Neurotransmitter Criteria

Cell Adhesion Molecule Inhibition


Glomerular Filtration


A glomerulus is a capillary tuft surrounded by Bowman's capsule in nephrons of the vertebrate kidney. It receives its blood supply from an afferent arteriole of the renal circulation. Unlike most other capillary beds, the glomerulus drains into an efferent arteriole rather than a venule. The resistance of the arterioles results in high pressure in the glomerulus aiding the process of ultrafiltration where fluids and soluble materials in the blood are forced out of the capillaries and into Bowman's capsule.




A glomerulus and its surrounding Bowman's capsule constitute a renal corpuscle, the basic filtration unit of the kidney. The rate at which blood is filtered through all of the glomeruli, and thus the measure of the overall renal function, is the glomerular filtration rate (GFR).

The first place where urine is formed in the kidney, filters fluid from the blood.


Afferent circulation

The afferent arteriole that supplies the glomerulus is a branch off of an interlobular artery in the cortex.


Layers

If a substance can pass through the endothelial cells, glomerular basement membrane, and podocytes, then it is known as ultrafiltrate, and it enters lumen of proximal tubule. Otherwise, it returns through the efferent circulation, discussed below.

Endothelial cells

The endothelial cells of the glomerulus contain numerous pores (fenestrae) that, unlike those of other fenestrated capillaries, are not spanned by diaphragms. The cells have openings which are so large that nearly anything smaller than a red blood cell passes through that layer.

Because of this, the endothelial cells lining the glomerulus are not usually considered part of the renal filtration barrier.

Glomerular basement membrane

The glomerular endothelium sits on a very thick (250-350 nm) glomerular basement membrane. It is not only uncharacteristically thick compared to most other basement membranes (40-60 nm), but it is also rich in negatively charged glycosaminoglycans such as heparan sulfate.

The negatively-charged basement membrane repels negatively-charged proteins from the blood, helping to prevent their passage into Bowman's space.

Podocytes

Podocytes line the other side of the glomerular basement membrane and form part of the lining of Bowman's space. Podocytes form a tight interdigitating network of foot processes (pedicels) that control the filtration of proteins from the capillary lumen into Bowman's space.

The space between adjacent podocyte foot processes is spanned by a slit diaphragm formed by several proteins including podocin and nephrin. In addition, foot processes have a negatively-charged coat (glycocalyx) that limits the filtration of negatively-charged molecules, such as serum albumin.

The podocytes are sometimes considered the "visceral layer of Bowman's capsule", rather than part of the glomerulus.

Intraglomerular mesangial cell

Intraglomerular mesangial cells are found in the interstitium between endothelial cells of the glomerulus. They are not part of the filtration barrier but are specialized pericytes that participate indirectly in filtration.

Testosterone Production



Animation Description: This animation represents a visual interpretation of the production of testosterone and is not indicative of clinical effectiveness.
The hypothalamus releases gonadotropin-releasing hormone (GnRH) in pulses every 60 to 90 minutes to stimulate the pulsatile release of luteinizing hormone (LH) from the pituitary gland into the bloodstream.
LH binds the LH receptor on the Leydig cells of the testes.
Binding initiates a cascade of events which include the conversion of cholesterol (depicted as LDL here) to pregnenolone followed by a series of reactions, which convert pregnenolone to testosterone.
Testosterone, secreted by the testes, diffuses into the peripheral circulation to be carried to target tissues.
In liver, muscle and adipose tissue, testosterone binds directly to its androgen receptor (AR) to exert its biological effect.
In skin, hair, the prostate gland and gonadal tissue, testosterone must be converted to dihydrotestosterone (DHT) by 5-alpha-reductase in order to bind the androgen receptor.
In bone and brain, testosterone is converted by aromatization to estradiol (E2), which binds the estrogen receptor (E2R) to carry out its effects.

There is an accompanying accredited online resource, http://www.ManagingTD.ca that contains the learning materials, as well as videos, animations & an interactive algorithm.

Classical and Alternative NF-kappaB Pathways




This animation reviews the classical and alternative NF-kappaB pathways that can be targeted for inhibition. It was presented at an independent satellite symposium "Expert Perspectives in Individualized Treatment of Hematologic Malignancies" at the 2010 ASCO meeting in Chicago, Illinois.

Scenes Description.
Scene 1: In the classical pathway, incoming stimuli to cell surface receptors initiate a cytoplasmic cascade, beginning with the activation of the IKK-gamma/IKK-alpha/IKK-beta complex.

IKK-beta becomes phosphorylated.

Scene 2: The IKK complex phosphorylates the IkappaB that is bound to the p50/p65 subunits of NF-kappaB and inhibits its activity.

Scene3: Phosphorylated IkappaB undergoes ubiquitinylation followed by proteasomal degradation. This permits NF-kappaB translocation to the nucleus, leading to gene transcription of anti-apoptotic and inflammatory proteins.

Scene 4: Bortezomib inhibits proteasomes, preventing the degradation of IkappaB, thereby indirectly inhibiting NF-kappaB transcription activity.

Scene 5: In the alternative pathway, extracellular stimuli stimulate cell surface receptors, which leads to the activation of NIK.

Scene 6: NIK phosphorylates dimerized IKK-alpha.

Scene 7: The RelB/p100 complex is phosphorylated by the IKK-alpha dimer.

Scene 8: Upon ubiquitinylation, p100 is cleaved. This yields a RelB/p52 complex which translocates to the nucleus to transcribe proteins related to lymphoid organ development and homeostasis.

How Antioxidants work