Anna-Lena Hellstr?m, MD

• Urotherapist and Professor,
• Queen Silvia Children? Hospital,
• G?teborg, Sweden

Although it is not known what determines whether or not autophagy will result in cell death, it is generally believed that the degree and duration of autophagy plays a role ulterior motive buy cheap inderal 80 mg on-line. Lysosomal proteases, cathepsin B, D, and L, have been shown to mediate apoptosis in a number of cell types arteria alveolaris superior posterior inderal 80 mg generic. However, the fundamental mechanisms involved in autophagy and the specific roles played by these proteins in sequestering vesicle formation remain to be elucidated pulse pressure low buy inderal no prescription. In addition, the roles of autophagy in physiology and pathology of mammalian cells are only beginning to be realized hypertension cardiovascular disease discount inderal 10mg fast delivery. There are certainly differences involving apoptosis, and the primary one is the high incidence of colon cancer compared to cancer of the small bowel, but there are also many similarities hypertension ranges buy genuine inderal online. The comparisons and contrasts between the two tissues avoid redundancy and often provide obvious explanations of differences in physiology and pathology heart attack 40 generic inderal 10mg fast delivery. The intestinal epithelium provides an interesting yet complicated model in which to study apoptosis. This tissue has one of the most rapid turnover rates known, as cells are lost into the lumen and replaced by the progeny of stem cells. Apoptosis plays a role both in the loss of cells and in regulating the number of stem cells. Both proliferation and apoptosis are affected by the hormones, growth factors, and influences that regulate the growth of all tissues in the body. In addition, however, the lining of the gut Chapter 13 Programmed Cell Death in the Gastrointestinal Tract 385 is subjected to luminal contents in the form of nutrients, digestion products, bacteria, and growth factors. For the most part, these studies have focused on describing spontaneous apoptosis and damage or stress-induced apoptosis. Many of these have identified the roles of members of the Bcl-2 family of proteins and p53. However, there have been few studies that have examined the overall regulatory process of apoptosis in the intestine. There has been little progress in developing appropriate in vitro models of normal intestinal cells. The most widely used intestinal cell lines have been developed from tumors and are abnormal. Villus 3 Days Enterocytes Goblet cells Enteroendocrine cells Crypt Proliferative Transit cells Stem cell(s) 13. The crypt to villus ratio varies from approximately 14 crypts per villus in the duodenum to about 6 crypts per ileal villus. The longer duodenal villi each contain approximately 7800 cells, whereas those in the ileum contain about 2100. Following division of the stem cell, one daughter cell remains anchored as the new stem cell, while the other undergoes several divisions in the lower and middle thirds of the crypt. The total number of dividing and non-dividing cells in a crypt varies according to its location, just as the number of cells per villus varies. Duodenal crypts contain approximately 530 cells, whereas the average number of cells per ileal crypt is 360. During migration, the cells mature into three of the four terminally differentiated cell types of the adult small intestinal epithelium: the absorptive enterocyte, the entero-endocrine cell, and the mucous-secreting goblet cell. Thus, each of the four main cell types arises from progenitors of a single multipotent stem cell. The whole process from proliferation to differentiation to shedding occurs in a few days. Despite the absence of villi, proliferation and migration are also involved in cellular differentiation in the colon. Together with cells from additional crypts, the surface cells make up the so-called intracryptal tables, the flat areas between the crypts. Colonic crypts, like the crypts in the small intestine, are monoclonal and populated by the progeny of a single stem cell. The highest frequency of apoptosis coincides with positions 4 and 5 from the base of the crypt, which is the presumed location of the stem cells. Although few apoptotic cells have been observed in sections from the lower and mid regions of the villi, this incidence rises with increasing distance from the crypt. This process of cell removal is certainly regulated to maintain the number of villous cells. However, it is uncertain whether apoptosis is regulated or whether apoptosis occurs in response to detachment from the basement membrane. These findings indicate that apoptosis plays an important role in regulating the number of stem cells in the epithelium of the small intestine and, therefore, the number of cells leaving the crypts and migrating onto intestinal villi. Apoptosis in the colonic epithelium occurs at a much lower rate than it does in the small intestine and is not confined to the crypts. Instead, cells are spontaneously eliminated at low rates irrespective of their positioning. Knockout studies have shown that, as in the case of the small intestinal epithelium, spontaneous apoptosis in the colonic epithelium occurs independently of both p53 and Bax. Detachment-induced cell death or anoikis has been shown to occur in isolated human intestinal cells100 and in mammary, renal, and bronchial epithelial cells. The first question arose out of the relatively infrequent observations of obvious apoptotic cells on the villus. The distribution of apoptotic cells was not uniform, and they increased in number with position toward the villous tip. These cells, for the most part, occupy positions 4 and 5 from the base of the crypt (the stem cell positions). Spontaneous apoptosis in the small intestinal crypt occurs at the same rate in p53-deficient mice as in wild-type animals. Bcl-2 is not expressed in small bowel epithelial cells,96 and as one would surmise, Bcl-2/ and normal mice have the same rate of apoptosis of small intestinal epithelial cells. They reported that epithelial cells of the small bowel activated caspase 3 as they approached the area of shedding and before they displayed the morphological features of apoptosis. Since caspase 3 is the major executioner caspase, and its activation is the culmination of the signaling pathway leading to apoptosis, we can conclude that the apoptotic process is well underway before effete cells appear apoptotic. In conclusion, these studies105,107 provided strong evidence that intestinal cell number is regulated by apoptosis as well as by proliferation and that the apoptotic rate is linked to the proliferative rate. Do dying cells detach from the extracellular matrix before being shed into the lumen These cells showed evidence of apoptosis such as vacuoles and chromatin condensation. Frequently, the intercellular spaces beneath these cells were occupied by large lymphocytes. Support for the concept that cells may detach from the extracellular matrix, thus initiating apoptosis while still on the villus, comes from studies of the localization of the extracellular recognition molecule, J1/tenascin. These authors also suggested that J1/tenascin may be involved in the process of enterocyte shedding. These data taken together suggest, although they certainly do not prove, that mature enteroctyes may detach from the extracellular matrix and undergo apoptosis before shedding into the lumen. Regardless of the mechanisms involved, the processes of cell proliferation and loss are linked. What is not known is whether the increased proliferation compensates for increased cell loss or whether the opposite situation exists. These include ionizing radiation, chemical mutagens, chemotherapeutic drugs, and food products. In addition, activation of the extrinsic pathway via the so-called death receptors results in a more physiological apoptotic response. Apoptosis is part of the result of procedures such as small bowel resection and ischemia reperfusion and has been investigated to determine its contribution to the overall response. A variety of agents have been tested for their protective effect on the gut mucosa and their ability to prevent apoptosis during exposure to radiation or chemotherapeutic agents. The goal of these studies has been to discover a means to protect the lining of the intestine during cancer therapy. A variety of cytotoxic drugs, mutagens, and ionizing radiation results in apoptosis of intestinal epithelia. Ijiri and Potten112 found that all cells in the crypt were capable of apoptosis, but their susceptibility was dependent on the type of damaging agent. The early and low-dose apoptotic response associated with stem cells of the small intestine is dependent on p53. As would also be expected from the distribution of the protein, increased numbers of apoptotic cells were found in colonic crypts of the Bcl2/ animals. Results using the chemotherapeutic agent 5-fluorouracil are similar to those with -irradiation; p53-null mice are resistant to apoptosis following administration of this drug compared to wild-type animals. Interestingly, spontaneous apoptosis was not altered by the absence of Bcl-w in crypts from either tissue. Both -irradiation and 5-fluorouracil, however, caused significantly higher levels of apoptosis in Bcl-w/ mice than in their wild-type counterparts. Bcl-w, therefore, seems to play a significant role in damage-induced apoptosis in both tissues, whereas Bcl-2 regulates apoptosis only in the colon. Although p53, Bcl-2, and Bcl-w have important roles in the regulation of damage-induced apoptosis in the gut epithelia, Bax expression was without effect. In all of the previously mentioned studies, apoptosis was quantified by identifying apoptotic cells. In both large and small intestine, caspase activation was rare in control, untreated mice. Exposure to 8 Gy radiation increased caspase 3 activity in the crypts of both tissues, where it was confined to apoptotic bodies. Thus, the determination of caspase 3 activity produced results identical to histological techniques and provided an additional method for examining cell death in vivo. It is obvious from the previously discussed experiments that knockout studies are extremely useful in determining whether or not a specific protein is involved in apoptosis. The primary disadvantages to these studies include: (1) the gene is absent from the entire animal and it is unknown what compensatory changes have occurred, (2) the development of null mice is expensive and timeconsuming, and most important, (3) these studies tell nothing about the regulatory pathways that actually influence the levels of the proteins being studied. Using morphological techniques and caspase 3 activation, the number of apoptotic cells was approximately twofold greater in the mice in which IkB kinase had been ablated compared to controls following treatment with 8 Gy -radiation. Whole-cell extracts of isolated intestinal epithelial cells from the conditional IkB kinase knockout mice contained higher levels of p53 than the controls. To this point we have said little about the role of the extrinsic or "death receptor" pathway in damage-induced apoptosis. One of them involves ChK1, a serine/threonine checkpoint kinase, which is active at S-phase and G2/M checkpoints. Even though cells died, the intestine was able to compensate by re-populating itself with cells containing functional Chk1. A major role in these cells of the Fas/FasL system is controlling the immune response by regulating the number of lymphocytes. Fas is also expressed in non-lymphoid tissues at sites of immune privilege (ovaries, uterus, testes) and at sites commonly infiltrated by lymphocytes (small and large intestine, liver, and lung). Cell loss is especially important in tissues that proliferate as rapidly as the intestinal epithelium. Several groups have explored the significance of apoptosis in the response to small bowel resection by examining the effects of various gene products involved in apoptosis on the adaptive response. Seven days following resection there were significant increases in all of these parameters in both groups and no significant differences in the increases. The apoptotic index was determined by counting apoptotic cells in the crypts, and the results indicated that apoptosis was not altered in the p53-null mice following small bowel resection. In both groups, apoptosis increased approximately 25%, which matched the 23% increase in proliferation. Although this correlation supports a role for apoptosis in maintaining the new equilibrium in cell growth, its significance has not been established. The major conclusion from this study was that the increase in apoptosis following small bowel resection occurs via a p53-independent mechanism. They concluded that intestinal hyperplasia following resection was significantly increased in the mice overexpressing Bcl-2. In the mice overexpressing Bcl-2, these increases were significantly greater than in the wild-type resected group. The investigators did not quantify apoptosis so the actual role of cell death in the results can only be surmised. Studies involving the genetic manipulation of the Bax gene, however, have shed considerable light on the role of apoptosis in the adaptive response to small bowel resection. They observed the usual increases in ileal wet weight, crypt depth, and proliferative rates in both groups. Resection significantly increased the rate of apoptosis in the control group; however, the apoptotic index in the Bax-null mice was unchanged. These data supported the conclusion that increased apoptosis following small bowel resection is Bax dependent, and that enterocyte proliferation and apoptosis are regulated via different mechanisms during intestinal adaptation.

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A connection between the cochlear duct and the remaining portion of the saccule is maintained but confined to a narrow pathway, the ductus reuniens hypertension 2014 ppt buy inderal 80 mg with mastercard. In the lOth week, this cartilaginous shell undergoes vacuolization, and two perilymphatic spaces, the scala vestibuli and scala tympani, are formed hypertension guidelines 2014 cheap inderal 10 mg on line. The cochlear duct is then separated from the scala vestibuli by the vestibular membrana and from the scala tympani by the bas ilar membrane blood pressure form discount inderal online master card. With further development, however, they form two ridges: the inner ridge, the future spiral limbus, and the outer ridge arteria bologna 8 marzo order inderal 40 mg amex. The outer ridge forms one row of inner and three or four rows of outer hair cells, the sensory cells of the auditory system blood pressure of 150/90 buy inderal 40 mg low price. They are covered by the tectorial membrane, a fibrillar gelatinous substance attached to the spiral limbus that rests with its tip on the hair cells pulse pressure 46 buy inderal 10mg line. Central portions of the walls of these outpocketings eventually appose each other. Whereas one end of each canal dilates to form the crus ampullare, the other, the crus nonampullare, does not widen. Because two of the latter type fuse, however, only five crura enter the utricle, three with an ampulla and two without. Cells in the ampullae form a crest, the crista ampullaris, containing sensory cells for maintenance of equilibrium. Similar sensory areas, the maculae acusticae, develop in the walls of the utricle and saccule. During formation of the otic vesicle, a small group of cells breaks away from its wall and forms the statoacoustic ganglion. The ganglion subsequently splits into cochlear and vestibular portions, which supply sensory cells of the organ of Corti and those of the saccule, utricle, and semicircular canals, respectively. This pouch expands in a lateral direction and comes in contact with the floor of the first pharyngeal cleft. The distal part of the pouch, the tubotympanic recess, widens and gives rise to the primitive tympanic cavity, and the proximal part remains narrow and forms the auditory tube (eustachian tube). Ossicles the malleus and incus are derived from cartilage of the first pharyngeal arch, and the stapes is derived from that of the second arch. Although the ossicles appear dur ing the first half of fetal life, they remain embedded in mesenchyme until the eighth month. The endodermal epithelial lining of the primitive tympanic cavity then extends along the wall of the newly developing space. Because the malleus is derived from the first pharyngeal arch, its muscle, the tensor tympani, is innervated by the mandibular branch of the trigeminal nerve. The stapedius muscle, which is attached to the stapes, is innervated by the facial nerve, the nerve to the second pharyngeal arch. During late fetal life, the tympanic cavity expands dorsally by vacuolization of surrounding tissue to form the tympanic antrum. After birth, the epithelium of the tympanic cavity invades the bone of the developing mastoid process, and epithelium-lined air sacs are formed (pneumatization). Later, most of the mastoid air sacs come in contact with the antrum and tympanic cavity. These swellings (auricular hillocks), three on each side of the external meatus, later fuse and form the defini tive auricle. Furthermore, because the hillocks are derived from neural crest cells, external ear defects are often associated with malformations in other organs derived from neural crest cells, such as the face, skull, and heart. If too loud a sound, causing potentially damaging vibrations, occurs, the ten sor tympani together with the stapedius muscle stretches the membrane even tighter to prevent it from vibrating too forcefully. Amplification results from two factors: (1) the large size difFerence between the tympanic membrane (55 mm^) and the oval window (3. Pressure produced by movement of the stapes at the oval window ereates a fluid wave in the cochlea that is balanced by movement of the round window. Near the oval window, the basilar membrane is attached by shorter stiffier fibers to the side of the cochlea; farther along the cochlea, the fibers are longer and more flexible. In the seventh month, this plug dissolves, and the epithelial lining of the floor of the meatus participates in formation of the definitive eardrum. Occasionally, the meatal plug persists until birth, resulting in con genital deafness. This movement is sensed by adjacent hair cells that send impulses back through nerve fibers of the acoustic segment of the statoacoustic nerve. The internal ear originates from the otic vesicle, which in the fourth week of development detaches from surface ectoderm. This vesicle divides into a ven tral component, which gives rise to the saccule and cochlear duct and a dorsal component, which gives rise to the utricle, semicircular canals, and endolymphatic duct. The epithelial structures thus formed are known collectively as the membranous labyrinth. Except for the cochlear duct, which forms the organ of Corti, all structures derived from the membranous labyrinth are involved with equilibrium. The middle ear, consisting of the tympanic cavity and auditory tube, is lined with epithelium of endodermal origin and is derived from the first pharyngeal pouch. The ossicles, which transfer sound from the tympanic membrane to the oval window, are derived from the first (malleus and incus) and second (stapes) pharyngeal arches. The extemal auditory meatus develops from the first pharyngeal cleft and is separated from the tympanic cavity by the tympanic membrane (eardrum). The eardrum consists of (1) an ectodermal epithelial lining, (2) an intermediate layer of mesenchyme, and (3) an endodermal lining from the first pharyngeal pouch. What is the embryologic origin of the tym panic (middle ear) cavity, auditory tube, and tympanic membrane (eardrum) With dosure of the neural tube, these grooves form outpocketings of the forebrain, the optic vesicles. These vesicles subsequently come in contact with the surface ectoderm and induce changes in the ectoderm necessary for lens formation. The inner and outer layers of this cup are initially separated by a lumen, the intraretinal space. Invagination is not restricted to the central portion of the cup but also involves a part of the inferior surface. Formation of this fissure allows the hyaloid artery to reach the inner chamber of the eye. During the seventh week, the lips of the choroid fissure fiise, and the mouth of the optic cup becomes a round opening, the future pupil. During these events, cells of the surface ectoderm, initially in contact with the optic vesicle, begin to elongate and form the lens placode. During the fifth week, the lens vesicle loses contact with the surface ectoderm and lies in the mouth of the optic cup. Adjacent to this photoreceptive layer is the mantle layer, which, as in the brain, gives rise to neurons and supporting cells, including the outer nuclear layer, inner nuclear layer, and ganglion cell layer. On the surface is a fibrous layer that contains axons of nerve cells of the deeper layers. Nerve fibers in this zone converge toward the optic stalk, which develops inte the optic nerve. Henee, hght impulses pass through most layers of the retina before they reach the rods and cones. The anterior fifth of the inner layer, the pars ceca retinae, remains one cell layer thick. In the adult, the iris is formed by the pigment-containing external layer, the unpigmented internal layer of the optic cup, and a layer of richly vascularized connective tissue that contains the pupillary muscles. Fxternally, it is covered by a layer of mesen chyme that forms the ciliary muscle; on the inside, it is connected to the lens by a network of elastic fibers, the suspensory ligament or zonula. The inner layer later forms a highly vascularized pigmented layer known as the choroid; the outer layer develops into the sclera and is continuous with the dura mater around the optic nerve. The anterior chamber forms through vacuolization and splits the mesenchyme into an inner layer in front of the lens and iris, the iridopupillary membrane, and an outer layer continuous with the sclera, the substantia propria of the cornea. Henee, the cornea is formed by (1) an epithelial layer derived from the surface ectoderm, (2) the substantia propria or stroma, which is continuous with the sclera, and (3) an epithelial layer, which borders the anterior chamber. The posterior chamber is the space between the iris anteriorly and the lens and ciliary body posteriorly. The anterior and posterior chambers communicate with each other through the pupil and are filled with fluid called the aqueous humor produced by the ciliary process of the ciliary body. The clear aqueous humor circulates from the posterior chamber into the anterior cham ber providing nutrients for the avascular cornea and lens. From the anterior chamber, the fluid passes through the scleral venous sinus (canal of Schlemm) at the iridocorneal angle where it is resorbed into the bloodstream. By the end of the seventh week, these primary lens fibers reach the anterior wall of the lens vesicle. Growth of the lens is not finished at this stage, however, because new (secondary) lens fibers are continuously added to the central core. Here, it forms the hyaloid vessels, which during intrauterine life supply the lens and form the vascular layer on the inner surface of the retina. O p tic nerve fibers C entral a rte ry of retina network of fibers between the lens and retina. The nerve fibers of the retina returning to the brain lie among cells of the inner wall of the stalk. During the seventh week, the cho roid fissure closes, and a narrow tunnel forms inside the optic stalk. As a result of the continuously increasing number of nerve fibers, the inner wall of the stalk grows, and the inside and outside walls of the stalk fuse. Cells of the inner layer provide a network of neuroglia that supports the optic nerve fibers. Its center contains a portion of the hyaloid artery, later called the central artery of the retina. On the outside, a continuation of the choroid and sclera, the pia arachnoid and dura layer of the nerve, respectively, surround the optic nerve. At this stage, there is a single eye field that later separates into two optic primordia. Thus, the lens ectoderm is essential for proper formation of the optic cup, such that without a lens placode, no cup invagination occurs. When the optic vesicle begins to invaginate to form the pigment and neural layers of the retina, the lens placode invaginates to form the lens vesicle. Nerve fibers of the eye also occupy this groove to reach the optic areas of the brain. The cornea is formed by (1) a layer of surface ectoderm; (2) the stroma, which is continuous with the sclera; and (3) an epithelial layer bordering the anterior chamber. In taking a history of a young woman in her lOth week of gestation, you become con cerned that she may have contracted rubella sometime during the fourth to eighth weeks of her pregnancy.

Surgical resection of large incompletely treated intracranial arteriovenous malformations following stereotactic radiosurgery blood pressure kiosk for sale purchase 40mg inderal with mastercard. With careful preoperative planning and embolization, stereotactic radiosurgery, advances in microsurgical technique, and compulsive perioperative management, excellent results overall can be obtained arrhythmia when falling asleep inderal 80 mg without a prescription. Other fairly constant branches are the inferolateral trunk, which supplies the segment of the cranial nerves running into the lateral sellar compartment, and the capsular artery of McDonnel heart attack now love cheap generic inderal uk. Although not always angiographically visible, these anastomoses are anatomically constant blood pressure medication diarrhea order inderal 10mg without prescription. Posterior drainage is through the basilar plexus and the superior and inferior petrosal sinuses arteria bologna 23 novembre buy generic inderal from india. Inferolaterally, connections exist through dural veins draining into the pterygoid plexus hypertension in pregnancy buy 10 mg inderal. Intermittently, the cavernous sinus can receive drainage from the inferomedial surface of the brain. This vessel provides arterial supply to the dura of the tentorium (tentorial artery or artery of BernasconiCassinari) and the hypophysis (inferior hypophysial artery). As a general rule, direct fistulas have a more dramatic manifestation and quite often tend to exhibit the "classic" triad of exophthalmos, chemosis, and visual loss. Diplopia is common and related to ischemic dysfunction of cranial nerves, mechanical compression of the nerves, and restricted movement secondary to venous engorgement of the orbital contents. The pattern of double vision created by engorgement of the orbital contents and restricted movement may not fit with a particular cranial neuropathy. Anteriorly placed fistulas drain through the superior ophthalmic vein and have a significant exophthalmic component. With direct fistulas, it can be difficult to exactly define the location and size of the fistulous tract because of high flow. Endovascular treatment is the mainstay of management, and it is usually performed through a transarterial approach. After detachable balloon treatment, up to a third of patients can experience worsening of preexisting or new extraocular motility deficits. Postoperative deficits are usually transient but can be permanent in about 15% of patients. Detachable coils overcome some of the problems encountered with detachable balloons. The main advantage of detachable coils is their ability to be retrieved in the event of inadequate placement. Coils are available in different sizes and shapes and can be easily adapted to the individual characteristics of the specific patient. When deploying coils, if retrograde cortical venous drainage exists, it is important to obliterate this portion of the fistula first with coils to avoid redirecting residual flow preferentially to this portion of the fistulous communication and incur the risk of intracranial venous engorgement and hemorrhage. Disadvantages of Onyx include very slow injection rates and high penetration, which increases the risk of obliterating the supply to cranial nerves with subsequent ischemic neuropathies. Onyx can be used in combination with coils to occlude the small residual fistula that sometimes persists after coil embolization. Ideally, covered stents should be able to immediately seal the defect in the artery wall. In reality, there is often a mismatch between the size of the stent and the diameter of the vessel, so blood can still "find its way" between the vessel wall and stent into the fistula and create an "endoleak" that results in angiographic persistence of the fistula. Drawbacks of the current covered stents include the stiffness of these systems, which makes neuronavigation difficult with resultant vasospasm, and problems with endoleaks. In addition, the need for dual antiplatelet therapy makes their use impractical in patients with recent major trauma who are at risk for systemic bleeding complications. Indications for treatment include increased intraocular pressure, progressive or disabling symptoms, retrograde cortical venous drainage (present in more than a third of patients requiring treatment),17 frank intracranial hemorrhagic manifestation, and cosmetic deformity. Whether intermittent carotid compression is indeed successful or the results observed are a mere consequence of the tendency for spontaneous thrombosis in some of these patients is unknown. Surgical treatment, indicated in patients with cortical venous drainage if an effective endovascular route is not feasible, is rarely necessary. With advancements in endovascular techniques, numerous routes of access and different occlusion methods are available. It is generally used as a palliative maneuver to decrease symptoms in patients with fistulas without dangerous features and as an adjunct to Gamma Knife radiosurgery. Creative approaches with different endovascular devices in combination have been reported. When these routes are not immediately available, percutaneous access though the superior ophthalmic vein via surgical cutdown is a well-established procedure. Detachable or fibered coils are generally preferred, although liquid embolic agents, often in combination with coils, have also been used. Complete obliteration of the fistula can be achieved in 84% of patients with a single endovascular procedure. Cranial neuropathies improve in the majority of patients but may fail to improve in up to 11%. Frequently, these new postoperative deficits are transient and improve over a 1- to 2-month period after the procedure. The drawback of radiosurgery is the latency time during which patients continue to be exposed to the symptoms and the potential for intracranial hemorrhage in those with retrograde cortical venous drainage. To obviate this limitation of radiosurgery, Pollock and coworkers advocated a staged approach consisting of Gamma Knife radiosurgery followed by embolization. After radiosurgery, transarterial particle embolization can be performed with the goal of achieving rapid improvement in symptoms. In this situation, particle embolization can be also used with the goal of decreasing flow to the lesion while radiosurgery takes effect. Of those with decreased visual acuity or visual field defects, 88% experienced resolution of their symptoms and 77% of those with diplopia noticed improvement or resolution. Endovascular treatment is the main therapeutic option, and different techniques and embolic agents are available. Surgical therapy is rarely indicated, whereas radiosurgery has, in our opinion, a definite role in patients with indirect fistulas and minor symptoms. Angiographic follow-up of traumatic carotid cavernous fistulas treated with endovascular stent graft placement. Stereotactic radiosurgery for the treatment of low-flow carotid-cavernous fistulae: results in a series of 25 cases. Percutaneous transfemoral embolization of an indirect carotid-cavernous fistula with cortical venous access to the cavernous sinus. Transvenous embolization of dural carotidcavernous fistulas by multiple venous routes: a series of 27 cases. Dangerous extracranial-intracranial anastomoses and supply to the cranial nerves: vessels the neurointerventionalist needs to know. Transvenous embolization with a combination of detachable coils and Onyx for a complicated cavernous dural arteriovenous fistula. A technical contribution to the exact angiographic localization of carotid cavernous fistulas. Transvenous embolization of a dural arteriovenous fistula of the cavernous sinus through the contralateral pterygoid plexus. Management of 100 consecutive direct carotidcavernous fistulas: results of treatment with detachable balloons. Trans-arterial embolization therapy of dural carotid-cavernous fistulae using low concentration n-butyl-cyanoacrylate. Transvenous embolization of a dural carotidcavernous sinus fistula vis the inferior ophthalmic vein. Stereotactic radiosurgery and particulate embolization for cavernous sinus dural arteriovenous fistulae. Combined covered stent and Onyx treatment for complex dural arteriovenous fistula involving the clivus and cavernous sinus. Transvenous treatment of spontaneous dural carotid-cavernous fistula using a combination of detachable coils and Onyx. Transvenous n-butyl-cyanoacrylate infusion for complex dural carotid cavernous fistulas: technical considerations and clinical outcome. Placement of covered stents for the treatment of direct carotid cavernous fistulas. Transvenous embolization of dural carotidcavernous fistulae with transfacial catheterization through the superior ophthalmic vein. HydroCoil occlusion for treatment of traumatic carotid-cavernous fistula: preliminary experience. These fistulas are frequently idiopathic but can be associated with venous thrombosis,2,3 trauma, tumor, previous neurological surgery,1,4 meningitis,5 or sinus infection. Gait ataxia, seizures, myelopathy, cerebral edema, ischemia, subarachnoid hemorrhage, or any combination of these signs or symptoms may also be present. The sudden disappearance of a bruit usually indicates thrombosis of the draining vein or veins and resolution of the fistula. It can also represent more ominous shunting of venous blood into cortical venous channels sufficiently distant from the middle ear such that pulsatile tinnitus is no longer appreciated by the patient. According to the Borden classification, type I fistulas have anterograde drainage into a dural venous sinus or meningeal vein. These fistulas are benign, often asymptomatic or characterized by a cranial bruit, and have a high rate of spontaneous remission. The venous sinus may be patent but largely defunctionalized because of high-flow venopathy causing reversal of flow into arterialized leptomeningeal veins. Such drainage is frequently but not always due to occlusion of the arterialized dural sinus. When the sinus is patent, the point of the fistula is located either between the meningeal artery and leptomeningeal vein or between the meningeal artery and a segment of arterialized dural venous sinus that is thrombosed at either end or somehow isolated from the rest of the sinus, thereby causing reversal of drainage into leptomeningeal veins. Lasjaunias and associates proposed that the source of intracranial hemorrhage in these cases is not the fistula itself but rather ectatic, thin-walled arterialized veins. High-flow venopathy in sinuses not involved in the fistulous drainage, however, may predispose to undesirable venous sinus thrombosis; such patients are advised to take at least 81 mg of aspirin daily. A bruit is often auscultated over the mastoid process ipsilateral to the arterialized transverse/sigmoid sinus and can be diminished by compression of the ipsilateral common carotid/occipital arteries. Thereispialsupplyfromthe posterior temporal branch of the left posterior cerebral artery (black arrow) and dural supply from extracranial muscular (open arrows) and intradural posterior meningeal branches (white arrow) of the left vertebral artery. A B Compression Therapy Compression therapy is seldom used currently, except in patients with Borden type I fistulas as a possible first step before neuroendovascular therapy. Compression of the ipsilateral carotid or occipital artery (if the latter vessel is a known feeder to the fistula) is performed for 30 minutes at a time, three times a day. If compression of the carotid artery is chosen, patients are instructed to use the contralateral arm. In case hemispheric ischemia ipsilateral to the compressed artery and paresis of the contralateral upper extremity develop as a result of overzealous compression, the arm will fall away and the compression will necessarily be self-limited. Transvenous coil embolization plus occlusion of the recipient venous pouch is the mainstay of endovascular therapy and offers the best chance of cure. In the latter case, transvenous occlusion of the sinus blocks eventual venous egress, thus further elevating pressure in the arterialized subarachnoid vein. A triaxial system consisting of a 6 French shuttle sheath advanced to the jugular bulb, a 4 or 5 French vertebral catheter, and a microcatheter provides maximum support. Differentiation of the recipient arterialized venous pouch from the sinus responsible for normal cortical venous drainage is crucial because in the latter drainage may occur via the sinus wall instead of the sinus. Inadequate embolization of a sinus with leptomeningeal venous drainage or embolization of the parent sinus without occlusion of the parallel venous channel receiving arterial inflow22 may aggravate the venous hypertension by impeding venous egress and diverting arterialized blood to the subarachnoid veins. There is a small risk of perforation and particularly subdural extravasation with this approach. When entry to the diseased sinus is not feasible because of venous thrombosis, venopathy, or tortuosity, access can sometimes be secured from the contralateral transverse sinus across the torcular Herophili. If the goal is to preserve sinus patency, a slow-setting liquid adhesive such as the Onyx Liquid Embolic System (Micro Therapeutics, Inc. Onyx often streamlines along the venous intima in a controlled, laminar fashion and occludes points of the fistula without causing hemodynamic compromise. Transvenous embolization with other liquid nonadhesive agents (Eudragit E mixture) has also been described. Thereisretrograde reflux of contrast into the superior sagittal sinus and left hemisphericveins. Access to a distally occluded right transverse sinus is achieved across the torcular with a hydrophilic 0. Transarterial therapy is indicated when transvenous routes are inaccessible, the fistula directly communicates with subarachnoid veins, the magnitude of the arteriovenous shunt precludes adequate angiographic evaluation of the sinus or iatrogenic venous infarction is a concern, or the goal is palliation, not cure. Secondary recruitment of collateral shunts to the nidus after incomplete embolization is well known. Follow-up angiography after particulate embolization and angiographic "cure" is essential to document the absence of fistula recurrence. It is highly radiopaque because of the addition of micronized tantalum powder and is formulated in two viscosities, Onyx-18 and Onyx-34, which contain 6% and 8% ethylene vinyl alcohol, respectively. Before Onyx embolization of a feeding artery, superselective catheterization of the vessel is performed to ensure optimal microcatheter placement. Vasospasm around the microcatheter is undesirable during Onyx or particulate embolization because partial or complete arrest of flow would impede distal migration of the embolic agent. Onyx forms an embolus that solidifies from outside to inside over a period of several minutes, during which time it can be pushed through the artery. Onyx differs from other transarterial embolic agents in its permeative ability, even for a relatively remote nidus. This is in distinction to a pial arteriovenous malformation, for which primary resection of the draining vein could lead to premature edema/hemorrhage because of a rapid increase in intranidal pressure. Sinus pressure is 29% to 58% of mean systemic blood pressure, and blood gas is purely arterial at the beginning of the procedure and returns to normal venous values after occlusion of the fistula.

Cigarette smoking has been linked to an increased risk for orofacial clefts (cleft lip and cleft palate) blood pressure chart related to age purchase inderal with paypal. The progestins ethisterone and norethisterone have considerable androgenic activity, and many cases of masculinization of the genitalia in female embryos have been reported prehypertension causes symptoms buy inderal overnight delivery. M ost commonly, these agents in terfere with the action of estrogen through its receptor to cause developmental abnormalities of the central nervous system and reproductive tract heart arrhythmia xanax cheap inderal online. Furtherm ore, a high percentage of these women had reproductiva dysfunction caused in part by congenital malformations of the uterus, uterine tubes, and upper vagina blood pressure procedure order inderal in united states online. Today, environmental estrogens are a con cern, and numerous studies to determine their effects on the unborn are under way arteria znaczenie slowa inderal 10mg generic. M aternal Disease D iabetes Birth control pills, containing estrogens and progestogens, appear to have a low teratogenic potential hypertension specialist buy inderal 40 mg online. Some recent epidemiologic studies also suggest that women who take corticosteroids during pregnancy are at a modestly increased risk for having a child with an orofacial cleft. Furtherm ore, any treatm ent for infertiUty, Disturbances in carbohydrate metabolism dur ing pregnancy in diabetic mothers cause a high incidence of stillbirths, neonatal deaths, abnormally large infants, and congenital malfor mations. The risk of congenital anomahes in children born to mothers with pregestational diabetes (diabetes diagnosed before pregnancy; both type 1 [insulin dependent] and type 2 [non-insulin dependent]) is three to four times that for offspring of nondiabetic mothers and has been reported to be as high as 80% in the offspring of diabetics with long-standing dis ease. The increased risk is for a wide variety of malformations, including neural tube defects and congenital heart defects. Factors responsible for these abnormalities have not been delineated, although evidence suggests that altered glucose leveis play a role and that insulin is not teratogenic. Also, strict control of maternal glucose levels beginning be fore conception and continuing throughout gestation reduces the occurrence of malformations to incidences approaching those in the general population. The risk for birth defects associated with gestational diabetes (diabetes that is first di agnosed during pregnancy) is less clear, with some, but not all, studies showing a slightly increased risk. Given that the onset of gesta tional diabetes is believed to be after the critical period for inducing structural birth defects (3 to 8 weeks gestation), some investigators have suggested that any observed increased risk may be due to the fact that some women diagnosed with gestational diabetes probably had diabetes before pregnancy, but it was not diagnosed. Finally, recent studies show that poor maternal nutrition prior to and during pregnancy contributes to low birth weight and birth defects and that severe starvation during pregnancy is associated with a two- to threefold increase in schizophrenia in the offspring. Obesity Obesity has reached epidemic proportions in the United States and has nearly doubled in the past 15 years. Prepregnancy obesity is associated with a twofold increased risk for having a child with a neural tube defect. Hypoxia Hypoxia induces congenital malformations in a great variety of experimental animals. Although children born at relatively high alti tudes are usually lighter in weight and smaller than those born near or at sea level, no increase in the incidence of congenital malformations has been noted. In addition, women with cyanotic cardiovascular disease often give birth to small infants but usually without gross congenital malformations. Further examination revealed that the fish contained an abnormally high level of organic m ercury, which was spewed into M inamata Bay and other Coastal waters of Japan by large industries. Many of the m oth ers did not show any symptoms themselves, indicating that the fetus was m ore sensitive to mercury than the m other. In the United States, similar observations were made when seed corn sprayed with a mercury-containing fungicide was fed to hogs and the meat was subsequently eaten by pregnant women. Likewise, in Iraq, several thousand babies were affected after mothers ate grain treated with mercurycontaining fungicides. Lead has been associated with increased abortions, growth retardation, and neurological disorders. Male-Mediated Teratogenesis A number of studies have indicated that exposures to chemicals and other agents, such as ethylnitrosourea and radiation, can cause mutations in male germ cells. Epidemiological investigations have linked paternal occupational and environmental exposures to mercury, lead, solvents, alcohol, cigarette smoking, and other compounds to spontaneous abortion, low birth weight, and birth defects. Advanced paternal age is a factor for an increased risk for some types of structural birth defects, Down syndrome, and new autosomal dominant mutations. With respect to mutations, men transmit a higher num ber of mutations to their children than women and the age of the father is the dominant factor in determining how many de novo mutations appear in the child. Even transmission of paternally mediated toxicity is possible through seminal fluid and from household contamination from chemicals brought home on work clothes by the father. In combination, these techniques are designed to detect malformations, genetic abnormahties, overall fetal growth, and complications of pregnancy, such as placental or uterine abnormalities. The use and development of in Utero therapies have heralded a new concept in which the fetus is now a patient. The approach may be transabdominal or transvaginal, with the latter producing images with higher resolution. Ultrasound image sliowing position of tlie fetal skuli and placement of the needle into the amniotic cavity [arrow] during amniocentesis. The technique is safe and commonly used, with approximately 80% of pregnant women in the United States receiving at least one sean. Im portant parameters revealed by ultrasound include characteristics of fetal age and growth; presence or absence of congenital anomalies; status of the uterine environment, including the amount of amniotic fluid. All of these factors are then used to determine proper approaches for management of the pregnancy. Determination of fetal age and growth is cru cial in planning pregnancy management, especially for low-birth-weight infants. In fact, studies show that ultrasound-screened and -managed pregnancies with low-birth-weight babies reduced the mortality rate by 60% compared with an unscreened group. Fetal age and growth are assessed by crow n-rum p length during the 5th to the lOth weeks of gestation. Congenital malformations that can be determined by ultrasound include the neural tube defects anencephaly and spina bifida (see Chapter 18); abdominal waU defects, such as omphalocele and gastroschisis (see Chapter 15); and heart (see Chapter 13) and facial defects, in cluding cleft lip and palate (see Chapter 17). Ultrasound can also be used to screen for Down syndrome and some other chromosomerelated abnormalities through a test called nuchal translucency. Then, based on this risk assessment, a woman can decide whether she wants invasive testing, such as am niocentesis, which would provide a definitive diagnosis. Maternal Serum Screening A search for biochemical markers of fetal status led to development of m aternal serum screen ing tests. In addition, fetal cells, sloughed into the amniotic fluid, can be recovered and used for metaphase karyotyping and other genetic analyses (see Chapter 2). Unfortunately, the harvested cells are not rapidly dividing, and therefore, cell cultures containing mitogens must be established to provide sufficient metaphase cells for analysis. Once chromosomes are obtained, m ajor chromosomal alterations, such as translocations, breaks, trisomies, and monosomies, can be identified. With special stains (Giemsa) and high-resolution techniques, chromosome-banding patterns can be determined. Cells may be analyzed immediately, but accuracy of results is problematic because of the high frequency of chromosomal errors in the normal placenta. Therefore, cells from the mesenchymal core are isolated by trypsinization of the external trophoblast and cultured. Because of the large number of cells obtained, only 2 to 3 days in culture are necessary to permit genetic analysis. Thus, the time for genetic characterization of the fetus is reduced compared with amniocentesis. However, there have been indications that the procedure carries an increased risk for limb reduction defects, especially o fth e digits. In the past, with the exception of ultrasonography, these prenatal diagnostic tests were not used on a routine basis. Fetal Surgery Because of advances in ultrasound and surgical procedures, operating on fetuses has become possible. Because of risks to the mother, infant, and subsequent pregnancies, however, procedures are only performed in centers with well-trained teams and only when there are no reasonable alternatives. Several types of surgeries may be performed, including placing shunts to remove fluid from organs and cavities. For example, in obstructivo urinary disease of the urethra, a shunt may be inserted into the fetal bladder. Ex Utero surgery, in which the uterus is opened and the fetus is operated on directly, has been used for repairing congenital diaphragmatic hernias, removing cystic (adenomatoid) lesions in the lung, and repairing spina bifida defects. Also, in recent years, fetal intervention has become available for certain congenital heart defects. Research in this field is focusing on hematopoietic stem cells for treatment of immunodeficiency and hematologic disorders. Gene therapy for inherited metabolic diseases, such as Tay-Sachs and cystic fibrosis, is also being investigated. Ultrasound is used to guide insertion of a needle into the um bilical cord vein, and blood is transfused directly into the fetus. Effects of teratogens depend on the m aternal and fetal genotype, the stage of development when exposure occurs, and the dose and duration of exposure of the agent. Many techniques are available to assess the growth and developmental status of the fetus. Ultrasound can accurately determine fetal age, growth parameters, and can detect many mal formations. Combinations of maternal serum screening and ultrasound to detect nuchal translucency can be used for detecting Down syndrome and some other chromosome-related abnormalities. This fluid can be analyzed biochemically and also provides cells for culture and genetic analysis. In recent years, risks associated with these procedures have decreased, and consequently, these procedures have been made more widely available. Modern medicine has also made the fetus a patient who can receive treatment, such as transfusions, medications for disease, fetal surgery, and gene therapy. A young woman who is planning a fam ily seeks advice about folie acid and other vitamins. A young insulin-dependent diabetic woman who is planning a family is concerned about the possible harmful effects of her disease on her unborn child. At the end of the fourth week, sderotome ceUs become polymorphous and form loosely organized tissue, called mesenchyme, or embryonic connective tis sue. Itis characteristic for mesenchymal ceUs to migrate and to differentiate in many ways. This layer of meso derm forms bones of the pelvic and shoulder gir- dles, limbs, and sternum (see page 154). In some bones, such as the flat bones of the skull, mesenchyme in the dermis differentiates directly into bone, a process known as intram embranous ossification.

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