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186 Cards in this Set
- Front
- Back
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non-enzymatic glycosylation example
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Hemoglobin A1c
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antagonistic pleiotropy
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no genetic pressure after reproductive age
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"Progeria"
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Hutchinson Gilford Syndrome
children look senile at 11 or 12yo; age of death is 12 from MI/artherosclerosis. There was no CNS degeneration; autosomal dominant mutation in Lamin-A --> this causes deposition of protein forming shell around nucleus preventing nucleus from exchanging material; there is nuclear blebbing. it's not actually aging |
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senecence or immortal, what's dominant
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senescence is dominant; it's nl growth
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what is aging
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sum of the deteriorative changes w/ time during post-maturational life that underly an increasing vulnerability to challenges, thereby decreasing the ability of the organism to survive
aging itself does not result in disease but renders the individual more susceptible to dz |
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examples of primary aging
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menopause
greying of hair balding in men loss of muscle mass atrophy of thymus they're on the clock... |
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measurements of aging
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max life span (120 yrs for us)
- seems to stay, but the chance of getting close is increasing age-specific mortality rates biomarkers of age -things that vary with age and are used as surrogates physiologic age |
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methods to increase longevity
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decrease body tempareature (only for cold blooded animals)
gene manipulations in insulin/growth hormone/IGF-1 ptwy Caloric restriction antioxidant enzyme overexpression? |
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homeostenosis
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with age more susceptible to disease
the precipice crosses physiologic reserves; |
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Visual changes with age
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periorbital tissue atrophies
decreased lachrymal gland production smaller pupil anterior chamber more shallow lens yellows (decreased transmission of blue light) lens less elastic (can't see close objects) - presbyopia small decrease in static acutiy marked decrease in dynamic visual acuity marked slowing of dark and light adaptation increased need for contrasting colors impaired glare discrimination - can't drive at night - light get's scattered |
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auditory changes with age
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decreased cerumen production
dull thickened white typanic membrane loss of organ corti hair cells loss of choclear neurons bilateral hearing loss for high frequencies (speech can be cut off - and so it's better to use other sound to say it again) larger threshold to determine differences in pitch impaired ability to determine source of sound decreased speech discrimination decreased ability to focus on target sound and ignore extraneous noise (central processing auditory deficit) CPAD this process is NOT dementia |
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implications - keep in mind when talknig to older pt
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perform H&P in well lit room
avoid back lighting increase volume of voice not pitch if necessary rephrase questions if misheard, don't repeat eliminate extrinsic noise let pt see your lips when sparking |
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body composition changes with aging
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total water decreased
body fat increased muscle mass decreased bone mass decreased height decreased |
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heterogeneitiy with aging
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old people are more different from each other than the young people are
interactions with age, disease, past experiences 70yo women 15.5 and 37 s -- how long it takes for them to run - ex 1/3 changes are subclinical 1/3 are disuse 1/3 primary aging |
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2 main theories about why aging is happening
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1) homeostatic failure - either in regulatory control systems (like the immune or endocrine systems) or generalized cellular failure (like free radical or AGE mediated damage)
2) Intrinsic: Genetic program similar to developmental-antagonistic pleiotropy or telomere shortening -centralized clock theory -glucocorticoid theory -immunologic theory of aging -apoptosis 1b ) Extrinsic/Stochastic/Environmental (not quite the same as damage of the homeostatic mechanisms) -free radical damage -wear and tear theories -error catastrophe theory -AGE/glycosylation If we do age because of a genetic program, then we should be able to induce that in culture; |
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reactive molecules from the outside that are "the devil outside" causing aging (extrinsic causes)
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glucose
-non-enzymatic glycosylation ( such as Hg A1c) -AGE (Adcanced glycation end products) Oxygen/ROS (induced free radicals) -Peroxide -Hydroxyl -Peroxynitrite oxidation and glycation can produce damage and modify function of cellular components. |
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why is the wear and tear theory not good
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wear and tear is like how cars break; they break at a constant rate and there are still very old cars still going... people are not cars
but with humans it's not a constant rate of death - but there is an increase in death rate as the age increases; |
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extrinsic damage can lead to DNA damage
who's more suceptible, who is less so? |
the damage can occur to cellular or mitochondrial DNA.
Repair enzymes work to correct the damage, but mito has less active DNA repair. The mitochondrial repair is decreased with age; repair mechanisms for nuclear DNA seem to keep up pretty well no matter how old |
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antagonistic pleiotropy
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there's no genetic pressure on genes harmful effect after reproductive age -->
so, if there is a gene that provides an advantage when you're young, this might be a disadvantage when you get older: for example a gene causing stronger bone and higher calcium deposition; but later this will lead to arterial calcification; |
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examples of dysregulation of cell proliferation in aging
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inappropriate cell division
-atherosclerosis (smooth muscle cells) -prostatic hypertrophy -cancers inadequate cell division -decreased T-cell response to immunologic stimuli -atherosclerosis (endothelial cells) -slow wound healing -balding |
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define cellular scenescence
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normal cells, not stem cells, run out of the ability to divide
these cells get bigger, and they happily continue, but never divide to any stimulus; cells from malignant tumors will not senesce, but will divide ad infinatum normal cells have limited proliferative potential typical pattern of cell growth: Phase 1: adjustment to conditions Phase 2: rapid growth linear for 20-50doublings as cells approach their maximum, their growth rate slows |
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lifespan and fibroblast doublings
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they're directly correlated
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immortal cells
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cancer cells
germ line cells certain stem cells, likely but it may depend on their "stemness" |
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what do we learn by taking the nucleus out and putting young nucleus in...
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senescent cells produce proteins in their cytoplasm that suppresses replication :
with the young nucleus, cells divide slowly; put that nuleus into a young cytoplasm --> rapid mitosis put old nuc into old cytoplasm --> slow mitosis |
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what do we learn from cell fusion studies:
senescent cell + immortal cell --> |
fusion is scenescent
so senescence is a dominant trait |
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what do we learn from cell fusion studies:
immortal cell + immortal cell --> |
senescent or immortal;
if they can senescene together, their mutations/genes making them immortal come from different pathways; --> we found 4 groups of pathways that determine scenescence from immortalization. all cancers tested to date fit into the 4 groups: group A = chromosome 6 group B = chr 4, MORF4 group C = Chr 1 Group D = Chr 7 ex: crossing B with C they will provide each other and scenesce immortal cells come from B with B etc take a cell group B (HeLa immortal) and give it chromosome 4, it will senesce |
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what makes the clock of the cell, how does the cell count?
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Telomeres
at end it's AGGGTT newborn w/ 2000 repeats at end, old poeple have less requires telomerase to keep up with number, or else few repeats are lost with each division - b/c DNA polymerase can't get to the end of chromosome tumor cells 90% and germ line have telomerase, not those that senesce knockout telomerase --> senesce giving telomerase -->delay in senescence |
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Hutchinson Gilford syndrome
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Progeria
body looks like it's old. no changes in CNS developemnt rare autosomal dominant death by MI/heart failure Lamin-A gene mutation Lamin-A gene mutant product makes a shell inside the nucleus --> can't get out progerin is permannetly modified --> stiff cant get in and out the nucleus it's not accelerated aging -no cognitive changes, no bone changes, prominent atherosclerosisi(human diseases) , it's segmental progeroid syndrome, not aging |
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normal growth is a _____ process
cells become ______ b/c recessive gene defects cell proliferation control and cellular senescence are dictated by_________, not random accumulation of damage |
dominant
immortal active, genetic events, |
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plane crash scenario in desert:
dehydration of old and young |
OLD guy is more likely to become dehydrated:
1) old has decreased ability to retain water and 2) salt; 3) old guys have decreased body water to start with; 4) longer time to reach maximum capacity; 5) decreased recognition of thirst; young can concentrate up to 1200mOsm, the old has max of 700mOsm |
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water deprivation test in young vs old
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deprivation made old more hyperosmolar and they drank less after that;
they don't sense thirst; |
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old people are more likely to get hyperthermic because
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not as good at sweating
has decreased effectiveness of sweating because of less skin arteriole vasodilation he has decreased maximal sweat output by sweat glands old people can't recognize increased body temperature; |
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why is old kidney not good with water?
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the nephrons making the most concentrated urine are the ones that preferentially die
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real reasons why people died in the Chicago heat wave
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old people won't sleep with the window open due to crime
don't have money to run the AC didn't have friends to go to dementia |
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volume overload in older
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renal perfusion decreases
takes longer to supress the ADH - so the maxial dilution is reached later; also not as dilute also 1/3 less kidney by mass old don't respond as well to ANP and BNP venous compliance is decreased - they won't make as much urine to get rid of it |
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diet of older woman: ask her to be on low sodium diet; she comes back - what changed?
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complaining = she's actually doing it
her BP has decreased - the BP meds weren't needed! |
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drug dosing for elderly : valium story
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she's been increasing the dose
now she's stopped using it but even afer detox she's still tired Valium likes fat - so it's stored there - and that's also why it can get to the brain well; so she's storing it, so the washout can take weeks |
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hypothermia and older people: slept in garden
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risks for getting hypothermia:
-impaired temperature recognition -don't shiver -brown fat is decreased -pili in skin are not used - no goosebumps -old brain is very sensitive to changes in temperature -vasoconstriction impaired - continue to send warm blood to cold areas -decreased heat production per body weight - less lean weight = less metabolic weight you're not dead till you're warm and dead: -heart rate drops when you're really cold -hypothemia protects the brain hypothermia instead of hyperthermia usually means overwhelming sepsis has a poorer prognosis - with infection, cold is bad |
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formation of the placenta: initial steps - how does the blastocyst even implant?
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blastocyst attaches to the uterine endometrium during implantation
trophoblastic cells produce enzymes to digest the extracellular matrix thus, the bastocyst invades into the uterine lining |
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what are the extra-embryonic membranes, and what do they do
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Amnion - creates fluid space around the embryo
yolk sac - some vertebrates need yolk sac for nutrition; humans don't; contains early blood cells Allantois - small membrane that becomes part of the umbilical cord chorion- embryo's contribution to the placenta |
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formation of the placenta: the actual formation
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The chorion proliferates and creates finger-like projections that invade further into the uterine wall
These chorionic villi secrete enzymes that break down endometrial stroma and surrounding capillaries Capillary rupture causes formation of small, blood-filled cavities --> intervillous spaces NOTE: Maternal and fetal circulations are entirely separate |
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why is there not thrombosis of the placenta?
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Placental Anti-Thrombotic Activity
Placental vascular thrombosis can result in pregnancy loss Trophoblasts actively secrete substances into the intervillous space to prevent platelet and leukocyte adhesion and aggregation |
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functions of placenta
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1) Allows exchange of nutrients, gases, waste
2) Releases hormones: -Prevent menstruation (hCG, progesterone) -Prepare mammary glands to produce milk -Prepare body for labor and delivery (estrogen) |
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what's the placenta made of
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Combination of fetal and maternal tissue
Fetal tissue --> chorion Maternal tissues --> part of endometrium |
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which antibodies can pass through placenta?
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IgG only
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nontransferrable substances (mom to baby)
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heparin, transferrin, IgA IgM IgD
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harmful and transferrable via placenta
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ToRCHES
Toxoplasmosis, Rubella, CMV, Herpes, HIV, Syphillis, drugs, CO, other poisons, strontium 90 |
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CO goes to
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globus pallidus
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Mechanisms of transfer of materials via the placenta
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-Bulk flow (aka “solvent drag”)
-Simple diffusion (passive transfer of solutes in response to concentration/electrical gradients) -Facilitated diffusion (channels, carrier mediated active transport) -Endocytosis/exocytosis |
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what moves by bulk flow
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most electrolytes
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what moves by simple diffusion
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O2, CO2, FA, Steroids, highly charged electrolytes, fat soluble vitamins, most drugs
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what moves across placenta via active transport
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Amino acids, some big ions (Ca2+, Fe, I-, PO43-), water soluble vitamins
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moves by facilitated diffusion
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sugars, IgG
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how do drugs cross placenta?
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Mainly simple diffusion
Factors that affect transfer include: -Molecular weight (<600 Daltons diffuse easily) -Degree of ionization (non-ionized diffuse easily) -Lipid solubility (liphophilic molecules diffuse easily) -Protein binding (non-protein bound diffuse easily) |
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hCG made by Placenta - why?
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Human chorionic gonadotropin
Produced by trophoblasts Prevents dissolution of corpus luteum, thereby sustaining progesterone production by CL until placenta takes over Detectable by 8 days post-conception, peaks at 8-9 weeks, and falls precipitously by 13-14 weeks AND Estrogens hCG stimulates trophoblasts to produce estrogens Placenta does NOT have sufficient machinery to produce estrogens de novo The fetal adrenal gland produces abundant dehydroepiandrosterone (DHEA) --> to placenta to be converted to estrogens (estriol, estrone, and estradiol) Stimulates growth of myometrium and maternal mammary glands At a high threshold level (estrogen lvl is high enough), myometrial oxytocin receptors are upregulated |
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progesterone made by placenta - why?
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Progesterone
Necessary for maintenance of a quiescent, non-contractile uterus (contra-estrogen work) Anti-inflammatory and immunosuppressive functions --> protect conceptus from immunological rejection by mother |
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placental size - affecting factors
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Placental weight is influenced by the hormonal milieu
Other factors include: placental blood flow, nutrient delivery, oxygen delivery |
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Placenta Accreta
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accreta, increata, percreta,
Placenta attached to wall of uterus 1:5000 pregnancies More common in women with previous Cesarean deliveries High maternal and/or fetal morbidity and mortality Symptoms manifest during labor and delivery, usually with massive bleeding Interferes with normal post-delivery contractions --> severe hemorrhaging Mother may need hysterectomy if bleeding cannot be controlled 3 “variants” Accreta (~75-77%) – placenta invades to the muscular layer (but not into it) of uterus Increta (~15-17%)– placenta invades into muscular layer of uterus, but not through serosa Percreta (~5%) – placenta invades through muscular layer and serosa and attaches to other organs |
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Placenta Previa
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Presence of placental tissue overlying or proximate to the internal cervical os
In up to 1:250 pregnancies Most common complication: bleeding (spotting --> hemorrhage) Risk factors: -Smoking -Multiple gestation -Previous uterine surgery (c-section in the lower uterine segment) 3 types: 1/3 1/3 1/3 (they can change overtime) marginal 40% partial 30% complete 20-30% Affects on fetus: -Fetal malpresentation -Premature rupture of membranes -Intrauterine growth restriction – not entirely clear -Vasa previa (cord stayed where it is bc the placenta retreated- can rip!) and velamentous cord insertion (portion of fetal vessels are naked and enter marginally into placenta) -Amniotic fluid embolism (high incidence seen with ANY placental pathology) |
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Placental Abruption
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contraction and separation after birth is normal; if this is before it's born, the child doesn't get oxygen anymore;
Placental separation from uterus prior to birth 1:100 pregnancies Risk factors: -Abdominal trauma -Premature rupture of membranes -Smoking Location matters Symptoms -Asymptomatic (bad) -Vaginal spotting -Uterine/lumbar pain (lumbar pain can be normal, but a change in lumbar pain - more pressure/pain..) -Hemorrhaging Can have fatal consequences for fetus |
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Fetal Conditions Associated with Placental Abnormalities
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Chorioamnionitis
Intrauterine growth restriction Oligohydramnios Polyhydramnios hydrops fetalis |
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Chorioamnionitis
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inflammation of the chorion and the amnion:
Ascending infection by usual vaginal colonizers after rupture of membranes; it's a CLINICAL diagnosis: Maternal fever during labor ≥100.4°F And two of the following Maternal or fetal tachycardia Uterine tenderness Foul vaginal discharge Maternal leukocytosis Risk factors: Age <21 years Low socioeconomic status Prolonged rupture of membranes (>18-24 hours) Internal fetal monitoring Fetal consequences Sepsis/meningitis Mortality ~15% in preterm infants Cytokine storm results in increased risk for development of bronchopulmonary dysplasia and poor neurodevelopmental outcomes CONTRAINDICATION: steroids |
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Intrauterine Growth Restriction IUGR
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def: something pathological
(not small for gestational age def: < 10th percentile, large for gest age is >90th) Implies pathology - differentiate from SGA infants Obstetric diagnosis (fetus falling off curve) Major cause: inadequate delivery of substrates to the fetus (abnormalities in utero-placental unit) Other causes: Toxins, infectious agents, maternal diseases, genetic: trisomy 13... what's affected first: weight, length and then head Either symmetric (head, length and weight are equally affected) or asymmetric (weight is most affected, length less affected, and head circumference least affected) Symmetric implies either: congenital infection* or low genetic potential for growth Asymmetric implies: chronic malnutrition and implicates the placenta |
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Amniotic Fluid
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Early production is fluid from placenta and fetal lung
After 16 weeks most is fetal urine Volume is controlled by some reabsorption across the placenta and by fetal processing, through swallowing Functions: allows free movement, cushions against injury, bacteriostatic, necessary for normal fetal lung development |
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Oligohydramnios
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< 400 ml or AFI < 8
Decreased production absent kidneys, poor renal blood flow Flow problems obstruction to urine flow Increased loss rupture of membranes kid is stuck - lung problems Fetal consequences Pulmonary hypoplasia Cord compression IUGR Orthopedic deformities |
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Polyhydramnios
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> 2,000 ml
Etiologies Absent fetal swallowing (obstruction, neuromuscular) Upper GI obstruction (duodenal atresia) Hydrops (excessive fetal extracellular fluid) |
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Hydrops fetalis
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Refers to the presence of two or more of the following abnormal fetal fluid collections:
Ascites Pleural effusion Pericardial effusion Skin edema Polyhydramnios Fetal/neonatal mortality rate is 50-90% Etiologies: (first 2 are most important) 1) Genetic (most common; aneuploidy, metabolic storage diseases) 2) Cardiovascular (structural, arrhythmias; high output failure) Vascular malformations Thoracic or abdominal lesions that obstruct venous return to the heart Severe anemia Infectious diseases Management depends on etiology |
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Hydrops fetalis as cause or effect of polyhydramnios and high output cardiac failure?
diagnosis?? causes of HF? types? |
Hydrops can cause polyhydramnios if the severity of the edema causes obstruction of the esophagus, and prevents the normal passage of amniotic fluid through the GI tract. Also, it can cause polyhydramnios if the etiology of they hydrops is such that the infant's swallowing mechanisms are affected.
Hydrops, by definition is NOT high output cardiac failure. Hydrops simply implies that there are abnormal fluid accumulations in >/= 2 body compartments, specifically, skin edema, ascites, pericardial and pleural effusions. Polyhydramnios is usually a consequence of the impaired passage of amniotic fluid, as above, and is usually the last "abnormal fluid collection" to appear. Hydrops can cause polyhydramnios if the severity of the edema causes obstruction of the esophagus, and prevents the normal passage of amniotic fluid through the GI tract. Also, it can cause polyhydramnios if the etiology of they hydrops is such that the infant's swallowing mechanisms are affected. Understand that the diagnosis of hydrops is a fetal one; a neonate that develops these fluid collections after birth has anasarca, the differential for which is entirely different! High output cardiac failure can cause hydrops, as hydrops is a manifestation of in utero congestive heart failure (whether is it high output failure or low output failure). The etiology of hydrops is multifactorial, and can result from any of the items listed in the slide presentation (the most common, as I had mentioned) are genetic and cardiovascular. Not that you need to know this for my class, remember to differentiate immune hydrops from non-immune hydrops. The difference is simple; the cause of immune mediated hydrops, far and away, is immune mediated hemolysis (Rh incompatibility, ABO incompatibility), versus non-immune causes (essentially the long laundry list of things in my slide presentation). |
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Can you clarify what is meant by "symmetric" and "asymmetric" intrauterine growth restriction (IUGR)?
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Symmetric IUGR means that the weight, length, and head circumference are all equally affected. The most common cause for symmetric IUGR is genetic (things like Trisomy 13 or 18) or congenital infections that occur early (in the 1st trimester) during organogenesis, disrupting the entire fetus' normal growth potential.
If the congenital infection occurs later in preganancy, you may get asymmetric IUGR. By asymmetric, it is implied that the first growth measure to suffer is weight gain. If the insult causing growth restriction persists, or is severe enough, linear growth will then suffer, and lastly, head circumference. The most common cause of asymmetric IUGR is a deficiency in nutrient delivery, implicating the utero-placental unit. |
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hydrocephalus ex vacuo
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water took up space after brain atrophied
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neuronal numbers over age
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losses of large neurons are not as significant as those of the small ones
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sites of neuronal loss over age
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significant loss over post central and superior temporal
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changes of the neuronal synapses over age
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less interconnected with less branches in between the neurons with age
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recovery after lesion compared in old
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is impaired in old rat brain
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aging on the number of neural progenitor cells in the hippocampus
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aging does not alter the number of neural progenitor cells in the old hippocampus
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changes in neurotrophins with age
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decreased
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neurotransmitter changes with age
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Acetylcholine are decreased, but not uniform; this NT is so important for memory; decrease is max in nucleus basalis of meynert; very different from alzheimers disease
decrease in 5HT - depression in age decrease in NE decrease DA - striatum |
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enzyme changes in age
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not uniform decrease...
MAO - increase in hindbrain, frontal cortex choline acetyl transferase - down in caudate, hippocampus; while it's normal in other areas- but not the generalized fall seen in alzheimers |
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the changes in cognition w/ age are trainable?
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yes, they're not irreversible
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Dementia
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Impaired long or short term memory
suficent to interfere w/ work, normal social activities, or relationships with others -impaired abstract thinknig/judgement -impaired naming aphasia, apraxia, agnosia visual spacial difficulties -personality change these are not normal agning |
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plaques and tangles
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alzheimers
helical fibers make up the tangles |
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delerium comes when?
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old brain + systemic stress
-infxn, MI, drugs ---> can make a cognitively normal person confused this confusion is associated with increased mortality marker for brain reserve limitation |
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delerium def
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reduced ability to maintain and shift attention
disorganized thinking at least two of the following -reduced consciousness -perceptual disturbances -sleep-wake cycle disturbance -psychomotor activity increased or decreased -disorientation to time, place or person -memory or learning impairment features that develop over hours or days and fluctuate during the day |
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attention and inattention test for older pple
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say months backwards - care about whether they stay on task - not really if they get the answers right
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fMRI shows young vs old
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old brain has to work harder to get an answer
they're compensating/using reserves since the reserves are all being used, it's easier to cross the precipice |
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spinal cord changes w/ age
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drop in lumbosarcal then in the thoracic cord
30-50% decrease in anterior horn cells in lumbosacra 30% loss of myelinated fibers in posterior root ganglia similar losses in lateral white columns |
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implications of age changes on PE
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absence of achilles tendon reflex
decreased vibratory sense in both feet limited up gaze beyond horizontal impaired rapid altering movements sluggish pupillary reflexes diminshed light touch can't stand on one leg and can't draw a 2D representation of 3D objects; |
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age changes in SNS
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baroreceptors decreased
heart response to b-agonists is decreased dilitation response to b-agonists is decreased plasma NE is increased, NE turnover is increased, .. |
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NE when standing up
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response of NE is actually increased with age - the responsiveness seems to be maintained
that's an alpha phenomenon whierd since we know that the responsiveness of the SNS is decreased; |
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sinus arrythmia with age
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very small changes in heart rate with respiration - with age
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falls, orthostatic hypotension and old people
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falls are common
20min after breakfast is increased bc blood going to intestine risks: increased sway without visual input - decreased proprioception, loss of cerebellar neurons, slower light dark accomodation, weakness of ankle muscles, orthostatic hypotension, slowed reaction time, 50% are accidental - so all this might not help/explain the fall |
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% of body weight in newborn vs adult
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In the newborn, the brain makes up over 10% of the body weight, while it constitutes 2% in adults
In full term infants, the brain weighs 350 g By 1 year of age, the brain weighs 1000 g At puberty the brain weighs 1250 g in girls and 1375 g in boys. |
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major events in brain development
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Major events in brain development:
Neural tube formation Gross brain development Neuronal proliferation and migration |
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Neural tube formation
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The nervous system develops from the neural plate (composed of embryonic ectoderm)
The neural plate subsequently forms the neural tube and the neural crest The neural tube and neural plate will form the brain and spinal cord Closes by 27-28 days of development Fusion of NT starts in the cervical region and progresses both in a cephalad and caudad direction |
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Anencephaly
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Prevalence of 9.4/100,000 live births
2-4% recurrence risk if one sibling had it, 10% if 2 had it Risk factors include Caucasian race and mothers at either age extreme Up to 12.7% can have associated findings of cleft lip/palate, omphalocele Brainstem function (breathing, sucking, gag) are usually present Death occurs in vast majority by 2 days, all by 2 weeks failure to close is in the midline - if you have one, you're likely to have more midline abnormalities - cleft palate, undescended testes... |
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Encephalocele
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Herniation of brain and/or meninges through a defect in skull
Can be occipital (~75%), nasopharyngeal, or parietal Up to 5/10,000 live births Can be isolated or part of a syndrome (e.g., Meckel Gruber), and recurrence is dependent on this Size can be highly variable, as well as contents Impairment dependent on location and size of defect Management is surgical |
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material in sac - encephalocele
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non functioning neural tissue
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Spina Bifida
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Most common neural tube defect (NTD)
Failure of the neural tube to close Associated with Chiari II malformation downward displacement of cerebellar tonsills and medulla Impairs flow of CSF through posterior fossa, leading to hydrocephalus Outcomes depend on level of lesion --> higher the lesion, the worse the outcome |
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Chiari II Malformation
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Cerebellar tonsil herniation – chiari II
Meningocele Meningomyelocele |
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Spina Bifida Occulta
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May not cause neurdevelopmental diffuculties until later in infancy and childhood
Delay in developing sphincter control Delay in walking or gait disturbances Asymmetry of legs/feet Pain in the back/legs |
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Gross CNS Development
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Division of the neural tube due to formation of vesicles and flexures
Differential growth rates result in formation of cerebral hemispheres, deep nuclei, midbrain, pons, medulla, and cerebellum 3 primary brain vesicles form during 4th week of gestation (forebrain-prosenecephalon, mesencephalon, diencephalon) Formation of commissures begins between 6 & 12 weeks (we look at the Corpus Callosum first) |
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Holoprosencephaly
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1 in 15,000 live births (most pregnancies spontaneously abort)
Severe facial anomalies may be present (ex. cyclops) Up to 30% have normal facies Most infants are severely affected, exhibiting total failure of neurodevelopmental advancement maybe just one central incisor |
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Agenesis of the Corpus Callosum
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Can be an asymptomatic malformation
If neurodevelopment is abnormal, this malformation is not isolated (associated anomalies: Chiari malformation, encephalocele, holoprosencephaly) if there are any developmental delay it's probably not isolated agenesis, but syndromic gyri become more radial without the corpus |
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Neuronal Proliferation & Migration
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All neurons and glia are derived from the subependymal cells located in the ventricular and subventricular zones
defects in migration are worse Neuronal proliferation largely occurs between 40-110 days of gestation Migration occurs between 40-190 days During this proliferation and migration, fissuration of the brain occurs The relative size and proportions of the brain and its subdivisions do not match the adult brain until 2 years of life As opposed to proliferation disorders, migration disorders result in overt brain malformations, whose hallmark is aberrant gyral development |
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Micrencephaly
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Due to impaired proliferation -> a small but well-formed brain is seen
Newborns may not show neurologic abnormalities Subsequent striking neurodevelopmental delay occurs not 100%, Dr. Feign was micrencephaly |
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Schizencephaly
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split in the brain
Agenesis of a portion of the germinative zones, resulting in a gap in the cerebral wall (a cleft) Bilateral --> more likely to result in cognitive, motor disturbances and seizures vs. unilateral Prognosis depends on size and location of defect |
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Lissencephaly
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Can have normal head size at birth, then microcephaly
Initial hypotonia, evolving into hypertonia Paucity of spontaneous movements Feeding disorders |
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Polymicrogyria
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Multitude of small gyri
Severe hypotonia and weakness Poor responses to visual, acoustic, tactile stimuli Seizures and severe developmental delay |
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Initial Assessment of neonate
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Alertness
Tone and bulk Able to bear weight Jittery? Irritable? “Primitive” reflexes |
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Babinski
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gone by 12mo
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Grasp
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weak at 3mo, dissapear by 12mo
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Moro
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disseapear by 3-4mo
stimulated by sudden move, loud noise |
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root/suck
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dissapear by 3-4mo
stimulated by cheek/side of mouth stroke |
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stepping
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dissapear by 3-4mo
infant held upright feet touched to flat surface |
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asymmetric tonic neck
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stimulated: while supine, neck turned to one side so that chin is above shoulder
fencer position dissapear by 2-3mo |
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changes of the CNS with aging overview
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brain weight
loss of neurons (more in the large than in the small neurons - some evidence for regeneration) reduced synaptic density neurofibrillary tangles (alzheimers) neuritic plaques "intellectual function" |
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heterogenous loss of neurons with age
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post-central gyrus is not decreased,
but the superior temporal is decreased, as well as pre-central |
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synapses density with age
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decreased synaptic connections
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recovery after injury change with age
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worse recovery with age,
it takes way longer, and less |
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changes in neurotrophins with age
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nerve growth factor and IGF-1 both produced locally
keys to happy and healthy neurons local decreases in both neurotropins in old rats data suggestive but less conclusive in older healthy people |
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muscle mass in age
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mass decreases, there is replacement of fat in between; also there is fat inside the muscle
30-40% from age 30-80 not linear, loss may accelerate with age muscle loss makes up most of the loss of the lean body mass seen iwth aging = Termed "sarcopenia" Creatinine production (primarily in muscle) decreases 50% from 25-90 kidney function goes down by 30%, creatinine goes up by 30% so if you measure the serum creatinine of an old person - guess what - it hasn't changed at all! it fools you because the creatinine production also goes down |
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implications of sarcopenia
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is bad
implicated in decrease performance and increase number of falls removes reserves do that bed rest may be permanent contributes to metabolic abnormalities of elderly -insulin resistance -cold intolerance |
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what is so bad about the loss of muscle bulk with age?
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major factor in decreased muscle strength with aging is decrease in muscle bulk:
-young are stronger then mass predicts -old are slightly weaker than mass predicts increased intramuscular fat with age: -at age 40, non-contractile tissue is 8% of CSA -at age 70, non-contractile tissue is 18% of CSA old muscle is injured more easily and recovers more slowly |
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decreases in strength with age
legs vs arms? men vs women? grip experiment? but |
From age 20-70, strength decreases 50% in legs
-non-linear decline -accelerates with increasing age -30% decrease in strength from 50-70 -80 year olds are 30% weaker at knee extensor than at 70 Loss of smaller when corrected for loss in muscle mass (bc there is an independent factor: the nerves) decrease is same in men and women, so old women are the ones getting in trouble Legs loose faster, but arms and hands also decrease: grip strength decreases with age in a non linear fashion - it's maintained till about 50 and then it plummets GM study of assembly line: you can counter this age related decrease by use .. |
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decreased endurance of muscles with age?
perfusion? |
Decreased strenght (review):
40% decrease overall (average of arms and legs), wide variation between muscle groups upper body strength decreases LESS rapidly than leg Important role of activity - you can counteract the changes Decrease in endurance: Older pple fatigue faster than young ones, remaining muscle working at greater percentage of maximum function Decrease in number of capillaries per motor unit decreased maximum blood flow when you students contract there is no flow normally - in the old, however, they can't make enough force to close off their arteries - so some actually have more endurance-? not all obvious no, the endurance is less, because any perfusion that gets there is not going to make that old muscle contract harder modest decrease in blood flow at rest important decreases in maximal flow maximal oxygen extraction decreased with age muscle capillary density unchanged with age |
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Which fibers are most sensitive to aging?
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Fibers with highest myosin ATPase most sensitive to aging.
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muscle transplantation
experiments |
gives insight into site of lesions
young to old - looks bad old into young - looks ok -transplant EDL from 24m to 4m rats: graft functions well, not perfect, but the muscle looks pretty good -transplant from 4m to 24m rat poor regeneration, poor function so the key is the nerve component; the muscle component too, but nerve is more imptt |
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energetics in the muscle - aging
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can't maintain energetics while the muscle is contracting
decreased aerobic potential, and oxidative capacity decreased mitochondrial mass and mitochondrial concentration per g muscle non-invasive NMR study showes impaired Creatine Phosphate resynthesis Anaerobic metabolism is unchanged but key is, once it stops contracting, the ability to replenish creat phos is very diminished Altered energetics: Glycolytic > oxidative decreases in enzyme activity. Triose-phosphate dehydrogenase decreases with age. Lactate dehydrogenase decreases. Glycerol-3-phosphate dehydrogenase decreases |
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conctractile protein synthesis problems
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decreased rates of synthesis and degradation with aging, BUT the rate of synthesis is slowed less than the degadation --> net protein loss
but there is a discoordination: old rate have decreased mRNA for a-skeletal actin, normal for b-myosin heavy chain short term studies unenlightening relevant to long term changes rate of contraction/relaxation: force seems same, but it takes a long time to relax and replenish the Ca into the muscle |
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satellite cells with aging
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key for repair, growth and remodeling of muscle;
deficits in repair are apparent early in life Limited proliferative potential has implications for cell-based gene therapy of muscular diseases -this is evident in DMD... dedifferentiation to fat cells |
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old muscle injury
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slower to recover after damage
decrease in pluripotent satellite cells much smaller colony size in vitro after 6 wk in a cast: older people never return to pre-cast level of strenght and bulk |
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aging vs inactivity
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diaphragm relatively resistant to change
evidence that some aging effect is due to inactivity |
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anabolic hormones changes in aging
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not enough GH or IGF-1
response to IGF-1 and anabolic steroids is unchanged, but giving IGF-1 doesn't really help for atrophy. |
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chronic pain syndrome, female with cough
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on aspirin -- and then asthma due to lipoxygenases that are not inhbited
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staccato cough neonate
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Chlamydia trachomatis
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resistance training for older ladies showed
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huge changes in strength (145%) , less changes in mass (10%);
First: 7.5kg was what they lifted before that's weak! after 8weeks: 20kg BUT: most of the gain they had in the first week - it was a cognitive thing most of the actual change probably occurred at the neuromuscular junction |
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cartilage.joints changes with aging
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decreased ability to hold water
the proteoglycan aggegates fragment increased keratin sulphate and hyaluronidase |
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bone changes with age
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not so much like osteoporosis of menopause
the bone loss is parallel in ageing (women lower due to menopausal loss of bone) deposition slower than erosion, increased likelyhood for collapse, (bone marrow density does not perfectly predict fracture risk, also some microarchitecture) imbalance of osteoblast and clast - it is same as the estrogen associated in menopause - there's net bone loss due to: Osteoblasts are greatly reduced and oseoclasts are reduced but less so, bone marrow precursors are decreased skull gets thicker with age Sun-block problem --> changes in vit D metabolism GI CA decreases after age 70 -nutrition, exercise and vascular and neurological |
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ethnic differences bone mass
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blacks have more sk mass at any age
-lower risk of hip fracture... |
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summary
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Sk muscle decreases in mass, strength and quality with aging.
part of changes are due to changes at the NMJ resistance exercise can modify performance old joints work less well, but age does not equal osteoarthritis bone loss is also an age-related phenomenon in men and women |
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Review of muscle types
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type I - slow - dark meat
type II - fast IIa fast oxidative IIb fast glycolytic - white meat IIx fast motor nerve unit innervates only one type - The nerve determines what type the muscle is - so with reinnervation it can change it's type type is not intrinsic to the muscle |
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Age alterations in muscle composition
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Preferential loss of type II (fast), especially IIb (glycolytic - white), but type I (oxydative) also decrease
relative enrichment of type I Loss of strength correlates strongly with decrease in type II fibers Controversy exists as to the extent of this observation -Nerve changes can prompt switch from II to I as precursor to fallout Loss of total number of fibers and decrease in CSA of each fiber, especially type II Besides the type, also: A look inside: -increased lupofuscin deposition (long chain oxidized fat) -reduced size of myofibrils -loss in cross-sectional area of each myofibril is greater than loss in number of myofibrils -reduced number of myofibrils -increased connective tissue and fat |
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Changes at or proximal to the NMJ
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The number of Motor units decrease by 50% with age
Similar to relative denervation -loss of alpha motorneurons and re-innervation results in inefficient large motor units (one nerve is innervating more and more muscles) -mass of muscle preserved -strength of muscle declines in part bc stimulation failure In isolated nerve-muscle preparations -tension developed by old muscle is relatively well preserved after nerve stimulation hypoinnervated -decreased number of motor units -motor units enlarged as compensation -newly formed synapses are unstable -failure of synaptic transmission becomes more frequent -up to 25% of motor units essentially non-functional -many motor neurons have huge arbors -muscle not denervated but hypoinnervated -nerves provide growth TROPHIC factors for muscle and may determine the muscle fiber type -this becomes much more important after age 70 |
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Develop a differential diagnosis for limp in children
pain? |
Infections (septic arthritis, osteomyelitis, synovitis, meningitis)
Orthopedic/Mechanical (DDH (NOT PAINFUL aft first), fractures(pain), osteochondrosis) Neoplastic (toddler: neuroblastoma, Leukemia, infant/adolescent: osteosarcoma, osteoma, Ewing's sarcoma) Neuromuscular (Muscular dystrophy, Peripheral neuropathy, hereditary neuropathy) Rheumatologic (Henoch Schoenlein purpura, SLE, in adoleschents SLE and gout/pseudogout) Hematologic (sickle cell crisis, hemophilia) Intra-abdominal (appendicitis, Psoas absess, for adolescents also: PID and testicular torsion) |
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Identify risk factors for developmental dysplasia of the hip (DDH)
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Single umbilical artery (kidneys abnormalities go along with this)
Imperforate anus RUS: malformed, horseshoe kidney Chromosomes: normal (usually are!) [the karyotype will anyway] More common in females, type1DM, and cocaine-exposed mothers Prognosis largely dependent on associated anomalies Usually neurologic involvement in affected segments |
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Understand the types of craniosynostoses and their associated abnormalities
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Most common: Sagittal Synostosis (Scaphocephaly)
Metopic Synostosis (Trigonocephaly) Bicoronal Synostosis (Brachycephaly) Unilateral Coronal Synostosis (Frontal Plagiocephaly) Occipital Plagiocephaly (Unilambdoid Synostosis) Associations: Thalassemia Hyperthyroidism Mucopolysaccharoidoses Rickets Genetic Syndromes (ex. Apert, Crouzon) Diseases of the CNS (ex. micrencephaly) Risks: Risk Factors 1. Caucasian mother 2. Advanced maternal age 3. Male infant 4. Maternal Tobacco abuse 5. Mother living at high altitude 6. Fertility treatments 7. Paternal occupation in agriculture, forestry, mechanics 8. Maternal exposure to nitrosatables 1. Nitrofurantoin 2. Chlorpheniramine |
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Caudal dysgenesis
highly associated with |
Maternal Diabetes Mellitus - not well controlled
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Skeletal components arise from ...
when? Differentiation into |
mesoderm, in the 3rd week of gestation
Differentiation in the 4th week into: Fibroblasts Chondroblasts Osteoblasts --> Bone |
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Caudal dysgenesis:
risks prognosis neurologic problems? |
Defect originating during 3rd week of gestation, with other anomalies
Single umbilical artery (kidneys abnormalities go along with this) Imperforate anus RUS: malformed, horseshoe kidney Chromosomes: normal (usually are!) [the karyotype will anyway] More common in males, type1DM, and cocaine-exposed mothers Prognosis largely dependent on associated anomalies Usually neurologic involvement in affected segments |
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Case 2: Term female infant
Born with shortened limbs, abnormal facies, moderate respiratory distress X-ray shows destroyed femur |
Osteogenesis Imperfecta
Collagen I is abnormal; NOT a defect in bone mineralization or calcium accretion Defect is in collagen: nearly 400 mutations identified Result in bone fragility and deformity Collagen also found in ligaments, tendons, skin, sclera, and dentin there are 4 subtypes: I is mildest (blue sclera all life) II severe III severe IV mild |
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4 subtypes of OI
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Type I
Mildest type Can be autosomal dominant 5-15 x increased risk fractures Distinctive blue sclera throughout life Conductive hearing loss 2nd decade Aortic dissection Type II Perinatal onset, most severe OI Sporadic Short limbs, fractures in utero Blue sclera Broad, crumpled femurs Beading of ribs Fatal (pump in Ca, but the scaffolding is not present) Type III Severe, sporadic May have fractures at birth (long bones & skull especially) Postnatal fractures lead to short stature & kyphosis Triangular face Shortened life span—pulmonary death NORMAL SCLERA Type IV Fairly mild Autosomal dominant Not uncommonly diagnosed after childhood NORMAL SCLERA I and IV are AD the other sporadic; I is mildest, IV is mild; I has blue sclera thoughout; |
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Limb Development
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Limb buds form in the 5th week of gestation
Mesenchyme with cover of ectoderm Fingers and toes are formed by 8 weeks Absence of part of limb: meromelia Absence of a majority of limb: phocomelia Absence of entire limb: amelia Extra digits: polydactyly Fusion of digits: syndactyly There may be combined defects (i.e., polysyndactyly) |
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different dactylys
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Absence of part of limb: meromelia
Absence of a majority of limb: phocomelia [a flipper-like appendage attached to the trunk] Absence of entire limb: amelia Extra digits: polydactyly Fusion of digits: syndactyly There may be combined defects (i.e., polysyndactyly) |
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amniotic band syndrome
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amniotic band syndrome = abl fibrous bands through amniotic cavity – and this band will amputate where it hits;
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causes of developmental limb disorders
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some have genetic basis; some have acquired such as: amniotic band syndrome
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A first time mother brings in her 2 week old baby girl for routine examination
Was born breech, but no other complications On exam, you find: assymetric gluteal folds.. |
Developmental Dysplasia of the Hip:
Describes abnormal development of the hip with respect to instability of the joint and dysplasia of the acetabulum Hip instability can be a normal finding in up to 40% of infants True DDH occurs in 1-2/1000 births More common in: Females Breech position Caucasians Left hip cause: Acetabulum is very shallow at first; the head of the femur keeps banging into it – and this causes the acetabulum to fold; a child without nl kicking motion – not flexing at the hip; child born breech hasn’t has the same movements in utero; there’s a chance it’ll be dislocated and permanently = femoral dysplasia of hip It can be nl to feel a click in the first week of like – the maternal estrogen makes that joint a little bit lax – when the E fades, that’s when you can truly tell; so you get X-ray in 4-6wks |
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tests for DDH
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Barlow and/or Ortalani maneuvers:
Barlow: posterior pressure with knee in 90degree Ortalani: same but then abducted; listen for click or brute clunk PE: note assymetric posterior thigh creases, leg length discrepancy BUT: not reliable after 6-8 weeks U/S is typical diagnostic modality at 4-6 wks. If not diagnosed in timely fashion, child can have progressive degenerative hip disease Early diagnosis—may be able to correct with Pavlick harness -this thing is 24h for 6-9 weeks and they're NOT happy! |
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babies with DDH most commonly are...
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More common in:
Females Breech position Caucasians Left hip |
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Skull Development: whats cell origin
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Viscerocranium—flat bones of face, forms from neural crest cells
Neurocranium—from mesenchyme -Chondrocranium—base of skull -Flat bones of the remaining skull (non-facial) |
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Craniosynostosis
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Premature closure of the sutures
Sutures usually fuse around 15-24 months Can be autosomal dominant Scaphocephaly is most common (55% of cases) Boys affected more than girls 4:1 No racial differences Growth of the skull occurs PARALLELL to the closed suture More likely to have other associated abnormalities if >1 suture is involved, or for paired sutures, if bilateral involvement |
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Normal Gait development
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At 10-18 months, wide based gait with some bowing of the legs and arms outstretched, flat feet
At 2-3 years, stance becomes more narrow based, with more approximation of knees, still flat feet At 3-4 years, an adult gait is established At 4-5 years, vast majority of kids no longer have flat feet |
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Abnormal Gaits
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Toe walking after 2-3 years of age
In-toeing/knee-knocking Metatarsus adductus Limping |
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Limb Dx, now what?
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Every child with a limb also needs a rectal exam
Workup depends on etiology History will help narrow the DDx Acuity of onset Obvious physical findings (joint swelling, pain, erythema, etc.) Other associated findings (easy bruising, viral prodrome, etc.) Lab work (elevated ESR, C-reactive protein, imaging, etc.) Treatment will depend on etiology |
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Presentation of Primary Immune Deficiency
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“Classic” presentation
Male Newborn – 5 years of age ↑ frequency of “normal” infections (e.g., otitis media) Eczema Autoimmune diseases (vasculitis, hemolytic anemia, SLE) |
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10 month male
History of H. flu otitis at 6 months Mom also reports “bad” eye infection in the neonatal period (medical record describes “gonococcus grew from eye discharge”) Infant presenting with fever, continuous crying (‘inconsolable’), poor feeding x 2 days, and rash x 6 hours Full sepsis evaluation performed CBC showed increased WBCs, with left shift in differential CSF 125k WBCs/hpf GPC in pairs CSF grew Neisseria meningiditis in 12 hrs. You check a CH50 [total hemolytic activity of serum—assesses complement system] CH50 is low |
H. flu in an immunized child is not nl
rash is called pupura fulminans - N.meningitidis point: Of the N.Meningiditis, H.influ, and Gonnorhea, you look at the recurrant N.Meningiditis = think terminal complement deficiency C56789 Complement Deficiency: Pyogenic infections (H. flu OM at 6 months) Gonococcal eye infection at 3 months [usually in the first days if it's passed at birth, the topicals don't kill all the gonococcus, but more of the chlamydia] Meningococcal meningitis currently Neisseria infections --> think terminal complement deficiency |
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11 month old male
3 episodes otitis media since birth Now with fever x 2 months Mom states “He’s acting sicker than when we came in 3 weeks ago” “Just completed the medicine for the abscesses that were lanced at that time” You quickly examine him: Mouth exam as shown, RR 70s, nasal flaring, intercostal retractions, grunting Would you like to place a saturation monitor & get a blood gas? Saturation 81% (room air) ABG 7.22, pCO2 67, pO2 54 Next step? Your resident suggests a nitroblue tetrazolium (NBT) dye reduction test NBT test is abnormal (less blue) Diagnosis? |
You intubate him; tracheal aspirate grows Candida
CBC is normal IgG is elevated Diagnosis? NBT - the oxidative burst is tested, the dye can't be changed in color if you're missing it -Abscesses -Candida pneumonia, thrush [Thrush in mouth is not abnormal, but Candida is abnormal] -Normal WBC, elevated IgG -Think of phagocytic defect -Check for abnormal NBT Chronic Granulomatous Disease Abnormal oxidative killing mechanisms of phagocytes (can’t produce “oxidative burst”) -Abnormal NBT Leads to granuloma formation class of organisms that kids with CGD is more susceptible to: bacteria that produce catalase. This breaks H2O2, so whatever this kid had left of that is destroyed [staph aureus] |
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Male
“Keeps a head cold” “Keeps a diaper rash” Mom brought him in for a new rash Mom states that his previous rashes cleared up pretty good when she used some of Grandpa’s eczema cream on him ‘But this one just keeps getting worse’: -pustular rash all over -scraping shows: FUNGUS Remainder of exam unremarkable WBC 10k (normal, borderline) Diff: 10 segs, 75 lymphs, 15 monos Platelets 78k (low) Lab calls with an unusual finding on review of the blood smear: Basophilic giant granule in cytoplasm of neutrophils Appearance: Oculocutaneous albinism Rash (h/o eczema) CBC with neutropenia, thrombocytopenia Abnormal granules in WBCs Rash consistent with disseminated Candida Diagnosis? |
Chediak-Higashi Syndrome
Impaired intracellular killing in phagocytosis due to abnormal lysosome packaging [microtubular polymerization defect] Giant cytoplasmic granules in peripheral PMNs |
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class of organisms that kids with CGD is more susceptible to:
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class of organisms that kids with CGD is more susceptible to:
bacteria that produce catalase. This breaks H2O2, so whatever this kid had left of that is destroyed [staph aureus] |
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9 month male
PMHx 3 episodes of otitis media Pneumococcal pneumonia at 6 months Mom brings him in for “bad diarrhea” Dry mucous membranes, no tears (mom states diarrhea for a week) Lungs clear, abdomen soft but somewhat tender (no significant guarding) Do you want to send a stool sample? Organism identified in the diarrheal stool: Giardia CBC shows low WBC Ig G <100mg/dL; no detectable IgM or IgA Giardia diarrhea, low immunoglobulins = suspect B cell defect You decide to order Total B cells Total T cells, T helper & T suppressor cells & ratio Normal to increased mature T lymphs B cells undetectably low Diagnosis? |
X-linked agammaglobulinemia:
... supposed to see a thymic shadow... XLA patients do not generate mature B cells.[2] B cells are part of the immune system and normally manufacture antibodies (called immunoglobulins) which defends the body from infections by sustaining an immunological humoral antibody response. Patients with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Bruton's tyrosine kinase (Btk) gene which leads to a severe block in B cell development (at the pro-B to pre B cell stage) and a reduced peripheral IgG Immunoglobulin antibody production in the serum. Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR. [3] Patients typically present in early childhood with recurrent infections, particularly with extracellular, encapsulated bacteria.[4] It occurs in a frequency of about 1 in 100,000 male newborns, and has no ethnic predisposition. XLA is treated by infusion of human antibody. Treatment with pooled gamma globulin cannot restore a functional population of B cells, but it is sufficient to reduce the severity and number of infections due to the passive immunity granted by the exogenous antibodies.[4] XLA is caused by a mutation on the X chromosome of a single gene identified in 1993 and known as Bruton's tyrosine kinase, or Btk other considerations: XLA patients are specifically susceptible to viruses of the Enterovirus family, and mostly to: polio virus, coxsackie virus (hand, foot, and mouth disease) and Echoviruses. These may cause severe central nervous system conditions as chronic encephalitis, meningitis and death. An experimental anti-viral agent, pleconaril, is active against picornaviruses. XLA patients, however, are apparently immune to the Epstein-Barr virus (EBV), as they lack B cells needed for the viral infection.[citation needed] It is not known if XLA patients are able to generate an allergic reaction, as they lack functional IgE antibodies. There is no special hazard for XLA patients in dealing with pets or outdoor activities.[4] Unlike in other primary immunodeficiencies XLA patients are at no greater risk for developing autoimmune illnesses. Agammaglobulinemia (XLA) is similar to the primary immunodeficiency disorder Hypogammaglobulinemia (CVID), and their clinical conditions and treatment are almost identical. However, while XLA is a congenital disorder, with known genetic causes, CVID may occur in adulthood and its causes are not yet understood. XLA was also historically mistaken as Severe Combined Immunodeficiency (SCID), a much more severe immune deficiency ("Bubble boys"). |
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Combined Defect:Severe Combined Immunodeficiency (SCID)
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Lack of T cell differentiation & proliferation, and sometimes also NK
Immunoglobulin production severely impaired (B cells present) Presents by 3 months Classic presentation: diarrhea, dermatitis, & FTT Absent peripheral lymphoid tissue Small, atrophic thymus (CXR) Eventually see opportunistic infections (P. carinii) Common childhood viruses usually fatal CMV pneumonia common & often fatal Anergic Severe lymphopenia (<1200/mm3) |
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effect of B cell - aging in mouse
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better to have more Ig's
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effect of T cell - aging - in mouse
test measured the mouse's response to PHA |
??
depending on the pathogen.. |
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Lymphocyte responsiveness to mitogen in aging
causes |
the responsiveness is associated with survival of humans
if they didn't respond to the mitogen at all, it's bad for survival the responses are decreased for Succinyl CoA thymus goes away |
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Antibody response to Flu vaccine with age
why give it? |
quantity decreased (1/3)
antibody affinity decreased (the shape is not so good) it protects them from dying from flu, but not from getting it or spreading it risk of develop influenza disease after immunization is highest among elderly demonstrating neither antibody not cell-mediated responses only 17% had an adqaute response to the quadrivalent response. 47% had no immune response to any of the antigens Fly vaccine is given to elderly bc it decreases with mortality associated with influenza, but it doesn't protect them well from getting and spreading herd immunity will not occur in old now we immunize nurses there's no change in aging with CD4/CD8 cells, so the problem is with the response itself |
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IL-2 production with age
|
IL2 is key to stimulate T cells
decreased when old ppls T-cells are activated the receptor's are decreased in number and affinity. supplemental IL2 improves mitogen response, but it won't reconstitute the immune system -- the affinity is just too low |
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memory cells with age
|
CD45RO+ cells accumulate with age
the naive Tcells CD45RA+ are decreased |
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Case: 85yo
had no fever, no real cough, no chills, not much WBC, with CXR with streaky lobe, mental changes how is there evidence for disease? Dx? |
Pneumonia
pneumo |
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Autosomal recessive
X-linked recessive |
Enzyme deficiencies (except Hunters and Fabry's which are X-linked)
Be Wise Fool's GOLD Heeds False Hope A Birte Wolff Has GOLD For A Head -Bruton -Wiskott -Fragile X -G6pd -Ocular albinism -Lesch-Nyhan -Duchenne -Hemophilia A/B -Fabry -Hunter's -Adenoleukodystrophy |
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local defenses of elderly
|
the mucociliary mechanism in the lung does not recover, so then they get sick again, this time with a bacterial infection
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...mised slide
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missed
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missed slide
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missed again
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prevalence of autoantibodies
|
increase with age
"anti-Thyroglobulin with normal thyroid can be seen in age" the effector immune system is messed up, so the factors are there, but they don't respond to disease bc the rest of the apparatus is not working |
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MGUS
|
monoclonal gammopathies of undetermined signifiance
10% of healthy old some get myeloma marker for... |
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Toll-like receptors
with age |
worms and flies have not immune system but they have this!
with age in mice, the response to TLR is decreased (IL6) with age - but evidence is not clear in people |
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Inflam-Aging??
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???
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Age and:
Thymus, IL-2 response of T-cells to mitogens anti-idiotype antibodies lvl of specific antibody response presence of autoimmune antibodies incidence of serum monoclonal immunoproteins delayed type hypersensitivity |
decreased/absent Thymus,
decreased IL-2 decreased response of T-cells to mitogens anti-idiotype antibodies not off decreased lvl of specific antibody response increased presence of autoimmune antibodies increased incidence of serum monoclonal immunoproteins decreased delayed type hypersensitivity |
