Shanklin Notes

Shanklin Notes

Tomorrow-stay home and study. Net week-think.
Many aspects of disease are straightforward. Neoplasms, inflammation, etc. The fifth column is development. How does the organism get to a mature state?
Gametes merge to form a blastocyst. Programming for development is in DNA.
Development is change from gametic genetic structure to a recognizable meso and gross structure which can contribute to furtherance of the species. Virus only does it with proper host.
What about bacteria?
Bacteria need a host to thrive.
Function of organisms is a function of the environment in which you find them.
Conserved genetic structures have common features. Adults are generally in stasis in terms of cessation of development. Not all tissues are at end of their developmental possibilities. Development is not always a straight line reaction. Sometimes there are retrogressions. Bile duct comes off liver. In healthy adult person it is a cylinder. In developing embryo it is a solid core of cells which have to change by apoptosis in center to restructure. Some cells differentiate into lining biliary epithelium.
Early aorta has series of arches in neck .Some retrogress by apoptosis or become incorporated. in other structures like left brachial artery.
Vertebrate body has rough bilateral symmetry. Adult kidneys are the third set to be formed. Babies with malformed kidneys are arrested at second stage.
Some fish have no glomeruli.
Kidneys have endocrine function-Vitamin D, erythropoetin, renin. We think of them as excretory, but has function above that.
Ex: lung has to do with estrogen metabolism in female.
Some deviations in development are significant- malformations or anomalies, or deformity in clinical situations. Malformation is alteration in structure.
During 3 stages of kidney formation, body is getting longer. Kidneys start near urethra. Body grows toward head from stimulus from neural tube.Kidneys move to wind up in mid body. Energy is used to reposition kidney. 1st gives way to mesonephros. 1st pronephros first, then meso (involved in movement), then metanephros. If signal does not go through, embryo gets stuck with mesonephros. Cannot adjust, so become cystic (cystic dysplasia). iThis can happen only on one side. Inducer after a period of time is within the organ itself.
Each kidney has one renal artery most of the time. Accessory renal artery can exist because supernumary vessel can be connected near upper pole. Ureter grows and gets longer. If you have a lower pole accessory it contacts ureter.Physical pressure could obstruct ureter. Backup causes renal pelvis to dilate.Residual pressure shuts down opening and backs up into kidney proper-interstital response- secretion- high blood pressure. Failure at 10-11weeks of development causes high blood pressure later, cured if renal artery is cut. If cyst is left from deviation, can alter flow and efficiency.
Renal interstitial cell= Renal arteries break up into lobars or interlobar into arcuate arteries into interlobular .Control depends on nerve sructure. We have between 3 nd 4 times the kidney we need.
Structure is highly integrated functionally. What does renal tubule do?
Developing kidney passes urine into amniotic fluid. The fluid turns over . Turnover rate of sodium is 30 min. Tracer substance can be used to determine this. (deuterium oxide in solution) Loss followed over time to get exchange rate.
Low dose Na24 and see what is picked up . mg/s exchange.
When organs start to function but are not mature,function augments their maturation. Know when functions begin.
Original heart is a tube with a receiving chamber and a pumping chamber. It has serial components. How does it become parallel?
What part of early embryo produces lungs? Part of foregut forms trachea and bronchi which secrete inducers into parenchyma to create lung.
When we look at the original truncus, it has cushions on either side. They grow to meet in middle. A helical form diverts one functional flow away from the other. Endocardial cushion is a complex process. Structures get bigger and orient to split.One to protolung and one to periphery. Malformations arise which are important. Endocardial cushion defect-Root of aorta meets membranous portion of interatrial spetum. This membrane is gone in the defect. Biventricular heart do not survive. Mild is correctible with surgery.
One of remnants of arch is ductus arteriosus- shunts blood from right ventricle back to aorta. regresses after birth. Once oxygen tension rises with breathing it constricts, then undergoes fibrous replacement by apoptotic involution. Not proper- blood retrogrades into lung and harms vessels- pulmonary hypertension. What if media is incorporated into aorta- causes coarctation. The localization of specialized tissue is as important as its function. Common bile duct passes through pancreas before emptying into duodenum. What if duct is misplaced or absent? Buffering is necessary for operation of intestinal enzymes.
Pyloric stenosis, annular pancreas- cause problems.
Lesion- tumor can be one, inflammatory response can be, bullet hole can be. What about a biochemical lesion? Absence of enzyme, disordered electrolyte compartment, rise in serum potassium following muscle injury? Often before you see change in cells you see changes in function.Lesion is abnormality usually defined by location and sequence of events leading to disease. For Tuesday- think about:
Down’s synrome has genetic element. Think about evidences for epigenetic contribution. What evidence would it take to consider challenging the axiom that it is a genetic disorder?

Couldn’t make heads or tails of the lecture today? You are not alone. Try this.
http://embryology.med.unsw.edu.au/embryo.htm
Also an idea for Monday:
Original Research Communications
Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome1,2,3
S Jill James, Marta Pogribna, Igor P Pogribny, Stepan Melnyk, R Jean Hine, James B Gibson, Ping Yi, Dixie L Tafoya, David H Swenson, Vincent L Wilson and David W Gaylor
1 From the Food and Drug Administration–National Center for Toxicological Research, the Division of Biochemical Toxicology, Jefferson, AR; the University of Arkansas for Medical Sciences, the Department of Biochemistry and Molecular Biology and the Department of Dietetics and Nutrition, Little Rock; the Arkansas Children's Hospital, the Division of Pediatric Genetics, Little Rock; Trisomy-21 Research, Inc, San Jose, CA; the Saginaw Valley State University, the Department of Chemistry, University Center, MI; and the Institute for Environmental Studies and Institute for Mutagenesis, Louisiana State University, Baton Rouge.

Background: Down syndrome, or trisomy 21, is a complex genetic disease resulting from the presence of 3 copies of chromosome 21. The origin of the extra chromosome is maternal in 95% of cases and is due to the failure of normal chromosomal segregation during meiosis. Although advanced maternal age is a major risk factor for trisomy 21, most children with Down syndrome are born to mothers <30 y of age.
Objective: On the basis of evidence that abnormal folate and methyl metabolism can lead to DNA hypomethylation and abnormal chromosomal segregation, we hypothesized that the C-to-T substitution at nucleotide 677 (677CT) mutation of the methylenetetrahydrofolate reductase (MTHFR) gene may be a risk factor for maternal meiotic nondisjunction and Down syndrome in young mothers.
Design: The frequency of the MTHFR 677CT mutation was evaluated in 57 mothers of children with Down syndrome and in 50 age-matched control mothers. Ratios of plasma homocysteine to methionine and lymphocyte methotrexate cytotoxicity were measured as indicators of functional folate status.
Results: A significant increase in plasma homocysteine concentrations and lymphocyte methotrexate cytotoxicity was observed in the mothers of children with Down syndrome, consistent with abnormal folate and methyl metabolism. Mothers with the 677CT mutation had a 2.6-fold higher risk of having a child with Down syndrome than did mothers without the T substitution (odds ratio: 2.6; 95% CI: 1.2, 5.8; P < 0.03).
Conclusion: The results of this initial study indicate that folate metabolism is abnormal in mothers of children with Down syndrome and that this may be explained, in part, by a mutation in the MTHFR gene.
American Journal of Clinical Nutrition, Vol. 70, No. 4, 495-501, October 1999
© 1999 American Society for Clinical Nutrition