Shanklin Last Lectures

Shanklin 3

Developmental disorders: General Aspects, Genetic Factors

Yesterday: Response to injury is also to preserve homeostatic metabolic status of individual. Energy is stored in glycogen and ATP in muscle. Has to be replenished.
Shock can be due to surge of endotoxin or blood loss. Vital functions dampen. ATP supplies discharge. Cardiac output drops, so the organism cannot restore ATP levels.
Genetics
Historical classifications human disease
1. aggressive- neoplasms
2. reactive – inflammation
3. submissive- atrophy
4. degenerative- calcification
5. development and maturation of tissues, organs, integrated functions
Developing organs respond to disease differently from mature ones. Most newsworthy diseases are infectious.
Measles can be theoretically eliminated by vaccination. Distemper in dogs is the same virus. Vaccine introduced in 1960s. Guam had outbreak 1994 Lowered vaccination age to 6 months. The graph is the number of cases they knew about. Vaccinated everyone- seemed to stop it. Graph says nothing about natural course of epidemic. Graph might represent epiphenomenon. Course of disease, or vaccination? Does not establish cause or effect.
There are pockets of measles virus around the world. There is a similar program for polio.

Abnrmalities of Early Development:
Malformations, teratomas, neoplasms occur in course of development. Can have malignant tumors in stillborns or newborns. If a tumor is in a fetus, because of growth potential of organism, tends to be large. Brain can be replaced by glioma.
Definitions:
Syndrome- set of symptoms that occur together. Pattern of malformations in genetics morphologically related.
Medical history as a database:
Anecdotal evidence is often derided, but used a lot. Doctors make decisions based on incomplete information. Anecdote becomes falsifiable hypothesis for testing for pathologists.
Children mostly die from accidents. 10% of childhood deaths are from cancer, a lot of those from leukemia.
Congenital malformations are important. 2059 auptopsies- 953 classifiable malformations. 403 clinically significant-death due to lesions or complications of attempts to correct lesions.
Abnormal fetoplacental hemodynamics. Placenta usually ovoid disk with cord from center. If it is off, circulation can flow one direction and one twin of two may fail to develop.
Ordinary blood grouping- RH- woman with Rh+ fetus will be sensitized to factor. These days vaccine can prevent problem. Double mismatch- (O woman, A fetus)-woman destroys fetal blood cells instead of sensitizing. B is more likely to cause problems.
Anemia of prematurity- most RBC in fetus made in liver. Little marrow- gradually expands. Prematurely born can become anemic quickly. Do not absorb iron well. ABO discovered 1930s.
Achondroplasic parents can have normal babies.
1960s Human chromosome count discovered to be 46 not 48. Number is not static. Ex: XXY or XXXY in Kleinfelter’s. Phenotypic presentation implies genetic abnormality causes phenotype. Does not mean we know how it works.

Down Syndrome- trisomy 21 or group G. Down babies have similarities. Broad face, eyes far apart, tranverse crease across hands (more common in first degree relatives).
Syndrome- low to low normal birth weight, brain small for body, microcephaly and brachycephaly, trainable, cheerful and pleasant, want to be around people.
Many have visceral disease- congenital heart disease, other problems. Have 150% SOD of normal. And gal-1-phosphate uridyl transferase.
There is repeat risk. Around age 20- can get translocation of chromosome for variant of Downs. Usual explanation- older ovary, abnormal disjunction more likely. Meiosis not studied as well as mitosis. Evidence is that it increases with age. Problem: Data from ovaries not available for running commentary. “Mongoloid” is old term.

Down Syndrome and Leukemia- myoblastic leukemia in stillborn.
Rate of birth: 1: 1087. Nondisjunction is descriptive name for abnormal separation of chromosomes. Colorado has twice the rate of Kansas. People compensate for the lack of oxygen at high altitude. Spaniards took over Peru- took 2 generations of adult adaptation to produce children at high altitude. Is it a matter of oxygen? No. Nutrition matters. Fewer Down’s babies with relatively high protein diet. Monosomy 21 can look like Downs. Mosaic Down Syndrome occurs with some cells normal and some abnormal.
Survival has improved with time. May be improved diagnosis. 50 years is about their life span. The chronic disease (heart, renal, diabetes) causes problems.
Adult polycystic renal disease- manifests genetic anticipation (nucleosides that run in triplets tend to multiply- above a critical number, disease occurs in next generation earlier.) Same thing in Huntingdon’s chorea.
Epigenetics- above and beyond genetics. Methylation of cytosine may be important. Body has 10^13 cells, 1:50,000 mosaic even in normal human.

Wed PM lecture

Objectives:
Systems biology

Healing after surgery requires AA intake. We do not have protein storage. Serum albumin is most mobile of structural poteins. Easily fungible. Hard tissue most easily fungible is lymphoid tissue. Prolonged borderline starvation leads to infection.
Pathology objectives:
Understand principles and steps of pathogenesis. Can study at molecular, cellular, tissue level. Pathogenesis of disease means an event that leads to a response that leads to a lesion with various consequences. Understand principles- can look up details. We focus on human. Career options: research biologist, paraclinical area (clinical pharm), ed research, hospital diagnostics.
No class tomorrow or Friday. As far as testing, take info from previous lecturers and be able to apply it to think up a solution to a problem. He wants to see imagination, logic, and careful organization. And don’t worry about getting copies of all his notes to memorize.