The MediastinumOverview • The mediastinum is the area centrally located between the right and left pleural cavities. • The mediastinum can be broadly divided into superior and inferior compartments. The Superior Mediastinum* is a space for structures to pass between the head/neck and the thorax. The Inferior Mediastinum* comprises the anterior, middle, and posterior sub-compartments. – Anterior mediastinum comprises connective and fatty tissue that protect the deeper structures. – Middle mediastinum comprises the heart and the roots of the great vessels; – Posterior mediastinum provides a passageway for structures in the thorax. Cross Section We first show the mediastinum in cross section to view its location between the pleural cavities. • We draw the external body, and indicate anterior and posterior; we draw the sternum and a vertebra, for context. • Then, indicate the right and left pleural cavities. • Between them, show the mediastinum.Sagittal Section Now, we draw the mediastinum in sagittal section so we can see the four compartments. • First, anteriorly, show the manubrium, sternal body, and xiphoid process; indicate the sternal angle between the manubrium and sternal body – this is a key landmark for the regions we'll soon learn. Posteriorly, show the spinal column; we'll omit the details, but indicate vertebrae TIV and TV.* • Inferiorly, show the diaphragm, which separates the thoracic and abdominal cavities.Middle compartment has a sac-like shape; it houses the pericardium, heart, and roots of the great vessels. Anterior compartment lies anterior to this, and extends from the sternal angle, superiorly, to the diaphragm, inferiorly. Posterior compartment lies posterior to the middle mediastinum, and, like the anterior mediastinum, extends from the sternal angle to the diaphragm. Superior mediastinum fills the space between the superior thoracic opening to the sternal angle. Key anatomical structures • The thymus lies within the superior and anterior regions; recall that this structure regresses after childhood. • Then, return to where the root and ascending portion of the aorta arise in the middle mediastinum, and show that the aorta continues through the superior and posterior compartments. We've also shown the branches of the aortic arch as they extend through the superior mediastinum. • Next, posterior to the heart, show the opening of the left pulmonary artery as it passes to the left lung; • The opening of the left bronchus; indicate that the trachea extends through the superior and posterior compartments of the mediastinum. • The esophagus also passes through these compartments. Pathology • Let's indicate some key masses that can develop in the mediastinum; we'll broadly categorize these by region of the mediastinum, but beware of overlap. • Anterior/superior mediastinum: thymoma, germ cell neoplasm, and lymphoma. • Middle mediastinum: pericardial cysts, bronchogenic cysts, lymph node enlargement, carcinoma, and lymphoma. • Posterior compartment: watch for neurogenic tumors and diaphragmatic hernias. Summary Table Superior compartment: • Thymus, esophagus, and trachea. • The aortic arch and its branches. • The superior vena cava, brachiocephalic veins, and the arch of the azygos vein. • The thoracic duct. • The vagus nerves, recurrent laryngeal nerves, phrenic nerves, and cardiac nerve.Anterior mediastinum: • Thymus. • Branches of the internal thoracic arteries and veins, and, the parasternal lymph nodes. • Middle mediastinum: • The heart and the roots of the great vessels. • The ascending aorta, pulmonary trunk, and pericardiacophrenic arteries. • The superior vena cava, pulmonary veins, and pericardiacophrenic veins. • And, the vagus nerves, phrenic nerves, and sympathetic nerves.Posterior mediastinum: • The esophagus. • Thoracic aorta. • Azygos, hemiazygos, and accessory hemiazygos veins. • The thoracic duct. • The vagus nerves and sympathetic nerves. References • Moore, K.L., Dalley, A.F., & Agur, A.M.R. Moore Clinically Oriented Anatomy, 7th ed. (Lippencott Williams & Wilkins, 2014). • Drake, R.L., Vogl, W., & Mitchell A.W.M. Gray’s Anatomy for Students (Elsevier, 2005). • Netter, F.H. Atlas of Human Anatomy, 4th ed. (Saunders, 2006). • Chung, K.W. & Chung, H.M. BRS Gross Anatomy, 7th ed. (Lippincott Williams & Wilkins, 2012). • Standring, S. & Gray, H. Gray's anatomy : the anatomical basis of clinical practice. 40th edn, (Churchill Livingstone/Elsevier, 2008). • Stoddard, Nathan, and David R. Lowery. “Anatomy, Thorax, Mediastinum.” In StatPearls. Treasure Island (FL): StatPearls Publishing, 2019. http://www.ncbi.nlm.nih.gov/books/NBK539819/.

Notes Photos of the internal heart Photos of the heart valvesKey Features of the Internal Heart: • The right side of the heart receives deoxygenated blood from the body and sends it to the lungs. • The left side of the heart receives oxygenated blood from the lungs and sends it to the body. • Review Systemic vs. Pulmonary Circulation • Review of Blood flow through the heartSepti (singular = septum) • Structurally and functionally divide the heart into right and left sides; each side operates as a muscular pump. - Interventricular septum divides right and left ventricles, inferiorly. - Interatrial septum divides right and left atria, superiorly.Chambers • Atria - Superior chambers • Ventricles - Inferior chambersValves • Ensure unidirectional blood flow through the heart.Right atrioventricular valve • Three cusps (aka, leaflets): - Anterior - Posterior - Septal • Because it has three cusps, this valve is called the "tricuspid valve."Left atrioventricular valve • Two cusps: - Anterior - Posterior • Because it has two cusps, it is called the bicuspid valve (aka, the mitral valve, because it is mitre-shaped). Semilunar valves: • Aortic and pulmonary semilunar valves ensure that blood travels from through the aorta and pulmonary trunk unidirectionally. Papillary muscles • Anchor AV valves. • Special extensions of the trabeculae carneae in the ventricles (papillary refers to their nipple-like shape). • The moderator band (aka, septomarginal trabecula) spans from the interventricular septum to the base of the anterior papillary muscle; it prevents the ventricle from overfilling, and contains a portion of the cardiac conduction system (which is addressed in a separate tutorial). Right ventricle has three papillary muscles, each named for its location: - Anterior - Posterior - Septal (which is sometimes absent)Left ventricle typically has two papillary muscles - Anterior - PosteriorChordae tendineae • Short cords that attach flaps of valves to papillary muscles to prevent prolapse (aka, eversion) of the valves, and ensure unidirectional blood flow through the chambers. Features of the Ventricles: • Walls of the left ventricle are more muscular and thicker than the walls of the right. - The left ventricle must produce more muscular force to pump blood to the body; in contrast, the right ventricle produces less force, as it sends blood to the nearby lungs. • Trabeculae carnae Irregular ridges of muscle on internal ventricular surface Features of the Atria: • Pectinate muscles line the anterior wall of the right atrium. These muscles also exist in the left atrium but are less abundant. • Fossa ovalis is a shallow depression in the wall of the interatrial septum. - The fossa ovalis is clinically significant from the moment of birth, when it seals off an opening in the interatrial septum called the foramen ovale. - In utero, the foramen ovale shunts blood directly from the right to left atrium, which allows the blood to bypass the nonfunctional lungs (the fetus receives oxygen directly from the maternal blood via the placenta). Immediately after birth, the interatrial septum fuses, which closes the foramen ovale; the fossa ovalis represents this fusion. - In some cases, septal fusion is incomplete (aka, patent foramen ovale), which can impede blood flow and, consequently, blood oxygenation. Great vessels • Arteries send blood away from the heart • Veins return blood to the heart Aorta • Arises from the left ventricle and arches posteriorly; carries oxygenated blood away from the left ventricle.Pulmonary trunk • Arises from the right ventricle and splits to form the right and left pulmonary arteries; pulmonary arteries carry deoxygenated blood away from the right ventricle, to the lungs.Pulmonary veins • Drain into the left atrium; return blood to the heart from the lungs. ("pulmonary" refers to the lungs"). Inferior and Superior vena cavae • Return deoxygenated blood from the body to the right atriumOpening of coronary sinus • Returns deoxygenated blood from the myocardium to the heart to right atrium. Cardiac veinsClick to view Ventricular and Outflow Development

Hormones: • Secreted by specialized cells (usually epithelial cells) • Transported via the blood • Bind with receptors on other tissues • Initiate physiological responses • Responsible for long-term regulation of: metabolism, growth, development, reproduction, and the internal environment (i.e., temperature) In contrast, neural mechanisms trigger rapid, short term responses Key endocrine structures and examples of their products:Hypothalamus • Synthesizes anti-diuretic hormone (ADH, aka, vasopressin), corticotropin-releasing hormone (CRH), and gonadotropin-releasing hormone (GnRH), among othersPituitary gland • Posterior lobe of the pituitary gland does not synthesize hormones, it release antidiuretic hormone, which, as we've indicated, is synthesized by the hypothalamus • Anterior lobe synthesizes adrenocorticotropic hormone (ACTH, aka, adrenocorticotropic hormone), growth hormone (GH), thyroid-stimulating hormone (TSH), and the gonadotropins (follicle-stimulating hormone and luteinizing hormone) Thyroid gland • Produces the thyroid hormones, T3 and T4, as well as calcitonin. - Clinical correlation: enlarged thyroid gland is called goiter.Parathyroid glands • Secrete parathyroid hormone (PTH)Heart • Specialized cells within it secrete atrial natriuretic hormone (aka, atriopeptin); this hormone is secreted in response to atrial stretching to increase sodium and water excretion in the kidneys Kidneys • Secrete erythropoietin and renin; erythropoietin stimulates red blood cell production, and renin aids in blood pressure regulation Adrenal gland • Cortex: cortisol • Medulla: catecholamines (norepinephrine and epinephrine)GI tract • Specialized cells throughout the gastrointestinal tract secrete hormones that aid in digestion and metabolism; gastrin and secretion are two examples Pancreas • Pancreatic islets secrete insulin and glucagon, which are hormones that regulate blood glucose levelsGonads • Produce large quantities of the reproductive hormones; the testes are a major source of the androgens, particularly testosterone, in males, and the ovaries are a major source of progestins and estrogensBe aware our that diagram is simplified for introductory purposes, and does not include all endocrine tissues nor the complex interactions between endocrine tissues For example, fat tissues also synthesize and secrete hormones, and, although the testes produce relatively large quantities of androgens, the adrenal cortex and ovaries also contribute to androgen levels Hormone Classes:Peptides and proteins • Vary in size • Are derived from amino acids • Are synthesized throughout the body • Examples: insulin (which comes from the pancreatic islets), growth hormone (from the anterior pituitary gland), and parathyroid hormone Steroid hormones • Are derived from cholesterol, which is present in food and produced endogenously • Steroid hormones are primarily produced in the adrenal cortex and gonads • Examples: cortisol and the reproductive hormones Amines • Are derived from tyrosine in the adrenal medulla and thyroid gland. • Include the: catecholamines (epinephrine, aka, adrenaline, and, norepinephrine, aka, noradrenaline, and, T3 and T4). Regulatory mechanisms that control the secretion of hormones and receptor response.Hormonal feedback mechanisms are physiological processes that are influenced by their own products: • In positive feedback, the hormonal pathway is reinforced by its own products to ensure additional secretion. This type of feedback is relatively rare. - For example, past a certain threshold, circulating estrogen triggers events that ultimately increase estrogen release from the ovaries • In negative feedback loops, physiological products inhibit the hormonal pathway to halt further secretion - For example, testosterone limits its own secretion via its effects on the hypothalamus and pituitary glandReceptor Regulation: • Hormones can also influence their effects at target tissues by altering the number or affinity of receptors to regulate receptor response: - In up-regulation, the presence of a hormone increases receptor response - In down-regulation, receptor response decreases

OverviewPlasma: 55% Formed Elements: 45% Plasma DetailsWater: 90% of plasma volume Acts as a transport medium, absorbs and distributes heat. Proteins: buffer blood pH, osmotic balance between interstitial fluid and blood, produce blood viscosity. Albumin is the most abundant; contributes to osmotic pressure. Immunoglobulin plays a role in immune defense. Fibrinogens are clotting factors.Electrolytes: buffer blood pH and help maintain blood's osmotic balance, regulate membrane permeability.Metabolic nutrients: respiratory gases (oxygen), glucose, fatty acids and vitaminsMetabolic waste: respiratory gases (carbon dioxide), urea and uric acidHormones Formed ElementsErythrocytes: 98-99% Transport oxygen and carbon dioxide. Leukocytes (white blood cells): 1-2%Granulocytes (granules visible after staining): - Basophils: inflammatory response - Eosinophils: parasitic infection and allergic reactions - Neutrophils: most abundant, engulf bacteriaAgranulocytes (granules not visible under microscope): - Monocytes: engulf bacteria - Lymphocytes: B and T cells, differentiate in bone marrow and thymusPlatelets: fragments of megakaryocytes, function in hemostasis Clinical CorrelationsDeep Venous Thrombosis (DVT): Poor blood flow causes clumping of blood fragmentsHemophilia: Occurs when a genetic mutation causes a clotting factor deficiency

Lymphatic Vessel Histology Key points: • Collect interstitial fluid, carry it to lymph nodes, and ultimately return it to systemic circulation via the thoracic ducts. - Interstitial fluid comprises blood plasma, white blood cells, and other elements. • Have multiple layers of smooth muscle that contract to propel the lymph. • Larger lymph vessels have valves which that unidirectional flow of lymphatic fluid by preventing backflow. • Valves arise from the tunica intima to promote unidirectional flow. • Anchoring filaments attach the vessel to surrounding interstitium. • Interstitial lymph enters through the openings in the vessel wallClinical Correlations: • Because the valves prevent backflow, lymph fluid travels unidrectionally. If the valves fail, lymph fluid pools and causes lymphedema (as with varicose veins, this is particularly relevant in the extremities). • Cancer cells can break from a tumor and travel within the lymph vessels; These cells can settle and proliferate to form new tumors in new areas (metastasis).

The fight or flight response isn't just a phrase; it's a vital body reaction that readies us for immediate action. This complex physiological and psychological response can be a life-saving ally and a chronic health enemy. This guide delves into how this stress response functions and explore ways to foster well-being.

The nervous system is a complex network of cells and tissues that carries messages between the brain and the rest of the body. The nervous system controls all body activities, from breathing and heart rate to movement, thoughts, and emotions.

The autonomic nervous system controls all involuntary functions of the human body. It is part of the peripheral nervous system (PNS).

• Eukaryotic cell contains an endomembrane system, which is a select group of membranous organelles that regulate protein trafficking and metabolism.

Carbon dioxide is transported from the tissues to the blood, to the lungs, and out into the environment.Three key forms of carbon dioxide present in the blood: • Dissolved CO2 constitutes about 5% of the total carbon dioxide content and contributes to the partial pressure; recall that the partial pressure of a gas is a major determinant of its diffusion. • Carbon dioxide bound to hemoglobin, constitutes about 3%, and is referred to as carbaminohemoglobin. The amount of carbaminohemoglobin in the blood is in part dependent upon the oxygen saturation: - The Haldane effect predicts that when blood oxygen increases, the affinity of hemoglobin for carbon dioxide decreases; in other words, when hemoglobin binds with oxygen, it more readily releases carbon dioxide. - Notice that this is the opposite of the Bohr effect, in which increased carbon dioxide reduces hemoglobin's affinity for oxygen. • Bicarbonate is the chemically modified form of carbon dioxide that comprises the majority of carbon dioxide in the blood. Be aware that the percentages of each type of carbon dioxide given here are approximations, because chemical reactions within the blood are ongoing. Three sites of carbon dioxide: • Peripheral body tissues as byproduct of aerobic respiration. • Red blood cells in the vessels. • Lung. Steps to remove carbon dioxide from the body: 1. Aerobic metabolism in the tissues produces carbon dioxide. 2. Partial pressure gradients between the tissues and the blood stream and also between the blood stream and the red blood cells, drives carbon dioxide diffusion into the red blood cells, where it mixes with H2O. 3. Within the red blood cell, show that carbonic anhydrase reversibly converts water and carbon dioxide to carbonic acid. 4. Carbonic acid dissociates to form hydrogen ions, which are buffered by hemoglobin, and bicarbonate, which can then exit the cell via chloride exchangers and enter the blood stream. 5. Bicarbonate enters the lungs, again via chloride exchangers; there, the reactions reverse to produce carbon dioxide, which is then expired during ventilation. Hypercapnia • Occurs when ventilation is inhibited and carbon dioxide accumulates. • Hypercapnia can cause acidosis (low blood pH), which depresses the central nervous system. • This can lead to a suite of symptoms, including headache and confusion; if extreme, hypercapnia can lead to coma.

ABO and Rh blood groups ABO and Rh groups are of particular clinical significance because they are most prevalent and most likely to be involved in detrimental transfusion reactions. ABO Blood Groups Comprises A and B antigens, which are oligosaccharide molecules produced on the surfaces of red blood cells (aka, erythrocytes). • These antigens are genetically determined by the alleles A, B, and O. • A and B are codominant, and O is recessive; so, from 6 possible genotypes, we get 4 phenotypic blood types.Antibodies A unique feature of the ABO blood group is that individuals produce antibodies against antigens absent in their blood. These antibodies attack the red blood cells displaying the corresponding antigens, causing agglutination and hemolysis. Type A blood • Blood type A is characterized by red blood cells with the A antigen on their surfaces • Anti-B antibodies, aka, agglutinins, circulate in the plasma • Addition of Type B blood/B antigens will cause agglutination.Type B blood • Blood type B is characterized by B antigens on the surfaces of red blood cells • Anti-A antibodies circulate in the plasma • Addition of Type A blood/A antigens will cause agglutination.Type AB blood • Type AB blood cells have both A and B antigens on their surfaces • Neither anti-A nor anti-B antibodies circulate in the plasma, which make sense: Anti -A or Anti-B antibodies would attack a person's own red blood cells. • Addition of A or B antigens does not cause agglutination.Type O blood • Type O has neither A nor B antigens on its red blood cells • Both anti-A and anti-B antibodies circulate in the plasma. • Addition of A or B antigens causes agglutination.Rh Blood Group • There are several Rh antigens, but the D antigen is most prevalent and most cross-reactive; thus, it is most clinically relevant. • D antigen is either present on the surface of red blood cells or not • It is coded for by two alleles: D and d. • Unlike the ABO blood types, antibodies against the D antigen are not pre-produced in Rh negative individuals. • Rh negative individuals produce anti-Rh antibodies in response to exposure to D antigens. • Thus, if Rh+ blood is added to Rh- blood that happens to have anti-Rh+ antibodies, agglutination will occur.Clinical Correlations: • Blood transfusion recipients and donors must be matched to avoid agglutination. • When an Rh negative woman gives birth to an Rh positive infant; invariably, there will be some mixture of maternal and fetal blood. Consequently, the mother's body will produce anti-Rh antibodies, which will have negligible, if any, immediate effects. But, the circulating anti-Rh antibodies will attack the red blood cells of any subsequent Rh positive fetus. Preventative assessment of maternal Rh status and immunization protects against this reaction.

Chest wall DisordersThese disorders limit chest wall restriction and limit air intake. Review compliance and restriction Ankylosing spondylitis Ankylosing spondylitis is a systemic inflammatory disease that affects the joints of the axial skeleton. Pulmonary involvement can be both direct and indirect: Direct involvement is via the development of interstitial lung disease. Indirect involvement occurs when joints of the thoracic cage, such as the costovertebral joints, become fused; thus, movement is limited, and chest wall compliance is reduced. Kyphoscoliosis Kyphoscoliosis is characterized by abnormal curvatures in both the coronal and sagittal planes; the resulting rib displacement can restrict chest wall movement. Kyphoscoliosis is a combination of two skeletal abnormalities: – Kyphosis is characterized by a posterior curvature. – Scoliosis is characterized by a lateral curvature. When restriction of the pulmonary system is severe, hypoxemia can result. Hypoxemia is the root of two common pulmonary complications of kyphoscoliosis: pulmonary hypertension and cor pulmonale. Neuromuscular diseases Neuromuscular diseases that affect the thorax can also cause pulmonary restriction: • Guillain-Barre Syndrome • Myasthenia gravis • Poliomyelitis • Muscular dystrophies

• Eukaryotic cell contains an endomembrane system, which is a select group of membranous organelles that regulate protein trafficking and metabolism.

ABO and Rh blood groups ABO and Rh groups are of particular clinical significance because they are most prevalent and most likely to be involved in detrimental transfusion reactions. ABO Blood Groups Comprises A and B antigens, which are oligosaccharide molecules produced on the surfaces of red blood cells (aka, erythrocytes). • These antigens are genetically determined by the alleles A, B, and O. • A and B are codominant, and O is recessive; so, from 6 possible genotypes, we get 4 phenotypic blood types.Antibodies A unique feature of the ABO blood group is that individuals produce antibodies against antigens absent in their blood. These antibodies attack the red blood cells displaying the corresponding antigens, causing agglutination and hemolysis. Type A blood • Blood type A is characterized by red blood cells with the A antigen on their surfaces • Anti-B antibodies, aka, agglutinins, circulate in the plasma • Addition of Type B blood/B antigens will cause agglutination.Type B blood • Blood type B is characterized by B antigens on the surfaces of red blood cells • Anti-A antibodies circulate in the plasma • Addition of Type A blood/A antigens will cause agglutination.Type AB blood • Type AB blood cells have both A and B antigens on their surfaces • Neither anti-A nor anti-B antibodies circulate in the plasma, which make sense: Anti -A or Anti-B antibodies would attack a person's own red blood cells. • Addition of A or B antigens does not cause agglutination.Type O blood • Type O has neither A nor B antigens on its red blood cells • Both anti-A and anti-B antibodies circulate in the plasma. • Addition of A or B antigens causes agglutination.Rh Blood Group • There are several Rh antigens, but the D antigen is most prevalent and most cross-reactive; thus, it is most clinically relevant. • D antigen is either present on the surface of red blood cells or not • It is coded for by two alleles: D and d. • Unlike the ABO blood types, antibodies against the D antigen are not pre-produced in Rh negative individuals. • Rh negative individuals produce anti-Rh antibodies in response to exposure to D antigens. • Thus, if Rh+ blood is added to Rh- blood that happens to have anti-Rh+ antibodies, agglutination will occur.Clinical Correlations: • Blood transfusion recipients and donors must be matched to avoid agglutination. • When an Rh negative woman gives birth to an Rh positive infant; invariably, there will be some mixture of maternal and fetal blood. Consequently, the mother's body will produce anti-Rh antibodies, which will have negligible, if any, immediate effects. But, the circulating anti-Rh antibodies will attack the red blood cells of any subsequent Rh positive fetus. Preventative assessment of maternal Rh status and immunization protects against this reaction.

Posterior lobe of the pituitary gland • The hypothalamus regulates the pituitary's endocrine functions via hormonal and neural mechanisms. • The pituitary gland, aka, hypophysis, divides structurally and functionally into the: • Anterior lobe and posterior lobe (aka neurohypophysis), which directly connects to the hypothalamus. • Direct connection allows the hypothalamus to communicate with the posterior lobe via neural connections – the posterior lobe is derived from neural tissue (hence its name "neurohypophysis"). • Infundibulum connects hypothalamus and posterior lobe. • Posterior lobe does not synthesize hormones but rather stores and secretes neurohormones synthesized by the hypothalamus. Pathway: Hypothalamo-hypophyseal tracts: • Paraventricular and supraoptic nuclei of the hypothalamus house the cell bodies of neurosecreting cells. • Neurosecretory cell traveling from the hypothalamus to the posterior lobe. • Cell body synthesizes and packages neurohormones in vesicles; • Axon delivers the vesicles to its terminal in the posterior lobe, where it stored until its release is signaled. • When signaled to do so, the vesicles release the neurohormone. • The hormone then enters the venous blood so that it can travel within the systemic circulation to reach its target organs.Two hormones secreted from the posterior lobe of the pituitary gland. Anti-diuretic hormone, ADH, is released in response to low blood pressure and/or water volume contraction. • ADH induces vasoconstriction, which counteracts low blood pressure; this explains its alternative name, vasopressin • ADH also acts on the distal nephron tubules of the kidneys to increase water reabsorption, which counteracts water volume contraction. • Central diabetes insipidus is caused by defects in the hypothalamic nuclei or in the mechanisms of axon transport. As a result, ADH is not secreted by the posterior pituitary, and individuals produce large quantities of dilute urine. Oxytocin • Smooth muscle contraction in lactating mammary glands and uterus. • In the breast, oxytocin promotes myoepithelial cell contraction and milk ejection. • Suckling promotes oxytocin release to facilitate breastfeeding. • In the uterus, oxytocin induces rhythmic myometrium contractions during parturition (to expel the fetus) and orgasm. • Stretch receptors in the vagina trigger its release.

Eukaryotic Cell Architecture SummaryPLASMA MEMBRANE • Often called phospholipid bilayer • Comprises: Proteins, Cholesterol, Carbohydrates. • Separates cell from external environment; controls the flow of material into and out of it.CYTOSOL • Aqueous solution that bathes organelles and contains a variety of molecules • Portion of cytoplasm not contained within organelles • Free ribosomesENDOMEMBRANE SYSTEM • Select group of membranous organelles that regulate protein trafficking and metabolismNUCLEUS • Nuclear envelope with pores (double-membrane) • Site of DNA replication and RNA synthesis (transcription) • Contains: chromatin, nucleolus (rRNA and ribosomal proteins)ENDOPLASMIC RETICULUM • Continuous with nuclear envelope • Cisternae enclose a space called the ER lumen • Rough ER: with bound ribosomes; site of protein synthesis, processing and secretion • Smooth ER: no ribosomes; lipid synthesis, carbohydrate metabolism, detoxificationTRANSPORT VESICLE • Keeps secretory proteins separate from proteins synthesized in the cytosolGOLGI APPARATUS • cis side faces the nucleus, trans side where cargo exits • Modifies, stores and secretes molecules that it receives from the ER • Synthesizes its own macromoleculesLYSOSOME • Vesicle that contains hydrolytic enzymes; digests endosomal cargoENDOSOME • Forms when cell engulfs nutrients or other particles via endocytosisRIBOSOMES • Two subunits: one large and one small • Synthesize proteins via translation • Can be bound to rough ER or free (suspended in cytosol)MITOCHONDRION • Double-membrane bound: inner membrane invaginates to form cristae • Space within cristae: matrix (contains free ribosomes) • Space between inner and outer membranes: intermembrane space • Synthesizes ATP via citric acid cycle and oxidative phosphorylation (couples oxidation of nutrients with ADP phosphorylation)PEROXISOME • Single-membrane bound vesicle • Produce hydrogen peroxide from detoxification of substances (i.e. alcohol)CYTOSKELETON • Microfilaments, intermediate filaments and microtubules • Anchors organelles and provides structural frameworkCENTROSOME • Where microtubules nucleate • Contains two small structure called centrioles • Functions in cell divisionDOUBLE MEMBRANE BOUND ORGANELLES • Nucleus • MitochondriaCLINICAL CORRELATIONS • Rough ER Network and Pancreatic beta cells – Specialize in synthesizing and secreting the peptide hormone insulin; large rough ER network proportional to their secretory activity • Smooth ER and Hepatic cells – Drugs and/or alcohol can induce the proliferation of smooth ER, which accelerates detoxification • Lysosomes and Tay-Sachs disease – Lysosomal storage disease that presents when lysosomes are missing a lipid-digesting enzyme (or its active form) – Lipids accumulate in cells because lysosomes cannot digest them; impair brain function

Neural Control of RespirationOverview Medulla • The medulla is the primary brainstem mediator of respiration. • Via the dorsal respiratory group (DRG), the dorsal (posterior) medulla controls sensory integration. - For its location, think: solitary tract nucleus. • Via the ventral respiratory group (VRG), the ventral (anterior) medulla controls motor output. - For its location, think: nucleus ambiguus. Phrenic nerve • C3, C4, C5 supply the phrenic nerve, which innervate the diaphragm: C3, C4, C5 "keep the diaphragm alive".Brainstem circuitry Ventral respiratory group (VRG) • Within the medulla, anteriorly, lies the ventral respiratory group (VRG), which lies within the ventrolateral medulla. - It provides innervation for motor output. - It is involved in the activation of both inspiration and expiration. Dorsal respiratory group (DRG) • Within the dorsal medulla (in the solitary tract nucleus), lies the dorsal respiratory group (DRG). - It provides sensory integration. - It receives sensory input related to the inspiration phase of respiration.Peripheral chemoreceptors Peripheral chemoreceptors act on the dorsal respiratory group • Peripheral innervation involves the aortic bodies (shown here in the arch of the aorta) and the carotid bodies in the carotid bifurcation. - The carotid and aortic bodies are chemoreceptors. - They respond to levels of arterial oxygen and carbon dioxide levels and blood acidity. Innervation to the brainstem respiratory center • Both cranial nerves 9 and 10 (we treat them jointly for simplicity) pass through the jugular foramen within the skull base across from the brainstem to innervate the dorsal respiratory group. secondary inspiratory muscles Key structures • Anterior face, tongue, pharynx, and larynx. Innervation • Cranial nerves 9, 10, and 12 innervate the secondary inspiratory muscles (again, we treat them jointly for simplicity). VRG innervation of CNs 9 and 10 • The ventral respiratory group acts upon these cranial nerves. primary inspiratory muscles Key structures • Thoracic cage, diaphragm, and intercostal muscles. Innervation • The ventral respiratory group innervates C3, C4, C5 motor neurons in the anterior horn of the spinal cord gray matter, which supply the phrenic nerve, which innervates the diaphragm (again: C3, C4, C5 "keep the diaphragm alive"). Intercostal nerves • Intercostal nerves innervate the intercostal muscles.Detailed anatomy of the DRG & VRG Dorsal respiratory group (DRG) • The dorsal respiratory group lies within the solitary tract nucleus of cranial nerves 9 and 10. Ventral respiratory group (VRG) Simplification of VRG microanatomy • First, add nucleus ambiguus of CNs 9 and 10. - This will help us continue to recall the important of CNs 9 and 10 and thus the medulla itself in respiratory control. • There are many subnuclei that constitute the ventral respiratory group; we'll only address the Bötzinger nuclei, here. • The Bötzinger complex lies within the superior aspect of the ventral respiratory group (some authors distinguish it from the ventral respiratory group, entirely). • The pre-Bötzinger complex is considered the "respiratory pacemaker." - Notably, it contains mu receptors, which makes it sensitive to opioids. - Thus, we can see one of the ways in which opioids (such as morphine) can depress our drive to breathe. Clinical correlation: Ondine's curse • Ondine's curse is the clinical eponym for the failure of automatic breathing during sleep. - It typically occurs from lower medullary or high cervical spinal cord lesions. - These patients are dependent on a ventilator when they sleep to survive.pontine respiratory control centers Apneustic center • The apneustic center is a nonspecific region in the posterior lower pons. - It promotes apneusis: a prolonged inspiratory pause. - It comprises diffuse lower pontine nuclei. Pneumotaxic center • The pneumotaxic center (aka the pontine respiratory group). - It prevents apneusis: it promotes regular breathing. - The pneumotaxic center comprises the medial parabrachial nucleus and the Kölliker-fuse nucleus. Functions Whereas these centers where formerly thought to be well-defined and to perform unique functions, now they are understood to be diffuse and their functions are no longer thought to be unique (the pneumotaxic center is not the only site to prevent apneusis, for instance*).Breathing Patterns We can use breathing patterns in comatose patients to localize the level of the CNS lesion, as follows: Patterns • Cerebral hemispheric lesions cause Cheyne-Stokes respirations. – Illustrate Cheyne-Stokes respirations as periods of hyperpnea (deep breathing) with apneas (cessation of breathing) • Midbrain lesions cause hyperventilation. - Illustrate hyperventilation as rapid, deep breathing. • High pontine lesions cause apneustic breathing. - Illustrate apneustic breathing as periods of long inspiratory pauses before release of air. • Low pontine lesions cause cluster breathing. - Illustrate cluster breathing as irregular clusters of breaths. • Medullary lesions cause ataxic breathing. - Illustrate ataxic breathing as a completely irregular breathing pattern. Limitations • Although these localizations are notoriously unreliable, they still give us a simple heuristic to follow when we examine comatose patients, which is essential.

Blood oxygen content: • Oxygen delivery to the tissues is essential for life • It is dependent upon: - Cardiac output, which we've discussed in detail, elsewhere, and, the - Oxygen content of the blood, which will be the focus of this tutorial. Oxygen content • Amount of oxygen per unit volume of blood. - Amount of dissolved oxygen + hemoglobin-bound oxygenDissolved Oxygen • "Free" within the blood and can easily diffuse out of the vessel into the tissues (for example, recall that oxygen rapidly diffuses from the pulmonary capillaries to the alveoli in the lungs). - 2% of the total oxygen content - Contributes to partial pressure, and therefore, drives diffusion. - Typically, the concentration of dissolved oxygen is ~ 0.3 mL of oxygen per 100 mL of bloodOxygen Consumption: • Given that the average rate of oxygen consumption in a person at rest is ~ 250 mL of oxygen per minute, the tissues cannot rely on dissolved oxygen, alone. Thus, additional oxygen must be held within the body, but also readily available to the tissues. • Hemoglobin solves this problem by reversibly binding oxygen and delivering it in the bloodstream to the tissues. Hb-Bound O2 • Hemoglobin is a globular protein, which comprises four subunits, each of which can bind a single oxygen molecule. - Can bind up to four total oxygen molecules, but can be bound to fewer. - Hemoglobin-bound oxygen comprises 98% of the total oxygen content; thus, it is a major contributor to total oxygen content and delivery. Amount of Hb is determined by two variables: • The percentage of saturation • The oxygen-binding capacity of hemoglobin present in the blood Saturation percentage • Refers to the percentage of hemoglobin subunits bound to oxygen; hemoglobin bound to two oxygen molecules is 50% saturated, and Hb bound to four oxygen molecules is 100% saturated. • Oxygen partial pressure determines the saturation percentage The oxyhemoglobin dissociation curve illustrates this relationship. • Sigmoid curve demonstrates how hemoglobin saturation changes in response to increasing partial pressure of oxygen. • Steep portion of the curve is due to positive cooperative binding: each time hemoglobin binds an oxygen molecule, its affinity for oxygen increases. It's as if hemoglobin is offered potato chips; after it gets one, it "craves" more. • Healthy systemic arterial blood is nearly 100% saturatedAdditional information about the oxyhemoglobin dissociation curve • "P 50" reflects the partial pressure value at which hemoglobin reaches 50% saturation. • If the curve shifts left or right, the P 50 will change to reflect hemoglobin's altered affinity for oxygen. • These changes can be predicted, as follows: - Factors that shift the curve to the right decrease hemoglobin's affinity for oxygen, and increase the P50 value; in other words, hemoglobin readily releases oxygen at lower partial pressures. - Factors that cause a leftward shift have the opposite effects: affinity is increased, and the P50 value decreases. - Some common causes of shifts include: • Increases in carbon dioxide and subsequent decreases in pH are shift the curve to the right; this phenomenon, called the Bohr effect, ensures that oxygen delivery meets tissue demand. • Alternatively, a decrease in carbon dioxide and increase in pH will increase affinity; this conserves oxygen when demand is low. • Increased body temperature, such as during strenuous activity, oxygen release is made easier, and, vice versa. • Increased altitude induces hypoxia, which decreases hemoglobin's affinity for oxygen to ensure oxygen release to the tissues, and, • Fetal hemoglobin (Hemoglobin F) causes a leftward shift; increased affinity facilitates oxygen loading from the maternal blood supply, despite very low placental partial pressure oxygen levels. Oxygen-binding capacity • Second variable needed to calculate the amount of oxygen-bound hemoglobin. • Oxygen-binding capacity is the maximum amount of oxygen bound to hemoglobin at 100% saturation. • It depends upon two variables: hemoglobin concentration and hemoglobin's capacity to bind oxygen. • Standard values - Hemoglobin concentration is 15 g/100 mL - 1 gram of hemoglobin A, the adult form, can bind 1.34 mL of oxygen. • So, typical oxygen-binding capacity: 15 grams/100 mL * 1.34 mL oxygen = 20.1 mL/oxygen per 100 mL blood;Now, we can say that with oxygen saturation at 100%, the total amount of oxygen-bound hemoglobin is 20.1 mL of oxygen per 100 mL of blood. Solve equation for total oxygen content: • Amount of dissolved oxygen equals 0.3 mL oxygen/100 milliliters of blood • Amount of hemoglobin-bound oxygen is 20.1 mL oxygen/100 milliliters of blood • Total oxygen content of blood is 20.4 mL oxygen per 100 milliliters of bloodKeep in mind that the values given here are for reference; physiological and pathological variations will alter the total oxygen content of blood, and, therefore, its delivery to the tissues.

Anti-Diuretic Hormone PhysiologyOverviewAnti-diuretic hormone, or ADH for short, is also called "arginine vasopressin" (AVP), or, simply, vasopressin. Responsible for regulating body water and blood pressure. - Review of body water osmotic, hyperosmotic, and hypoosmotic states, and the role of blood volume in determining blood pressure.ADH assists aldosterone during hemorrhage or other hypovolemic states – it does this by raising the intravascular volume to maintain tissue perfusion. - Thus, ADH is given during hypotensive crisis. Key pathologies of ADH include: - Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH), which occurs when ADH is excessively secreted. - Diabetes insipidus, when there is too little secretion of or reaction to ADH. Anti-Diuretic Hormone PhysiologyFirst, we show the hypothalamus and pituitary and that the anterior pituitary gland comprises clusters of hormone-producing cells. The posterior pituitary comprises neural tissue.ADH pro-hormones are produced in the supraoptic and paraventricular nuclei of the hypothalamus; on their way to the posterior pituitary, these prohormones are converted to ADH. From there, ADH is secreted into the blood stream and travels to its targets.Unlike anterior pituitary hormones, the posterior pituitary hormones are not stored until needed; instead, stimulation of the hypothalamic centers triggers their production and secretion on demand.Two triggers for ADH release: - ADH is released in response to minute increases in plasma osmolality (so, above ~ 280 milliosmoles per kilogram of water), for example, in response to hypernatremia. - ADH is also released in response to decreases in intravascular pressure, such as in hypovolemia.Serum OsmolalityChanges in serum osmolality are sensed by hypothalamic osmoreceptors, which triggers the release of ADH.We show a nephron, and show that ADH binds V2-receptors in the distal nephron, causing the insertion of special water channels called aquaporins. When ADH is present, the number of aquaporins increases so that more water is reabsorbed from the distal nephron. - Because more water is resorbed, urine volume is reduced and its osmolality is increased (in other words, the small amount of urine produced contains a high concentration of solutes).When osmolality returns to baseline, ADH release stops, and urine production returns to normal. - In the absence of ADH, water reabsorption is reduced, so urine volume increases and its osmolality decreases (the larger volume of urine is more dilute). Blood PressureChanges in blood pressure are sensed by baroreceptors in the chest (review baroreceptors).In response to reduced blood pressure, ADH is released and binds to V1A-receptors in the vascular smooth muscle. ADH causes vasoconstriction, which raises the intravascular blood pressure to maintain tissue perfusion. Osmolality vs Blood Pressure - It takes a higher concentration of ADH to achieve the vascular effects than to achieve the water-balancing effects in the nephron. - In hypovolemia, ADH will be released in high quantities, regardless of the osmotic state. - In hypervolemia, ADH release will be inhibited, regardless of the osmotic state. - In other words, blood pressure homeostasis is prioritized over water balance, which underscores the importance of tissue perfusion.SIADH Diabetes insipidus

Key Principles • The hypothalamus regulates the endocrine functions of the pituitary gland via hormonal and neural mechanisms; as we'll see, the hypothalamus can either stimulate or inhibit the the pituitary gland. • The pituitary gland (aka, hypophysis) is structurally and functionally divisible into two lobes. - The anterior lobe, aka, adenohypophysis, is derived embryologically from the foregut; it receives hypothalamic regulating signals via the hypothalamic-hypophyseal portal veins. - 6 tropic hormones are secreted by the anterior pituitary lobe; "tropic" means they act on target tissues to stimulate release of other endocrine products. - The posterior lobe, aka, the neurohypophysis, receives hypothalamic signals via neural connections. As we'll learn elsewhere, the posterior lobe is derived from neural tissues. Pathway: • Cell bodies of hypothalamic neurons send axons inferiorly towards the pituitary gland. • Axons deliver hypothalamic hormones to the portal blood vessels • Hypothalamic-hypophyseal portal blood vessels deliver blood and hormonal signals from the hypothalamus to the pituitary gland (hypophysis). The the primary capillary plexus forms at the base of the hypothalamus (specifically, at the median eminence); it arises from the superior hypophyseal artery and drains, via portal vessels, inferiorly to the secondary capillary plexus, which bathes the endocrine cells of the anterior pituitary lobe. • The secondary capillary plexus delivers neurohormones that stimulate or inhibit hormonal secretion by the nearby anterior lobe endocrine cells. • Upon secretion, the anterior lobe hormones drain into systemic venous return to the heart; from here, they circulate within the systemic arterial blood to reach their target tissues. CRH (corticotropin-releasing hormone) • Stimulates the corticotrophs of the anterior pituitary lobe to release ACTH (adrenocorticotropic hormone) • ACTH travels in systemic blood to reach the cells of the adrenal gland cortex. As we'll discuss elsewhere, ACTH causes the adrenal cortex to secrete its own endocrine products. GHRH (growth hormone-releasing hormone) stimulates somatotrophs of the anterior lobe to release growth hormone. - Growth hormone has widespread metabolic effects in the body, particularly in the musculoskeletal system. - Somatostatin (aka, growth hormone-inhibiting hormone), inhibits growth hormone secretion from the anterior lobe endocrine cells. GnRH (gonadotropin-releasing hormone) • Stimulates gonadotrophs in the anterior pituitary lobe to secrete FSH (follicle-stimulating hormone) and LH (luteinizing hormone), which travel in the bloodstream to act on gonadal cells (aka, ovarian and testicular cells) (details regarding these hormonal pathways are discussed elsewhere). Thyroid-releasing hormone • Released from the hypothalamus and triggers thyrotrophs to secrete thyroid-stimulating hormone, which stimulates endocrine cells of the thyroid gland. PRH (prolactin-releasing hormone) • Stimulates lactotrophs (aka, mammotrophic cells) of the anterior lobe to secrete prolactin, which triggers mammary gland growth and milk production in females. • PIH (prolactin-inhibiting hormone, aka, dopamine) inhibits the release of prolactin. • Bromocriptine (a dopamine agonist) is used to treat prolactinomas (prolactin-secreting tumors).

Pancreas Has both exocrine and endocrine functions. • Most of the pancreas comprises exocrine cells, called acini, that secrete digestive enzymes; the ducts that drain them secrete alkaline fluid. • Clusters of endocrine cells, called Islets of L

The parasympathetic nervous system is responsible for the “rest-and-digest” functions of the body. It becomes more active during times of relaxation.

Pancreas Has both exocrine and endocrine functions. • Most of the pancreas comprises exocrine cells, called acini, that secrete digestive enzymes; the ducts that drain them secrete alkaline fluid. • Clusters of endocrine cells, called Islets of L

The proprioceptive system is comprise of sensory receptors in our joints, muscles, and skin that work together to build body awareness.

Pituitary Gland - Aka, Hypophysis • Rests in the sella turcica, the saddle-shaped depression in the sphenoid bone. Hypothalamic Input: • The hypothalamus collects information from throughout the body and uses it to regulate pituitary hormone secretion. • Hypothalamic neuroendocrine cell axons terminate in the median eminence and posterior pituitary, where they secrete various neurohormones. – 5 hypothalamic hormones act on the anterior pituitary lobe. – 2 hypothalamic hormones are released by the posterior pituitary lobe.Anterior & Posterior Pituitary Lobes: • The anterior and posterior lobes originate from different embryologic tissues, which determines their cellular makeup and functions. • The anterior and posterior lobes are separated by the pars intermedia.Anterior Pituitary: • Anterior lobe is derived from epithelial tissue that grows out of the primitive oral cavity (Rathke's pouch). Pars distalis is the "lobe" part; the pars tuberalis* wraps around the pituitary stalk (be aware of intertextual variation regarding the pituitary stalk, infundibular process, and infundibular stalk). Hypothalamic-Hypophyseal Portal Circulation* – Primary plexus in median eminence – Secondary plexus in anterior lobe – These plexuses are connected via portal veins Histology:* The anterior lobe is sometimes referred to as the adenohypophysis because of its gland-like components; it is highly vascularized with various "-troph" cells that receive inhibitory and/or releasing signals from the hypothalamus via the hypothalamic-hypophyseal portal system. – Cords of epithelial cells are in close contact with vascular sinusoids. – Acidophilic cells include: Somatotrophs (~50% of anterior lobe), which release Growth hormone Lactotrophs (~15-20%) which release Prolactin – Basophilic cells include: Corticotrophs (~20%), which release Adrenocorticotropin Thyrotrophs (~5%), which release Thyroid-Stimulating Hormone Gonadotrophs (~10%), which release Follicle-Stimulating Hormone and Luteinizing Hormone. • Anterior pituitary hormones regulate reproduction, growth, and metabolism. Posterior Pituitary: Aka, neurohypophysis. • The posterior lobe is derived from nervous tissue of the hypothalamus. Maintains direct connection to the hypothalamus via the pituitary stalk*. – If pituitary stalk is cut superior to the pituitary gland but hypothalamus is still intact, the posterior pituitary hormones will still be secreted. The pars nervosa is the "lobe" part; the infundibulum* is a funnel-shaped connection to the hypothalamus. • The posterior pituitary lobe receives arterial blood. The posterior lobe is sometimes referred to as the neurohypophysis* because it comprises nervous tissue. • It releases 2 peptide hormones that are synthesized in large-bodied neurons with cell bodies in the hypothalamus: – Antidiuretic hormone (aka, arginine vasopressin/vasopressin) is produced primarily in cell bodies of the supraoptic nucleus. – Oxytocin is produced primarily in cell bodies of the paraventricular nucleus. Histology:* – Unmyelinated axons of supraoptic and paraventricular nuclei form the hypothalamic-hypophyseal tract. – Herring bodies are temporary dilations in the axons where ADH or oxytocin accumulate. – Pituitcytes have cytoplasmic processes that surround and support the axons (look like astrocytes) (pituicytes are the majority cell type in the posterior pituitary). • Released hormone enter fenestrated capillaries.Histopathology of Anterior Pituitary Adenomas • Pituitary adenomas are classified according to size, cell type, functional vs nonfunctional, genetics, etc. • "Benign" lesions are not without complications: – For example, growth hormone-secreting adenomas cause acromegaly and gigantism. • Growth hormone-secreting adenoma (image is with HE stain). – Microscopic features: granular cytoplasm, round nuclei with fine chromatin. – Reticular stains will show decreased reticulation in tumors. – May be diffuse, densely, or mixed diffuse and densely granulated (dense is more common). – Be aware that neoplastic ganglion cells can be present (rare, but associated with acromegaly) – Macroscopically, these tumors are often tan or gray. • Prolactin-secreting adenomas are the most common anterior pituitary hormone-secreting tumors. – Can be sparsely or densely granulated. – Microscopic features: small acidophilic or chromophlic cells arranged in sheets. • THS-secreting adenomas are rare. – Usually in people 50+ years old. – Functional: goiter and hyperthyroidism. – Microscopic features: chromophobic, elongated or angular cells in sheets with fibrosis. • ACTH-secreting adenomas = Cushing's Disease – Microscopic features: Basophilic cells, round nuclei surrounded by granular cytoplasm. – Usually in women 40-50+ years old (prepubertal tumors have equal male/female distribution) – Hyopercortisolaemia can cause Crooke's hyaline change in non-neoplastic corticotropic cells, which is characterized by rings of cytokeratin accumulation. • GNRH-secreting adenomas - Often present as "non-functional" macroadenomas that compress the optic chiasm or invade the cavernous sinus. – Functional turmors can cause ovarian hyperstimulation syndrome. – Microscopic features: Perivascular rosettes. • Null cell adenoma – Cannot be traced to a specific cell subtype (improved typing techniques are helping to reduce this diagnosis). – Microscopic features: Chromophobe. View MRI of pituitary adenomas with macro vs. micro, and additional details.