Donna D. Castellone, MS, MT(ASCP)SH

• Clinical Projects Manager, Hemostasis/Hematology
• Medical, Clinical, and Statistical Affairs
• Siemens Healthcare Diagnostics
• Tarrytown, New York

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The steep depolarization phase of the autorhythmic cell motion potential is caused by Ca2+ inflow. Blood flows down a stress gradient (P), from the very best pressure in the aorta and arteries to the lowest stress within the venae cavae and pulmonary veins. The pressure created when the ventricles contract known as the driving strain for blood move. Resistance of a fluid flowing by way of a tube will increase because the length of the tube and the viscosity (thickness) of the fluid improve, and as the radius of the tube decreases. Flow price is the amount of blood that passes one level in the system per unit time. At a relentless circulate price, the rate of move through a small tube is quicker than the velocity by way of a larger tube. The coronary circulation that supplies blood to the center muscle originates firstly of the aorta and drains immediately again into the chambers of the guts. Myocardial cells are linked to each other by intercalated disks that comprise gap junctions. In contractile cell excitation-contraction coupling, an action potential opens Ca2+ channels. Ca2+ entry into the cell triggers the release of extra Ca2+ from the sarcoplasmic reticulum through calcium-induced calcium release. The force of cardiac muscle contraction can be graded according to how much Ca2+ enters the cell. When ventricular pressure exceeds arterial stress, the semilunar valves open, and blood is ejected into the arteries. When the ventricles loosen up and ventricular stress falls, the semilunar valves shut, creating the second coronary heart sound. The quantity of blood pumped by one ventricle throughout one contraction is named the stroke volume. Homeostatic modifications in cardiac output are completed by various coronary heart fee, stroke volume, or each. Norepinephrine and epinephrine act on b1@receptors to pace up the rate of the pacemaker depolarization. The longer a muscle fiber is when it begins to contract, the greater the force of contraction. Epinephrine and norepinephrine increase the drive of myocardial contraction after they bind to b1@adrenergic receptors. Venous return is affected by skeletal muscle contractions, the respiratory pump, and constriction of veins by sympathetic exercise. Afterload displays the preload and the hassle required to push the blood out into the arterial system. What contributions to understanding the cardiovascular system did each of the following individuals make Put the following constructions in the order in which blood passes via them, starting and ending with the left ventricle: a. The main factor inflicting blood to circulate by way of the body is a(n) gradient. In humans, the value of this gradient is highest at the and in the. In a system by which fluid is flowing, strain decreases over distance due to. List the events of the cardiac cycle in sequence, starting with atrial and ventricular diastole. Describe what happens to stress and blood flow in each chamber at every step of the cycle. Two drugs used to reduce cardiac output are calcium channel blockers and beta (receptor) blockers.

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In the intestines, the presence of pathogens could trigger elevated motility and secretory diarrhea [p. The digestive and respiratory techniques are most susceptible to microbial invasion as a outcome of these areas have in depth areas of thin epithelium in direct contact with the exterior setting. The opening to the uterus is normally sealed by a plug of mucus that retains bacteria in the vagina from ascending into the uterine cavity. Secretions from exocrine glands and mechanical elimination of pathogens help the bodily obstacles. In the respiratory system, inhaled particulate matter is trapped by mucus lining the higher respiratory system. The mucus is then transported upward on the mucociliary escalator to be expelled or swallowed [p. Respiratory tract secretions, saliva, and tears contain lysozyme, an enzyme with antibacterial exercise. Lysozyme assaults cell wall parts of unencapsulated micro organism and breaks them down. Innate immunity either clears the infection or incorporates it till the adaptive immune response is active. First, patrolling and stationary leukocytes are attracted to areas of invasion by chemical alerts known as chemotaxins. Products of tissue injury, such as fibrin and collagen fragments, may also point out a location that wants defending. Once on site, activated leukocytes secrete their own chemotaxic cytokines to deliver additional leukocytes to the an infection web site. Tissue macrophages and neutrophils are the first phagocytic cells liable for the initial defense. If an area of an infection attracts numerous leukocytes, the fabric we call pus might kind. This thick, whitish to greenish substance is a group of dwelling and lifeless neutrophils and macrophages, together with tissue fluid, cell debris, and other remnants of the immune process. Phagocytosis Phagocytes are a useful group of white blood cells that engulf and ingest their targets by phagocytosis [p. The major phagocytes of the innate response are the neutrophils and macrophages. Phagocytosis is a receptor-mediated occasion, which ensures that only unwanted particles are ingested. The phagocyte receptors acknowledge many various sorts of international particles, each natural and inorganic, leading the cells to ingest everything from unencapsulated micro organism and cell fragments to carbon and asbestos particles. They will even ingest tiny polystyrene beads, providing a method that scientists in the laboratory analyze phagocytic exercise. In a sequence paying homage to a zipper closing 1, the ligands and receptors mix sequentially, so that the phagocyte surrounds the unwanted overseas particle. The course of is aided by actin filaments that push arms of the phagocytic cell around the invader. For instance, certain bacteria have evolved a polysaccharide capsule that masks their surface markers from the host immune system. Complete elimination of the virus requires activation of a particular immune response. Phagosome Ingested pathogen three Lysosomal enzymes digest pathogen, producing antigenic fragments. Antigenic fragment display viral antigen on its floor, which permits the virus to cover undetected contained in the cell. Inflammation has three essential roles in fighting an infection in damaged tissue: (1) attracting immune cells and chemical mediators to the location, (2) producing a bodily barrier to retard the unfold of infection, and (3) promoting tissue repair as soon as the an infection is under control (a nonimmunological function). The inflammatory response has 4 traditional indicators: redness (rubor), warmth (calor), swelling (tumor), and ache (dolor), all created when activated immune cells release cytokines.

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The pons acts as a relay station for info between the cerebellum and cerebrum. The midbrain controls eye motion and relays signals for auditory and visual reflexes. The cerebellum processes sensory information and coordinates the execution of movement. The thalamus relays and modifies sensory and motor info going to and from the cerebral cortex. The hypothalamus accommodates centers for behavioral drives and performs a key position in homeostasis by its management over endocrine and autonomic operate. The pituitary gland and pineal gland are endocrine glands situated within the diencephalon. Each cerebral hemisphere is divided into frontal, parietal, temporal, and occipital lobes. Cerebral grey matter contains the cerebral cortex, basal ganglia, and limbic system. The limbic system acts because the hyperlink between cognitive functions and emotional responses. It includes the amygdala and cingulate gyrus, linked to emotion and reminiscence, and the hippocampus, associated with learning and memory. Motor output contains skeletal muscle motion, neuroendocrine secretion, and visceral responses. Each cerebral hemisphere accommodates a main motor cortex and motor association space. The behavioral state system controls states of arousal and modulates the sensory and cognitive techniques. The diffuse modulatory systems of the reticular formation affect consideration, motivation, wakefulness, memory, motor control, mood, and metabolic homeostasis. The reticular activating system keeps the brain aware, or aware of self and surroundings. Electrical exercise in the mind varies with ranges of arousal and could be recorded by electroencephalography. Circadian rhythms are controlled by an inner clock within the suprachiasmatic nucleus of the hypothalamus. Motivation arises from internal indicators that shape voluntary behaviors related to survival or feelings. In sensitization, publicity to a noxious or intense stimulus creates an enhanced response on subsequent publicity. Information is first stored in short-term memory but disappears until consolidated into long-term reminiscence. The consolidation of short-term memory into long-term reminiscence appears to involve modifications in the synaptic connections of the circuits concerned in learning. Three mind techniques affect motor output: a sensory system, a cognitive system, and a behavioral state system. The cerebral cortex incorporates three practical specializations: sensory areas, motor areas, and association areas. Each hemisphere of the cerebrum has developed functions not shared by the other hemisphere, a specialization generally known as cerebral lateralization. The major somatic sensory cortex processes information about touch, temperature, and other somatic senses. The visual cortex, auditory cortex, gustatory cortex, and olfactory cortex obtain details about imaginative and prescient, sound, style, and odors, respectively. The capacity of human brains to change circuit connections and function in response to sensory enter and past expertise is called. The a half of the brain known as the is what makes us human, allowing human reasoning and cognition.

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These suggest the inconsistency between in vivo development and in vitro differentiation of pluripotent stem cells. Thus, further and extensive investigation and consideration are wanted before transferring the advances of in vitro improvement into purposes. An different approach to get hold of germ cells might be to convert other kinds of cells to germ cells instead of differentiating germ cells from pluripotent stem cells. These results suggest that methods such as transdifferentiation or other traditional strategies combined with new applied sciences could also be a method to get germ cells. Ethical issues are one other concern in the complete reconstitution of germ cells in vitro, especially human germ cells. Administrative tips are essential to instruct the applying of the relevant applied sciences and strategies. Obtaining top quality gametes continues to be the last word aim of reproductive biology sooner or later. Reconstituting human germ cell growth in vitro would give us new perspectives of fundamental analysis on germ cells, and supply new possibilities to deal with diseases arising from its anomalies. The knowledge and applied sciences can be utilized not only to help people, but also to preserve uncommon animal species and preserve species range. The zinc finger transcriptional repressor Blimp1/Prdm1 is dispensable for early axis formation but is required for specification of primordial germ cells within the mouse. Critical operate of Prdm14 for the institution of the germ cell lineage in mice. Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice. Proliferation and migration of primordial germ cells throughout compensatory development in mouse embryos. Extensive and orderly reprogramming of genomewide chromatin modifications related to specification and early growth of germ cells in mice. Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development within the mouse. Germ cell numbers in human embryonic and fetal gonads through the first two trimesters of pregnancy: analysis of six printed studies. Self-renewing epiblast stem cells exhibit continuous delineation of germ cells with epigenetic reprogramming in vitro. Offspring from oocytes derived from in vitro primordial germ cell-like cells in mice. Derivation of primordial germ cells from human embryonic and induced pluripotent stem cells is considerably improved by coculture with human fetal gonadal cells. Germline development from human pluripotent stem cells toward illness modeling of infertility. A mesodermal issue, T, specifies mouse germ cell fate by immediately activating germline determinants. A tripartite transcription factor network regulates primordial germ cell specification in mice. Cellular dynamics related to the genomewide epigenetic reprogramming in migrating primordial germ cells in mice. Suppression of Erk signalling promotes floor state pluripotency within the mouse embryo. In vitro-differentiated embryonic stem cells give rise to male gametes that may generate offspring mice. Spermatogenesis from epiblast and primordial germ cells following transplantation into postnatal mouse testis. Long-term proliferation in tradition and germline transmission of mouse male germline stem cells. Genetic and epigenetic properties of mouse male germline stem cells throughout long-term culture. Long-term ex vivo maintenance of testis tissues producing fertile sperm in a microfluidic device. Stra8 and its inducer, retinoic acid, regulate meiotic initiation in both spermatogenesis and oogenesis in mice. Gene expression dynamics throughout germline specification in mice recognized by quantitative single-cell gene expression profiling.

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In the face of constant diminished sympathetic input, goal tissues up-regulate [p. This complication of diabetes usually begins as a sensory neuropathy, with tingling and loss of sensation within the hands and feet. About 30% of diabetic patients go on to develop autonomic neuropathies, manifested by dysfunction of the cardiovascular, gastrointestinal, urinary, and reproductive methods (abnormal heart rate, constipation, incontinence, impotence). Contributing components that lead to damage or loss of myelinated and unmyelinated nerve fibers embody oxidative stress, inflammation, and disruptions to glucose metabolism. Both sympathetic and parasympathetic pathways encompass two neurons (preganglionic and postganglionic) in collection. One exception to this rule is the adrenal medulla, during which postganglionic sympathetic neurons have been modified into a neuroendocrine organ. All preganglionic autonomic neurons secrete acetylcholine onto nicotinic receptors. Sympathetic pathways originate in the thoracic and lumbar regions of the spinal wire. Most sympathetic ganglia are situated near the spinal twine (are paravertebral). The sympathetic department controls functions which may be useful in stress or emergencies (fight-or-flight). Somatic pathways are always excitatory, not like autonomic pathways, which may be both excitatory or inhibitory. A Somatic Motor Pathway Consists of One Neuron the cell our bodies of somatic motor neurons are situated either in the ventral horn of the spinal cord [p. These adhesive patches permit the former smoker to progressively lower nicotine levels in the physique, stopping withdrawal signs through the time the cells are down-regulating their receptors again to the conventional number. When Shanika reads the package deal insert previous to making use of her first nicotine patch, she notices a warning to keep the patches away from kids. An overdose of nicotine (highly unlikely when the patch is used as directed) could result in complete paralysis of the respiratory muscle tissue (the diaphragm and the skeletal muscles of the chest wall). This branching construction allows a single motor neuron to management many muscle fibers at one time. In addition, the neuromuscular junction includes extensions of Schwann cells that type a thin layer masking the top of the axon terminals. For years, it was thought that this cell layer simply provided insulation to pace up the conduction of the motion potential, but we now know that Schwann cells secrete quite so much of chemical signal molecules. These signal molecules play a important function within the formation and upkeep of neuromuscular junctions. Between the axon and the muscle, the synaptic cleft is filled with a fibrous matrix whose collagen fibers maintain the axon terminal and the motor end plate within the proper alignment. Is the ventral horn of the spinal wire, which incorporates the cell bodies of somatic motor neurons, gray matter or white matter Schwann cell sheath Axon terminal Motor end plate Mitochondrion (a) the neuromuscular junction consists of axon terminals, motor finish plates on the muscle membrane, and Schwann cell sheaths. Skeletal muscle fiber Motor end plate (c) Neuromuscular junction (d) An motion potential arrives at the axon terminal, inflicting voltage-gated Ca2+ channels to open. Why would administration of a drug that inhibits acetylcholinesterase (an anticholinesterase) improve muscle function in these sufferers This distinction is illustrated by the fact that the snake toxin a@bungarotoxin binds to nicotinic skeletal muscle receptors but not to those in autonomic ganglia. In skeletal muscle, net Na+ entry into the muscle fiber depolarizes it, triggering an motion potential that causes contraction of the skeletal muscle cell. You will study later about how inhibition of somatic motor pathways controls body movement. Somatic motor neurons do greater than merely create contractions: They are necessary for muscle well being. Without communication between the motor neuron and the muscle, the skeletal muscle tissue for movement and posture weaken, as do the skeletal muscle tissue for respiratory.

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For this cause, when cholesterol within the food regimen is absorbed from the digestive tract, it combines with lipoproteins to make it more soluble. There, white blood cells referred to as macrophages ingest ldl cholesterol and other lipids to turn out to be lipid-filled foam cells 2. As the condition progresses, the lipid core grows, and easy muscle cells reproduce, forming bulging plaques that protrude into the lumen of the artery 4. In the advanced phases of atherosclerosis, the plaques develop hard, calcified regions and fibrous collagen caps (5 � 7). The mechanism by which calcium carbonate is deposited continues to be being investigated. Scientists once believed that the occlusion (blockage) of coronary blood vessels by large plaques that triggered blood clots was the first reason for coronary heart attacks, but that mannequin has been revised. The new mannequin signifies that blood clot formation on plaques is extra dependent on the structure of a plaque than on its dimension. Atherosclerosis is now thought-about to be an inflammatory course of during which macrophages release enzymes that convert stable plaques to vulnerable plaques 8. Vulnerable plaques have skinny fibrous caps which are extra likely to rupture, exposing collagen and activating platelets that initiate a blood clot (thrombus) 9. If a clot blocks blood flow to the center muscle, a heart attack, or myocardial infarction, outcomes [see the Running Problem in Chapter 14]. Blocked blood move in a coronary artery cuts off the oxygen provide to myocardial cells supplied by that artery. The unusually high Ca2+ concentration in the cytosol closes hole junctions within the broken cells. Closure electrically isolates the damaged cells in order that they no longer contract, and it forces action potentials to discover an alternate route from cell to cell. If the damaged space of myocardium is massive, the disruption can result in an irregular heartbeat (arrhythmia) and probably end in cardiac arrest or dying. Hypertension Represents a Failure of Homeostasis One controllable risk factor for cardiovascular disease is hypertension-chronically elevated blood strain, with systolic pressures greater than one hundred forty mm Hg or diastolic pressures higher than 90 mm Hg. Hypertension is a common disease within the United States and is amongst the most common causes for visits to physicians and for the utilization of prescribed drugs. More than 90% of all patients with hypertension are thought of to have essential (or primary) hypertension, with no clear-cut cause aside from heredity. Cardiac output is usually regular in these folks, and their elevated blood strain appears to be related to increased peripheral resistance. Some investigators have speculated that the elevated resistance may be as a end result of an absence of nitric oxide, the regionally produced vasodilator shaped by endothelial cells in the arterioles. In the remaining 5�10% of hypertensive instances, the cause is more apparent, and the hypertension is taken into account to 15. Smooth muscle cells, attracted by macrophage cytokines, start to divide and take up cholesterol. Macrophages may launch enzymes that dissolve collagen and convert steady plaques to unstable plaques. Platelets that are exposed to collagen turn into activated and provoke a blood clot. For instance, the cause may be an endocrine disorder that causes fluid retention. A key feature of hypertension from all causes is adaptation of the carotid and aortic baroreceptors to greater pressure, with subsequent down-regulation of their exercise. Without enter from the baroreceptors, the cardiovascular management heart interprets the high blood pressure as "normal," and no reflex discount of pressure occurs. Hypertension is a risk issue for atherosclerosis because high strain within the arteries damages the endothelial lining of the vessels and promotes the formation of atherosclerotic plaques. In addition, high arterial blood pressure places additional pressure on the heart by rising afterload [p. When resistance within the arterioles is excessive, the myocardium must work harder to push the blood into the arteries. Amazingly, stroke quantity in hypertensive patients remains constant up to a mean blood pressure of about 200 mm Hg, despite the growing quantity of labor that the ventricle should carry out as blood pressure increases.

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The pressure of ventricular contraction additionally will increase under sympathetic stimulation. The increased drive of contraction combines with elevated coronary heart fee to increase cardiac output. Simultaneously, sympathetic input causes arteriolar vasoconstriction, growing peripheral resistance. Increased sympathetic activity on the granular cells of the kidneys increases renin secretion. Cardiovascular responses mix elevated cardiac output and elevated peripheral resistance to elevate blood strain. If dehydration is severe, compensation could also be incomplete, and blood stress might stay below normal. In extreme dehydration, however, Na+ reabsorption worsens the already high osmolarity. Vasopressin increases the water permeability of the renal accumulating ducts, permitting water reabsorption to conserve fluid. The net result of all four mechanisms is (1) restoration of volume by water conservation and fluid intake, (2) upkeep of blood strain by way of elevated blood quantity, elevated cardiac output, and vasoconstriction, and (3) restoration of regular osmolarity by decreased Na+ reabsorption and elevated water reabsorption and consumption. If blood pressure falls, elevated sympathetic output to the vasculature causes vasoconstriction. In the kidney, sympathetic innervation vasocontricts each afferent and efferent arterioles, lowering renal blood move and conserving fluid. Many of the medicine prescribed for hypertension act on pathways linked to the kidney. Diuretics decrease ion reabsorption within the ascending limb of the loop of Henle ("loop diuretics") or in the distal convoluted tubule (thiazide diuretics), causing additional water excretion along with the unreabsorbed ions. In a small percentage (6 5%) of individuals with hypertension, the trigger of hypertension is narrowing (stenosis) of the renal artery. Decreasing blood circulate to the kidney triggers a sequence of compensatory events that end in elevated blood stress. Insufficient vasopressin exercise within the nephron results in inability of the kidney to reabsorb water and make concentrated urine. The massive volumes of dilute urine produced in the absence of adequate vasopressin activity create a situation referred to as diabetes insipidus. Diabetes refers to the extreme flow of urine, and insipid is "with out style," meaning the dilute nature of the urine. Map the pathway that begins with renal artery stenosis and ends with hypertension. Hypersecretion of aldosterone and pathologies of vasopressin secretion and action are the commonest endocrine issues affecting fluid and electrolyte steadiness. Disorders of aldosterone secretion are pH Changes Can Denature Proteins the conventional pH vary of plasma is 7. Acidic secretions within the abdomen, for instance, could create a gastric pH as little as 1. Intracellular proteins, corresponding to enzymes and membrane channels, are particularly delicate to pH as a end result of the perform of those proteins depends on their three-dimensional form. Under extraordinary circumstances, metabolic natural acid manufacturing can increase considerably and create a disaster. In diabetes mellitus, abnormal metabolism of fat and amino acids creates strong acids often identified as ketoacids. If pH is just too high-the situation generally recognized as alkalosis- neurons turn into hyperexcitable, firing action potentials on the slightest sign. This situation exhibits up first as sensory modifications, similar to numbness or tingling, then as muscle twitches. If alkalosis is severe, muscle twitches turn into sustained contractions (tetanus) that paralyze respiratory muscular tissues. This is partly as a end result of a renal transporter that strikes K+ and H+ ions in an antiport trend. Potassium imbalance normally reveals up as disturbances in excitable tissues, especially the center. Acids and Bases in the Body Come from Many Sources In day-to-day functioning, the physique is challenged by consumption and manufacturing of acids more than bases.

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Regulation of male sex willpower: genital ridge formation and Sry activation in mice. Anomalies in human intercourse dedication provide distinctive insights into the complicated genetic interactions of early gonad development. Six1 and Six4 are important for Gdnf expression within the metanephric mesenchyme and ureteric bud formation, whereas Six1 deficiency alone causes mesonephric-tubule defects. Homeoproteins Six1 and Six4 regulate male intercourse willpower and mouse gonadal growth. Hoxa 11 structure, intensive antisense transcription, and function in male and female fertility. A conserved Hox axis in the mouse and human female reproductive system: Late institution and persistent grownup expression of the Hoxa cluster genes. Mechanisms of decreased fertility in Hoxa-10 mutant mice: uterine homeosis and lack of maternal Hoxa-10 expression. Genetic syndromes and genes involved in the growth of the female reproductive tract: a possible function for gene therapy. Wnt-7a maintains appropriate uterine patterning in the course of the growth of the mouse female reproductive tract. It supplies for the "gene shuffling" that leads to genetic variety in populations, and in addition ensures the genomic integrity and correct variety of chromosomes that produce healthy offspring. Meiosis is an area of intense investigation in the fields of developmental and reproductive medication. Given the space limitations of this chapter, readers are regularly referred to many glorious evaluations rather than major literature. The goal of this chapter is to provide genetic views on meiosis which may be helpful in the context of human well being, fertility, and illness. The emphasis is on how the advanced chromosomal dynamics of meiosis are revealed through the lens of insights derived from the evaluation of mutations within the controlling genes. The purview extends beyond human biology to research of meiosis in model animal organisms (particularly the laboratory mouse), which have recognized lots of the genes and proteins talked about on this review (Table 3. Finally, human well being issues relevant to meiotic processes are discussed with the attitude that information of meiotic mechanisms will improve the understanding of human fertility, infertility, health, and illness. Additionally, mitosis yields genetically equivalent cells whereas meiosis produces genetically distinct cells that turn out to be the gametes. These defining features of meiosis are enabled by pairing and recombination between homologous chromosomes, which units the stage for the 2 meiotic divisions. The end products form the haploid gametes, with one copy of each homologous chromosome. As the homolog pairing and synapsis processes progress, molecular recombination occurs between nonsister chromatids, a course of starting during the leptotene substage and lasting via the pachytene substage. After nuclear envelope breakdown, microtubules attach to kinetochores in metaphase I, followed by separation of homologs throughout anaphase I and cytokinesis in telophase on the finish of the first meiotic division. In the ensuing second meiotic division, sister chromatids align at metaphase and segregate during anaphase and telophase, producing haploid germ cells (1N, 1C). There is appreciable sexual dimorphism in the timing of meiotic events in mammals. In females (left panel), meiotic prophase is initiated throughout fetal growth after which is arrested at the finish of the primary meiotic prophase, around the time of delivery in mice. After ovulation and fertilization of the oocyte, meiosis is accomplished, leading to a haploid female pronucleus. In males (right panel), from puberty onward steady waves of germ cells enter meiosis. Following the second meiotic division, haploid germ cells bear extensive differentiation to form spermatozoa. Many of the vital thing events of meiosis happen during the first lengthy meiotic prophase in 5 distinct substages, diagrammatically illustrated right here.

References

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• Bickerstaff L, Pairolero P, Hollier L, et al: Thoracic aortic aneurysms: a population-based study, Surgery 92(6):1103-1108, 1982.