement occurring (from proprioception carried by the spinocerebellar tracts) and correcting accordingly via the output of the Purkinje cells. Cerebellar lesions therefore present as intention tremors.
- Cerebellum – movement and posture
- Purkinje cells – inhibitory
basal nuclei (ganglia)
role in complex motor actions, acting as "brakes" to excessive motor activity and so when a lesion exists, will generate resting tremors.
Dopaminergic neurons of the substantia nigra
project to both the direct and indirect pathways, so that both are affected by the neuronal loss seen in Parkinson disease.
(EEG) measures the electrical activity of large numbers of cortical neurons.
quiet wakefulness (awake but eyes closed – no visual stimulus)
normal in children, can indicate stress/disease in awake adults
- deep sleep or brain disease
- Rapid eye movement
- (REM) sleep occurs about every 90 minutes, with high levels of brain activity, e.g., dreaming. In contrast, non-REM sleep has four stages that will lessen throughout the evening.
the site of consolidation of short-term memory into long-term memory. This process is enhanced by long-term potentiation.
for emotional memory
myelinate in the CNS (vs. Schwann cells that myelinate in the PNS)
assist in immune functions
which contribute to the blood-brain barrier (in addition to the presence of continuous cerebral capillaries)
line the ventricles and contribute to CSF production