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We discuss molecular aspects of autophagy in Chapter 3 arrhythmia 16 year old generic zestoretic 17.5 mg otc, Cell Signaling Box 2-E Lysosome hydrolytic enzymes can be secreted · Some cell types can store and secrete lysosomal hydrolytic enzymes. Loss of function mutations in proteins critical for lysosomal function (such as lysosomal enzymes, lysosomal integral membrane proteins, involved in post-translational modifications and trafficking of lysosomal proteins) cause substrate accumulation and lysosomal storage defects. Many affected individuals are clinically normal at birth, an indication that impaired lysosomal function does not affect neuronal function during early brain development. You may like to focus again on 2-13 and 2-14 to review the pathway followed by hydrolytic enzymes to reach the lysosome and the highlights of the sequence steps of endocytosis, phagocytosis and macroautophagy (see Primer 2-D). Furthermore, the microscopy analysis of biopsied tissues and biochemical evaluation of accumulated cellular substrates can determine the underlying enzymatic defects of lysosomal storage material. These molecular complexes can derive from the turnover of intracellular organelles or enter the cell by phagocytosis. A number of genetic diseases lacking lysosome enzymes result in the progressive accumulation within the cell of partially degraded insoluble products. Amniocentesis to assay for -N-acetylhexosaminidase activity during prenatal development can diagnose the inherited autosomal recessive disease. Type 2 occurs at 2 to 3 months of age, is associated with neurologic symptoms and death usually occurs by 2 years of age. Type 3 is seen in the adult, is associated with hepatosplenomegaly and has a neurologic component. Mitochondria (2-17 and 2-18) the mitochondrion (Greek mito, thread; chondrion, granule) is a highly compartmentalized organelle. A mitochondrion consists of an outer mitochondrial membrane and an inner mitochondrial membrane creating an intermembrane space between them (see 2-17). The matrix is partitioned by infoldings of the inner mitochondrial membrane known as cristae. Targeting polypeptide signals and chaperones (Hsp60 and Hsp70) enable proteins to reach the matrix (see 2-18). It contains porins, proteins that form aqueous channels permeable to water-soluble molecules with a reduced molecular mass (less than 5 kd), such as sugars, amino acids and ions. The inner mitochondrial membrane is impermeable to the passage of ions and small molecules. Most of the proteins embedded in the inner mitochondrial membrane are components of the electron-transport chain, involved in oxidative phosphorylation. The mitochondrial matrix contains pyruvate (derived from carbohydrates) and fatty acids (derived from fat). These two small molecules are selectively transported across the inner mitochondrial membrane and then converted to acetyl coenzyme A (acetyl CoA) in the matrix. As the high-energy electrons travel along the electron-transport chain, energy is released by proton pumps as H+ across the inner mitochondrial membrane into the intermembrane space. The components of the electron-transport chain are present in many copies embedded in the lipid bilayer of the inner mitochondrial membrane. They are grouped into three large respiratory enzyme complexes in the receiving order of electrons: 1. Each complex is a system that pumps H+ across the inner mitochondrial membrane into the intermembrane space as electrons travel through the complex. If this mechanism did not exist, the energy released during electron transfer would produce heat. Four electrons and four H+ are added to each mitochondria across the outer mitochondrial membrane and converted in the mitochondrial matrix into acetyl coenzyme A (acetyl molecule of O2 for two molecules of H2O. Porins are permeable aqueous (H+) is released across the inner membrane into the intermembrane channels located along the outer mitochondrial membrane. These carriers donate their high-energy electrons to the electron-transport chain located in the inner mitochondrial membrane. When the cytochrome oxidase complex receives electrons from cytochrome c, it becomes oxidized and donates electrons to O2 to form H2O. Four electrons from cytochrome c and four H+ from the aqueous environment are added to each molecule of O2 to form 2H2O.

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The cytoplasm of the basal layer cells express keratin 5 and keratin 14 (K5 and K14) blood pressure chart 16 year old 17.5 mg zestoretic buy with amex, which are replaced in the upper layers by corneal-specific K3 and K12. The highly transparent stroma or substantia propria represents about 90% of the thickness of the cornea. Bundles of types I and V collagen form thin layers regularly arranged in successive planes crossing at various angles and forming a lattice, which is highly resistant to deformations and trauma. Box 9-B Cornea transplantation · Cornea transplantation, also known as penetrating keratoplasty, is the most common form of tissue allotransplantation (Greek allos, other) with a success rate of over 90%. It consists of a single layer of squamous epithelial cells, with impermeable intercellular spaces preventing influx of aqueous humor into the corneal stroma. The structural and functional integrity of the corneal endothelium is vital to the maintenance of corneal transparency (see Box 9-B). Middle tunic: Uvea (9-6 to 9-8; see 9-4) the uvea forms the pigmented vascularized tunic of the eye and is divided into three regions (see 9-4; see Box 9-C): 1. Basal laminae derive from the pigmented epithelium of the retina and the endothelia of the underlying fenestrated capillaries. The rest of the wall of the eye, the sclera (Greek scleros, hard), is opaque and lined inside by the middle or vascular pigmented layer that absorbs light. The limbus is the zone of transition of the epithelium of the conjunctiva with that of the cornea. Middle tunic: Uvea In the posterior two-thirds of the eye, the vascular layer is called the choroid. In the anterior part of the eye the vascular layer thickens to form the ciliary body. The smooth muscle of the ciliary body regulates the tension of the zonule or suspensory ligament of the lens and, therefore, is an important element in the mechanism of accommodation. Outer pigmented layer Retina Inner tunic: Retina It consists of two layers: (1) an outer pigmented layer (pars pigmentosa) and (2) an inner retinal layer (pars nervosa or optica). The retina has a posterior two-thirds light-sensitive zone (pars optica) and an anterior one-third light-nonsensitive zone (pars ciliaris and iridica). The scalloped border between these two zones is called the ora serrata (Latin ora, edge; serrata, saw-like). The retina contains photoreceptor neurons (cones and rods), conducting neurons (bipolar and ganglion cells), association neurons (horizontal and amacrine cells) and a supporting neuroglial cell, the Müller cell. Each eye contains about 125 million rods and cones but only 1 million ganglion cells. Axons from the retinal ganglion cells pass across the surface of the retina, converge on the papilla or optic disk, and leave the eye through many openings of the sclera (the lamina cribrosa) to form the optic nerve. The uvea can be affected by several inflammatory processes known as uveitis, which can target the iris (iritis), the ciliary body (cyclitis) and the choroid (choroiditis). The inflammatory destruction of the choroid can cause degeneration of the photoreceptors whose nutrition depends on the integrity of the choroid. The choroidal stroma consists of large arteries and veins surrounded by collagen and elastic fibers, fibroblasts, a few smooth muscle cells, neurons of the autonomic nervous system and melanocytes. The ciliary body is anterior to the ora serrata and represents the ventral projection of both the choroid and the retina. The basal cells of the corneal epithelium are anchored, to Bowman s layer by hemidesmosomes. Microvilli Corneal epithelium Desmosome Hemidesmosome, Bowman s layer Myelinated nerves can be found in the stroma. After crossing, Bowman s layer, nerves become unmyelinated and extend toward the surface in the intercellular spaces of the corneal epithelium. Schwann cell Stroma Fibroblasts the stroma is formed by collagen lamellae oriented at an angle to one another. Corneal endothelium is permeable to air oxygen used for various oxidative reactions, in particular glutathione reduction and oxidation. The neuroepithelial portion contributes the two layers of the ciliary epithelium: 1. An outer pigmented epithelial layer, continuous with the retinal pigmented epithelium.

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Enzymes of the smooth endoplasmic reticulum convert pregnenolone to progesterone to testosterone blood pressure medication dizzy spells best 17.5 mg zestoretic. Review 20-14 to integrate the various aspects of the hormonal regulation of spermatogenesis. The maintenance and progression of spermatogenesis depends also on other factors, involving Sertoli cell function. Let us focus on the most relevant functions: (1) Sertoli cells assist in the translocation of interconnected members of the spermatogonia progeny across inter-Sertoli cell tight junctions, from the basal compartment to the adluminal compartment of the seminiferous epithelium. This mechanism allows Sertoli cells to ensure a steady sperm release by timing the start of a new spermatogonial cell progeny. It enhances androgen concentration in the epididymis, assisting in sperm maturation (remote action). As a result of synchrony and overlapping spermatogenic cell progenies, a series of cellular combinations, called a cellular associations visualized in cross sections of seminiferous tubules. A spermatogenic cycle is defined as the time it takes for the reappearance of the same stage, or cellular association, within a given segment of the seminiferous tubule. A spermatogenic wave is defined as the distance (space) between two identical stages, or cellular associations, along the length of the seminiferous tubule. The progression of spermatogenic cell progenies in human testes is helicoidal, instead of linear as in rodents. The basis of epigenetics is the methylation of cytosine-phospho-guanosine (CpG) islands seen predominantly in actively transcribing genes. During spermatogenesis and oogenesis, the genetic imprints of the gametes are erased, allowing the epigenetic reprogramming of the embryos. Reprogramming consists of the differential expression of a number of alleles in the paternal and maternal gametes. The pluripotent inner cell mass of the blastocyst erases the epigenetic memory before implantation. Histone deacetylation enables histone methyltransferases to methylate histone 3 and recruit heterochromatin protein-1 to trigger chromatin condensation. As you already know, heterochromatin (condensed chromatin) is transcriptionally inactive. An increase in X-chromosome number is a common feature of testicular germ cell tumors. The tumor cells show large nuclei with an irregular outline and noticeable nucleoli. Teratoma is a benign germ cell tumor derived from a combination of tissues from all three embryonic layers (ectoderm, mesoderm and endoderm). The tumor consists of blood vessels surrounded by squamous tumor cells organizing glomerular-like structures known as Schiller-Duval bodies. Secretions from the epididymal duct, combined mainly with additional products of the prostate and seminal vesicles, contribute to the maturation and viability of the male gamete. This article starts by reviewing the major developmental steps of the gonads and the excurrent (efferent) ducts. This review leads to an understanding of the histology, function and clinical significance of the pathway followed by male and female gametes in the pursuit of fertilization. Recall that hematopoiesis and the development of melanocytes and mast cells depend on the c-kit receptor and its stem cell ligand. Coelomic epithelial cords grow into the mesenchyme of the gonadal ridge to form the outer cortex and inner medulla of the indifferent gonad. Development of the testes (21-1; see Primer 21-A) Until the seventh week of fetal development, there is one type of gonad common to both genders. Thereafter, in the female, the cortex develops into the ovary, and the medulla regresses. We have learned in Chapter 4, Connective Tissue, that Sox9 participates in chondrogenesis, by enabling cells in the perichondrium to differentiate into chondrocytes. Therefore, Sox9 is important for the development of the male reproductive system and the skeleton. The initial step of testicular development is the differentiation of the Sertoli cell population regulated by the Y chromosome.

Syndromes

• Prolactin blood test
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• Human immunodeficiency disease (HIV)
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• Yellow skin
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As basal epidermal cell clusters extend into the dermis prehypertension questions buy generic zestoretic canada, dermal fibroblasts form a small nodule (called a dermal papilla) under the hair germ. The dermal papilla pushes into the core of the hair germ, whose cells divide and differentiate to form the keratinized hair shaft. A bulbous swelling (called the follicular bulge) on the side of the hair germ contains stem cells, called clonogenic keratinocytes. Clonogenic keratinocytes can migrate and regenerate the hair shaft, the epidermis and sebaceous gland, forming pilosebaceous units, in response to morphogenetic signals. The first adult hair follicle cycle starts once morphogenesis is completed about 18 days after birth, the first hair in the human embryo is thin, unpigmented and spaced and is called lanugo. Terminal hair replaces vellus, which remains in the so-called hairless parts of the skin (such as the forehead of the adult and armpits of infants). Hair follicles are tubular invaginations of the epidermis responsible for the growth of hair. During the first 28 days of the telogen phase, hair follicles become quiescent because of growth Each hair follicle consists of two parts: 1. The hair shaft is a filamentous keratinized structure present almost all over the body surface, except on the thick skin of the palms and soles, the sides of the fingers and toes, the nipples and the glans penis and the clitoris, among others. A vascularized connective tissue core (dermal papilla) projects into the hair bulb, in close proximity to matrix cells A cross section of the hair shaft reveals, from the periphery to the center, three concentric zones containing keratinized cells (see 11-16): 1. The keratinization of the hair and internal root sheath occurs in a region called the keratogenous zone, the transition zone between maturing epidermal cells and hard keratin. The hair follicle is surrounded by a connective tissue layer and associated with the arrector pili muscle, a bundle of smooth muscle fibers aligned at an oblique angle to the connective tissue sheath and the epidermis. The autonomic nervous system controls the arrector pili muscle, which contracts during fear, strong emotions and cold temperature. When the hairs stand up, the attachment site of the muscle bundle at the epidermis forms a groove, the so called goose flesh. The hair follicle is associated with sebaceous glands with their excretory duct connected to the lumen of the hair follicle. When the arrector pili muscle contracts and the hair stands up, sebum is forced out of the sebaceous gland into the lumen of the hair follicle. Zone of dividing cells of the hair matrix, comparable to the stratum basale of the epidermis. This zone contains melanocytes which give color to the hair by passing melanin to the matrix cells. Patients with Griscelli syndrome have silvery hair because of a mutation in the myosin Va gene involved in the transport of melanin-containing melanosomes. The color of the hair depends on the amount and distribution of melanin in the hair shaft. Red hair has a chemically distinct melanin and melanosomes are round rather than ellipsoid. A structure that is not recognized in routine histologic sections of hairs is the peritrichial nerve endings wrapped around the base of the hair follicle. We discussed earlier in this chapter the participation of myosin Va in the transport of 410 melanin-containing melanosomes to keratinocytes (called matrix cells in the hair bulb) and the lack of hair pigmentation in patients with Griscelli syndrome caused by mutations of myosin Va, Rab27a and melanophilin genes. Lgr5+ stem cell pathways (11-17) Skin repairs efficiently after wounding and restores the barrier properties of the tissue but lacks appendages, such as hair follicles and sweat glands, that are required for normal skin function. They can differentiate into epidermal lineages and follow independent cell migration pathways to the interfollicular epidermis, the hair follicle and the sebaceous gland. Squamous cell carcinoma, basal cell carcinoma and hair-follicle tumors can originate from cells exiting the bulge following activation of specific genetic pathways. Regulatory factors (bone morphogenetic proteins and Notch and Wnt signaling), released by cells of the dermal papilla and neighboring adipose cells, are essential for maintaining the proliferative potential of the matrix and their differentiation into the various hair cell lineages. Which signaling pathways are involved in maintaining the stem cell populations of the skin Sonic Hedgehog (Shh) signaling is expressed in stem cells of the hair follicle and sebaceous gland during cell proliferation and differentiation. Their short ducts, lined by a stratified squamous epithelium continuous with the external root sheath of the hair, open into the hair canal (see arrow). Hair-independent sebaceous glands can be found on the lips, areolae of the nipples, the labia minora and the inner surface of the prepuce. Arrector pili muscle 3 Sebum Hair shaft 2 1 Sebaceous gland Basal lamina 1 Basal cells regenerate sebum-producing cells lost during the holocrine secretory process.

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The secretion of bile acids generates the osmotic gradient necessary for osmotic water flow into the bile canaliculus blood pressure normal range for adults 17.5 mg zestoretic buy otc. Finally, hydrolytic enzymes associated with the plasma membrane (ectoenzymes) of the bile canaliculus and bile duct produce nucleoside and amino acid breakdown products, which are reabsorbed by ductular epithelial cells. Phospholipids (mainly phosphatidylcholine) solubilize cholesterol (preventing the formation of cholesterol gallstones) and reduce the detergent action of bile salts in the small intestine. A number of hydrolytic enzymes on the luminal surface of the bile canaliculus (ectoenzymes) generate nucleosides and amino acids that can be taken up by the ductular epithelial cells. Composition of the bile (see Primer 17-A) the human liver produces about 600 mL of bile per day. The bile consists of organic components (such as bile acids, the major component; phospholipids, mainly lecithins; cholesterol; and bile pigments, bilirubin) and inorganic components (predominantly Na+ and Cl­ ions). Bile acids (cholic acid, chenodeoxycholic acid, deoxycholic acid and lithocholic acid) are synthesized by the hepatocytes. Cholic and chenodeoxycholic acids are synthesized from cholesterol as a precursor and are called primary bile acids. Deoxycholic and lithocholic acids are called secondary bile acids because they are produced in the intestinal lumen by the action of intestinal bacteria on the primary bile acids. The synthetic bile acid pathway is the major mechanism of elimination of cholesterol from the body. Micelles are formed by the aggregation of bile acid molecules conjugated to taurine or glycine. Bile secreted by the liver is stored in the gallblad- der and released into the duodenum during a meal to facilitate the breakdown and absorption of fats (see Chapter 16, Lower Digestive Segment). About 90% of both primary and secondary bile acids is absorbed from the intestinal lumen by enterocytes and transported back to the liver through the portal vein. The absorption of bile acids by the enterocyte is mediated at the apical plasma membrane by an Na+-dependent transporter protein and released through the basolateral plasma membrane by an Na+-independent anion exchanger. Bilirubin is reduced to urobilinogen by bacteria in the distal small intestine and colon. Urobilinogen is partially secreted in the feces, part returns to the liver through the portal vein and some is excreted in urine as urobilin, the oxidized form of urobilinogen. Bile acids establish an osmotic gradient that mobilizes water and electrolytes into the bile canaliculus. The sphincter of Oddi is a thickening of the circular muscle layer of the bile duct at the duodenal junction. During fasting, the sphincter of Oddi is closed and bile flows into the gallbladder. Bile secretion during meal digestion is initiated by the cholecystokinin-induced contraction of the muscularis of the gallbladder in response to lipids in the intestinal lumen, assisted by the muscular activities of the common bile duct, the sphincter of Oddi and the duodenum. Digestive Glands Concept Mapping and Essential Concepts Cholecystokinin stimulates the relaxation of the sphincter of Oddi, enabling bile to enter the duodenum. Note that cholecystokinin has opposite effects: it stimulates muscle contraction of the gallbladder and induces muscle relaxation of the sphincter of Oddi. Conditions affecting bile secretion Because bile secretion involves the hepatocytes, bile ducts, gallbladder and intestine, any perturbation along this pathway can result in a pathologic condition. For example, destruction of hepatocytes by viral infection (viral hepatitis) and toxins can lead to a decrease in bile production as well as an increase in bilirubin in blood (jaundice). Obstruction of the passages by gallstones, biliary tract diseases (such as primary sclerosing cholangitis) or tumors (for example, cholangiocarcinoma) can block the flow of bile, with bile reflux to the liver and then to the systemic circulation. Digestive glands Salivary glands Parotid gland Submandibular gland Sublingual gland Pancreas Hepatic lobule Hepatocyte plates Bile canaliculi Hepatic sinusoids Liver Portal space Hepatic artery/arteriole Portal venule Secretory portion Serous acinus Myoepithelial cells Long intercalated duct Short striated duct Mixed acinus Myoepithelial cells Short intercalated duct Long striated duct Mucous acinus Myoepithelial cells Poorly developed intercalated and striated ducts Serous acinus Centroacinar cells Myoepithelial cells absent Bile duct Lymphatic vessel Central venule Endothelial cells Kupffer cells Excretory duct Intercalated duct Striated duct absent Space of Disse Space of Mall Perisinusoidal cell Canal of Hering (cholangiole) · the three major digestive glands are: (1) the salivary glands: the parotid, submandibular and sublingual glands. Each acinus is drained sequentially by: (1) An intercalated duct, lined by low squamous-tocuboidal simple epithelium. Striated ducts converge toward interlobular ducts, found between lobules in the connective tissue interlobular septa. Lobar ducts join the main duct, which displays a stratified squamous epithelium near its opening in the oral cavity. Submandibular glands produce 70% of the saliva; the parotid glands contribute 25%. The main products in saliva are: (1) Lysozyme, which attacks the walls of bacteria. The digestive function of saliva relies on: (1) Amylase (ptyalin), which initiates the digestion of carbohydrates (starch) in the oral cavity.

References

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• Jernberg T, Lindahl B, Siegbahn A, et al: N-terminal pro brain natriuretic peptide in relation to inflammation, myocardial necrosis, and the effect of an invasive strategy in unstable coronary artery disease. J Am Coll Cardiol 2003;42:1909-1916.