Jingshen Wang PhD

• Assistant Professor, Biostatistics

https://publichealth.berkeley.edu/people/jingshen-wang/

Circulation of blood to the head and neck Arterial supply the paired arteries supplying the head and neck are the common carotid arteries and the vertebral arteries (Figs 5 erectile dysfunction treatment cialis order levitra 20 mg line. Carotid arteries the right common carotid artery is a branch of the brachiocephalic artery icd 9 code for erectile dysfunction due to medication buy discount levitra 10mg line. They pass upwards on either side of the neck and have the same distribution on each side erectile dysfunction diabetes type 2 treatment purchase levitra 10mg without prescription. At the level of the upper border of the thyroid cartilage each divides into an internal carotid artery and an external carotid artery erectile dysfunction tampa buy 10 mg levitra mastercard. The carotid sinuses are slight dilations at the point of division (bifurcation) of the common carotid arteries into their internal and external branches erectile dysfunction over 40 levitra 20 mg otc. The walls of the sinuses are thin and contain numerous nerve endings of the glossopharyngeal nerves erectile dysfunction bph levitra 20mg cheap. These nerve endings, or baroreceptors, are stimulated by changes in blood pressure in the carotid sinuses. The resultant nerve impulses initiate reflex adjustments of blood pressure through the vasomotor centre in the medulla oblongata (p. The carotid bodies are two small groups of specialised cells, called chemoreceptors, one lying in close association with each common carotid artery at its bifurcation. They are supplied by the glossopharyngeal nerves and their cells are stimulated by changes in the carbon dioxide and oxygen content of blood. The resultant nerve impulses initiate reflex adjustments of respiration through the respiratory centre in the medulla oblongata. The lingual artery supplies the tongue, the lining membrane of the mouth, the structures in the floor of the mouth, the tonsil and the epiglottis. The facial artery passes outwards over the mandible just in front of the angle of the jaw and supplies the muscles of facial expression and structures in the mouth. The temporal artery passes upwards over the zygomatic process in front of the ear and supplies the frontal, temporal and parietal parts of the scalp. The maxillary artery supplies the muscles of mastication and a branch of this artery, the middle meningeal artery, runs deeply to supply structures in the interior of the skull. Internal carotid artery this is a major contributor to the circulus arteriosus (circle of Willis). It ascends to the base of the skull and passes through the carotid foramen in the temporal bone. Circulus arteriosus (circle of Willis) the greater part of the brain is supplied with arterial blood by an arrangement of arteries called the circulus arteriosus or the circle of Willis. Four large arteries contribute to its formation: the two internal carotid arteries and the two vertebral arteries. The vertebral arteries arise from the subclavian arteries, pass upwards through the foramina in the transverse processes of the cervical vertebrae, enter the skull through the foramen magnum, then join to form the basilar artery. The arrangement in the circulus arteriosus is such that the brain as a whole receives an adequate blood supply when a contributing artery is damaged and during extreme movements of the head and neck. Anteriorly, the two anterior cerebral arteries arise from the internal carotid arteries and are joined by the anterior communicating artery. After travelling for a short distance the basilar artery divides to form two posterior cerebral arteries, each of which is joined to the corresponding internal carotid artery by a posterior communicating artery, completing the circle. The circulus arteriosus is therefore formed by: 2 anterior cerebral arteries 2 internal carotid arteries 1 anterior communicating artery 2 posterior communicating arteries 2 posterior cerebral arteries 1 basilar artery. From this circle, the anterior cerebral arteries pass forward to supply the anterior part of the brain, the middle cerebral arteries pass laterally to supply the sides of the brain, and the posterior cerebral arteries supply the posterior part of the brain. Venous return from the head and neck the venous blood from the head and neck is returned by deep and superficial veins. Superficial veins with the same names as the branches of the external carotid artery return venous blood from the superficial structures of the face and scalp and unite to form the external jugular vein. The external jugular vein begins in the neck at the level of the angle of the jaw. It passes downwards in front of the sternocleidomastoid muscle, then behind the clavicle before entering the subclavian vein. The venous blood from the deep areas of the brain is collected into channels called the dural venous sinuses. The main venous sinuses are listed below: the superior sagittal sinus carries the venous blood from the superior part of the brain. It begins in the frontal region and passes directly backwards in the midline of the skull to the occipital region where it turns to the right side and continues as the right transverse sinus. The inferior sagittal sinus lies deep within the brain and passes backwards to form the straight sinus. The straight sinus runs backwards and downwards to become the left transverse sinus. They run forward and medially in a curved groove of the skull, to become continuous with the sigmoid sinuses. Each curves downwards and medially and lies in a groove in the mastoid process of the temporal bone. Anteriorly only a thin plate of bone separates the sinus from the air cells in the mastoid process of the temporal bone. The internal jugular veins begin at the jugular foramina in the middle cranial fossa and each is the continuation of a sigmoid sinus. Behind the clavicle they unite with the subclavian veins, carrying blood from the upper limbs, to form the brachiocephalic veins. The left brachiocephalic vein is longer than the right and passes obliquely behind the manubrium of the sternum, where it joins the right brachiocephalic vein to form the superior vena cava. The superior vena cava, which drains all the venous blood from the head, neck and upper limbs, is about 7 cm long. It passes downwards along the right border of the sternum and ends in the right atrium of the heart. Circulation of blood to the upper limb Arterial supply the subclavian arteries the right subclavian artery arises from the brachiocephalic artery; the left branches from the arch of the aorta. They are slightly arched and pass behind the clavicles and over the first ribs before entering the axillae, where they continue as the axillary arteries. Before entering the axilla, each subclavian artery gives off two branches: the vertebral artery, which passes upwards to supply the brain, and the internal thoracic artery, which supplies the breast and a number of structures in the thoracic cavity. The axillary artery is a continuation of the subclavian artery and lies in the axilla. The first part lies deeply; then it runs more superficially to become the brachial artery. It runs down the medial aspect of the upper arm, passes to the front of the elbow and extends to about 1 cm below the joint, where it divides into the radial and ulnar arteries. The radial artery passes down the radial or lateral side of the forearm to the wrist. Just above the wrist it lies superficially and can be felt in front of the radius, as the radial pulse. The artery then passes between the first and second metacarpal bones and enters the palm of the hand. The ulnar artery runs downwards on the ulnar or medial aspect of the forearm to cross the wrist and pass into the hand. There are anastomoses between the radial and ulnar arteries, called the deep and superficial palmar arches, from which palmar metacarpal and palmar digital arteries arise to supply the structures in the hand and fingers. Venous return from the upper limb the veins of the upper limb are divided into two groups: deep and superficial veins. The deep veins follow the course of the arteries and have the same names: palmar metacarpal veins deep palmar venous arch ulnar and radial veins brachial vein axillary vein subclavian vein. The superficial veins begin in the hand and consist of the following: cephalic vein basilic vein median vein median cubital vein. The cephalic vein begins at the back of the hand where it collects blood from a complex of superficial veins, many of which can be easily seen. In front of the elbow it gives off a large branch, the median cubital vein, which slants upwards and medially to join the basilic vein. After crossing the elbow joint the cephalic vein passes up the lateral aspect of the arm and in front of the shoulder joint to end in the axillary vein. Throughout its length it receives blood from the superficial tissues on the lateral aspects of the hand, forearm and arm. It ascends on the medial side of the forearm and upper arm then joins the axillary vein. It begins at the palmar surface of the hand, ascends on the front of the forearm and ends in the basilic vein or the median cubital vein. The brachiocephalic vein is formed when the subclavian and internal jugular veins unite. It drains all the venous blood from the head, neck and upper limbs and terminates in the right atrium. Descending aorta in the thorax this part of the aorta is continuous with the arch of the aorta and begins at the level of the 4th thoracic vertebra. It extends downwards on the anterior surface of the bodies of the thoracic vertebrae. The descending aorta in the thorax gives off many paired branches which supply the walls of the thoracic cavity and the organs within the cavity, including the: bronchial arteries that supply the bronchi and their branches, connective tissue in the lungs and the lymph nodes at the root of the lungs oesophageal arteries, supplying the oesophagus intercostal arteries that run along the inferior border of the ribs and supply the intercostal muscles, some muscles of the thorax, the ribs, the skin and its underlying connective tissues. Venous return from the thoracic cavity Most of the venous blood from the organs in the thoracic cavity is drained into the azygos vein and the hemiazygos vein. Some of the main veins that join them are the bronchial, oesophageal and intercostal veins. The azygos vein joins the superior vena cava and the hemiazygos vein joins the left brachiocephalic vein. At the distal end of the oesophagus, some oesophageal veins join the azygos vein, and others the left gastric vein. A venous plexus is formed by anastomoses between the veins joining the azygos vein and those joining the left gastric veins, linking the general and portal circulations. The name changes when the aorta enters the abdominal cavity by passing behind the diaphragm at the level of the 12th thoracic vertebra. It descends in front of the bodies of the vertebrae to the level of the 4th lumbar vertebra, where it divides into the right and left common iliac arteries. When a branch of the abdominal aorta supplies an organ it is only named here and is described in more detail in association with the organ. However, illustrations showing the distribution of blood from the coeliac, superior and inferior mesenteric arteries are presented here (Figs 5. Many branches arise from the abdominal aorta, some of which are paired and some unpaired. Renal arteries supply the kidneys and give off branches, the suprarenal arteries, to supply the adrenal glands. The testicular and ovarian arteries are much longer than the other paired branches, because these organs begin their development in the region of the kidneys. As they grow, they descend into the scrotum and the pelvis respectively, and are accompanied by their blood vessels. It arises immediately below the diaphragm and divides into three branches: the left gastric artery supplies the stomach the splenic artery supplies the pancreas and the spleen the hepatic artery supplies the liver, gall bladder and parts of the stomach, duodenum and pancreas. It supplies the whole of the small intestine and the proximal half of the large intestine. Venous return from the abdominal organs the inferior vena cava is formed when the right and left common iliac veins join at the level of the body of the 5th lumbar vertebra. This is the largest vein in the body, and it carries blood from all parts of the body below the diaphragm to the right atrium of the heart. It passes through the central tendon of the diaphragm at the level of the 8th thoracic vertebra. Blood from the remaining organs in the abdominal cavity passes through the liver via the portal circulation before entering the inferior vena cava. Portal circulation In all parts of circulation described so far, venous blood passes from the tissues to the heart by the most direct route through only one capillary bed. In the portal circulation, venous blood passes from the capillary beds of the abdominal part of the digestive system, the spleen and pancreas to the liver. It then passes through a second capillary bed, the hepatic sinusoids, in the liver before entering the general circulation via the inferior vena cava. In this way, blood with a high concentration of nutrients, absorbed from the stomach and intestines, goes to the liver first. In the liver certain modifications take place, including the regulation of blood nutrient levels. The inferior mesenteric vein returns the venous blood from the rectum, pelvic and descending colon of the large intestine. The superior mesenteric vein returns venous blood from the small intestine and the proximal parts of the large intestine, i. The gastric veins drain blood from the stomach and the distal end of the oesophagus, then join the portal vein. The cystic vein, which drains venous blood from the gall bladder, joins the portal vein. Hepatic veins these are very short veins that leave the posterior surface of the liver and, almost immediately, enter the inferior vena cava. Circulation to the pelvis and lower limb Arterial supply Common iliac arteries the right and left common iliac arteries are formed when the abdominal aorta divides at the level of the 4th lumbar vertebra. In front of the sacroiliac joint each divides into the internal and the external iliac arteries. The internal iliac artery runs medially to supply the organs within the pelvic cavity.

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Al s o k n o w n audal agenes as ds ac r al agenes i s i r e n o me l i a i s c as in, c h a r a c t e r i ze d b y v a r y i n g d e g r e e s o f f l e xi o n, i n v e r s i o n, l a t e r a l r o t a t i o n, a n d o c c a s i o n a l f u s i o n o f the l o w e r l i mb s; d e f e c t s i n l u mb a r a n d s a c r a l v e r t e b r a e; r e n a l a g e n e s i s; i mp e r f o r a t e a n u s; a n d a g e n e s i s o f i n t e r n a l g e n i t a l s t r u c t u r e s e xc e p t the t e s t e s a n d o v a r i e s. It o c c u r s s p o r a d i c a l l y b u t i s mo s t f r e q u e n t l y o b s e r v e d a mo n g i n f a n t s o f d i a b e t i c mo the r s. T h i s p a t i e n t h a s l e f t - s i d e d l a t e r a l i t y s e q u e n c e a n d s h o u l d b e e v a l u a t e d f o r a d d i t i o n a l d e f e c t s. S i d e d n e s s i s e s t a b l i s h e d a t the t i me o f p r i mi t i v e s t r e a k f o r ma t i o n (g a s t r u l a t i o n) a n d i s r e g u l a t e d b y g e n e s oniu c h a s, s c hedgehog a n d Nodal t h a t b e c o me r e s t r i c t e d i n the i r e xp r e s s i o n. D e v e l o p me n t d u r i n g the t h i r d t o the e i g h t h w e e k s i s c r i t i c a l b e c a u s e t h i s i s w h e n c e l l p o p u l a t i o n s r e s p o n s i b l e f o r o r g a n f o r ma t i o n a r e e s t a b l i s h e d a n d w h e n o r g a n p r i mo r d i a a r e b e i n g f o r me d. E a r l y i n the t h i r d w e e k, g a s t r u l a t i o n begins to provide cells that constitute the three germ layers responsible for organogenesis. Late in the third week, differentiation of the central nervous s y s t e m i s i n i t i a t e d, a n d o v e r the n e xt 5 w e e k s, a l l o f the p r i mo r d i a f o r the ma j o r o r g a n s y s t e ms w i l l b e e s t a b l i s h e d. At the s e t i me s, c e l l s a r e r a p i d l y p r o l i f e r a t i n g, a n d c r i t i c a l c e l l - c e l l s i g n a l s a r e o c c u r r i n g. T h e s e p h e n o me n a a r e p a r t i c u l a r l y s e n s i t i v e t o d i s r u p t i o n b y o u t s i d e f a c t o r s, s u c h a s e n v i r o n me n t a l h a za r d s, p h a r ma c e u t i c a l a g e n t s, a n d d r u g s o f a b u s. T h u s, e xp o s u r e t o s u c h f a c t o r s ma y r e s u l t i n a b n o r ma l i t i e s k n o w n a s b i r t h d e f e c t s o r c o n g e n i t a l ma l f o r ma t i o n s. An e xc e s s o f a mn i o t i c f l u i d i s c a l l e d h y d r a mn i o s o r p o l y h y d r a mn i o s, a n d ma n y t i me s (3 5 %) the c a u s e i s u n k n o w n (i d i o p a t h i c). A h i g h i n c i d e n c e (2 5 %) i s a l s o a s s o c i a t e d w i t h ma t e r n a l d i a b e t e s a n d w i t h b i r t h d e f e c t s t h a t i n t e r f e r e w i t h f e t a l s w a l l o w i n g, s u c h a s e s o p h a g e a l a t r e s i a a n d a n e n c e p h a l y. T h e p l a c e n t a d o e s n o t a c t a s a c o mp l e t e b a r r i e r, a n d ma n y c o mp o u n d s c r o s s f r e e l y, e s p e c i a l l y l i p o p h i l i c s u b s t a n c e s, s u c h a s t o l u e n e a n d a l c o h o l. F u r the r mo r e, e a r l y i n p r e g n a n c y the p l a c e n t a i s n o t c o mp l e t e l y d e v e l o p e d, a n d the e mb r y o i s p a r t i c u l a r l y v u l n e r a b l. T h e s e e a r l y w e e k s a r e a l s o v e r y s e n s i t i v e t o i n s u l t b y c o mp o u n d s s u c h a s t o l u e n e, w h i c h c a u s e s the t o l u e n e e mb r y o p a t h y. S t a t u s o f the f e t u s i s c r i t i c a l f o r ma n a g i n g p r e g n a n c y, d e l i v e r y, a n d p o s t n a t a l c a r. S i ze, a g e, a n d p o s i t i o n a r e i mp o r t a n t f o r d e t e r mi n i n g the t i me a n d mo d e o f d e l i v e r y. K n o w i n g w h e the r b i r t h d e f e c t s a r e p r e s e n t i s i mp o r t a n t f o r p l a n n i n g p o s t n a t a l c a r. The s t s f o r d e t e r mi n i n g f e t a l s t a t u s a r e d i c t a t e d b y ma t e r n a l h i s t o r y a n d f a c t o r s t h a t i n c r e a s e r i s k, s u c h a s e xp o s u r e t o t e r a t o g e n s, c h r o mo s o me a b n o r ma l i t i e s i n e i the r p a r e n t, a d v a n c e d ma t e r n a l a g e, o r the birth of a previous infant with a birth defect. F a c t o r s t h a t i n f l u e n c e the a c t i o n o f a t e r a t o g eg e n oey (p e o f the mo the r a) n a r t a n d c o n c e p t u s,) (d o s e a n d d u r a t i o n o f e xp o s u r e t o the a g e n t s t a n d (b c), g e o f e mb r y o g e n e s i s w h e n e xp o s u r e o c c u r s. M o s t ma j o r ma l f o r ma t i o n s a r e p r o d u c e d d u r i n g the e mb r y o n i c p e r i o d (t e r a t o g e n i c p e r i o d), the t h i r d t o e i g h t h w e e k s o f g e s t a t i o n. H o w e v e r, s t a g e s p r i o r t o t h i s t i me, i n c l u d i n g the p r e i mp l a n t a t i o n p e r i o d, a n d a f t e r the e i g h t h w e e k (f e t a l p e r i o d) r e ma i n s u s c e p t i b l. T h e b r a i n, f o r e xa mp l e, r e ma i n s s e n s i t i v e t o i n s u l t t h r o u g h o u t the fetal period. T h e w o ma n i s c o r r e c t t h a t d r u g s ma y b e t e r a t o g e n i c. S e v e r e h y p e r the r mi a s u c h a s t h i s, h o w e v e r, i s k n o w n t o c a u s e n e u r a l t u b e d e f e c t s (s p i n a b i f i d a a n d a n e n c e p h a l y a t t h i s s t a g e o f g e s t a t i o n). T h e r e f o r e, o n e mu s t w e i g h the r i s k o f teratogenicity of an antipyretic agent with a low teratogenic potential, such as l o w - d o s e a s p i r i n, a g a i n s t the r i s k o f h y p e r the r mi a. In t e r e s t i n g l y, ma l f o r ma t i o n s h a v e b e e n a s s o c i a t e d w i t h s a u n a - i n d u c e d h y p e r the r mi a. N o i n f o r ma t i o n a b o u t e xe r c i s e - i n d u c e d h y p e r the r mi a a n d b i r t h d e f e c t s i s a v a i l a b l e, b u t s t r e n u o u s p h y s i c a l a c t i v i t y (r u n n i n g ma r a t h o n s) r a i s e s b o d y t e mp e r a t u r e s i g n i f i c a n t l y a n d p r o b a b l y s h o u l d b e a v o i d e d d u r i n g p r e g n a n c y. If a w o ma n h a s n o t b e e n t a k i n g f o l a t e a n d i s p l a n n i n g a p r e g n a n c y, s h e s h o u l d b e g i n the s u p p l e me n t 2 mo n t h s p r i o r t o c o n c e p t i o n a n d P. F o l i c a c i d i s n o n t o xi c e v e n a t h i g h d o s e s, c a n p r e v e n t u p t o 7 0 % o f n e u r a l t u b e d e f e c t s, a n d ma y p r e v e n t c o n o t r u n c a l h e a r t defects and facial clefts. P l a c i n g the mo the r u n d e r s t r i c t me t a b o l i c c o n t r o l u s i n g mu l t i p l e i n s u l i n i n j e c t i o n s p r i o r t o c o n c e p t i o n, h o w e v e r, s i g n i f i c a n t l y r e d u c e s the i n c i d e n c e o f a b n o r ma l i t i e s a n d a f f o r d s the g r e a t e s t o p p o r t u n i t y f o r a n o r ma l p r e g n a n c y. A s i mi l a r s c e n a r i o o c c u r s w i t h w o me n w h o h a v e p h e n y l k e t o n u r i a (P K U). C r a n i a l s u t u r e s a r e f i b r o u s r e g i o n s b e t w e e n f l a t b o n e s o f the s k u l l. M e mb r a n o u s r e g i o n s b e t w e e n the f l a t b o n e s a r e k n o w n a s f o n t a n e l l e s, the largest of which is the anterior fontanelle (soft spot). T hese sutures and f o n t a n e l l e s p e r mi)t mo l d i n g o f the h e a d a s i t p a s s e s t h r o u g h the b i r t h c a n a l a (a n d b) g r o w t h o f the b r a i n. G r o w t h o f the s k u l l, w h i c h c o n t i n u e s a f t e r b i r t h a s (the b r a i n e n l a r g e s, i s g r e a t e s t d u r i n g the f i r s t 2 y e a r s o f l i f. P r e ma t u r e c l o s u r e o f o n e o r mo r e s u t u r e s (c r a n i o s y n o s t o s i s) r e s u l t s i n d e f o r mi t i e s i n the shape of the head, depending on which sutures are involved. Craniosynostosis is often associated with other skeletal defects, and evidence suggests that g e n e t i c f a c t o r s a r e i mp o r t a n t i n the c a u s a t i ob l e s9. D e f e c t s o f the l o n g b o n e s a n d d i g i t s a r e o f t e n a s s o c i a t e d w i t h o the r ma l f o r ma t i o n s a n d s h o u l d p r o mp t a t h o r o u g h e xa mi n a t i o n o f a l l s y s t e ms. C l u s t e r s o f d e f e c t s t h a t o c c u r s i mu l t a n e o u s l y w i t h a c o mmo n c a u s e a r e c a l l e d s y n d r o me s, a n d l i mb a n o ma l i e s, e s p e c i a l l y o f the r a d i u s a n d d i g i t s, a r e c o mmo n c o mp o n e n t s o f s u c h c l u s t e r s. D i a g n o s i s o f s y n d r o me s i s i mp o r t a n t i n d e t e r mi n i n g r e c u r r e n c e r i s k s a n d t h u s i n c o u n s e l i n g p a r e n t s a b o u t s u b s e q u e n t pregnancies. F o r ma t i o n o f the v e r t e b r a e i s a c o mp l e x p r o c e s s i n v o l v i n g g r o w t h a n d f u s i o n o f the c a u d a l p o r t i o n o f o n e s c l e r o t o me w i t h the c r a n i a l p o r t i o n o f a n a d j a c e n t o n. N o t s u r p r i s i n g l y, mi s t a k e s o c c u r, a n d the y r e s u l t i n f u s i o n s a n d i n c r e a s e s a n d d e c r e a s e s i n the n u mb e r o f v e r t e b r a e (K l i p p e l - F e i l s e q u e n c e). S c o l i o s i s ma y a l s o b e c a u s e d b y w e a k n e s s o f mu s c l e s o f the b a c k. M u s c l e c e l l s a r e d e r i v e d f r o m the d o r s o l a t e r a l a n d d o r s o me d i a l r e g i o n s o f the s o mi t. T h e s e mu s c l e s i n c l u d e t h o s e o f the l i mb a n d b o d y w a l l. T h e s e a r e the e xt e n s o r mu s c l e s o f the v e r t e b r a l c o l u mn. P a r t i a l o r c o mp l e t e a b s e n c e o f the p e c t o r a l i s ma j o r mu s c l e, the d e f e c t k n o w n a s P o l a n d a n o ma l y, i s the mo s t l i k e l y d i a g n o s i s. P o l a n d a n o ma l y i s o f t e n a s s o c i a t e d w i t h s h o r t n e s s o f the mi d d l e d i g i t s (b r a c h y d a c t y l y) a n d d i g i t a l f u s i o n (s y n d a c t y l y). L o s s o f the p e c t o r a l i s ma j o r mu s c l e p r o d u c e s l i t t l e o r n o l o s s o f f u n c t i o n, s i n c e o the r mu s c l e s c o mp e n s a t. P a t t e r n i n g f o r mu s c l e s d e p e n d s o n c o n n e c t i v e t i s s u e t h a t f o r ms f r o m f i b r o b l a s t s. In n e r v a t i o n f o r mu s c l e s i s d e r i v e d f r o m the v e r t e b r a l l e v e l f r o m w h i c h the mu s c l e c e l l s o r i g i n a t e, a n d t h i s r e l a t i o n i s ma i n t a i n e d r e g a r d l e s s o f w h e r e the mu s c l e c e l l s mi g r a t. T h u s, my o b l a s t s f o r mi n g the d i a p h r a g m o r i g i n a t e f r o m c e r v i c a l s e g me n t s 3, 4, a n d 5, mi g r a t e t o the t h o r a c i c r e g i o n, a n d c a r r y the i r n e r v e s w i t h the m. F a i l u r e o f the l e f t p l e u r o p e r i t o n e a l me mb r a n e t o c l o s e the p e r i c a r d i o p e r i t o n e a l canal on that side is responsible for the defect. T his canal is larger on the left t h a n o n the r i g h t, c l o s e s l a t e r, a n d the r e f o r e ma y b e mo r e s u s c e p t i b l e t o a b n o r ma l i t i e s. T h e d e g r e e o f h y p o p l a s i a o f the l u n g s r e s u l t i n g f r o m c o mp r e s s i o n b y a b d o mi n a l v i s c e r a d e t e r mi n e s the f a t e o f the i n f a n t. T r e a t me n t r e q u i r e s s u r g i c a l r e p a i r o f the d e f e c t, a n d a t t e mp t s t o c o r r e c t the ma l f o r ma t i o n i n u t e r o h a v e b e e n ma d. It o c c u r s b e c a u s e o f a w e a k n e s s i n the b o d y w a l l c a u s e d b y a b n o r ma l c l o s u r e o f the v e n t r a l b o d y w a l l. S i n c e the b o w e l i s n o t c o v e r e d b y the a mn i o n, i t ma y b e c o me n e c r o t i c b e c a u s e o f e xp o s u r e t o the a mn i o t i c f l u i d. It i s a l s o p o s s i b l e f o r the b o w e l l o o p s t o t w i s t a r o u n d the ms e l v e s (v o l v u l u s), c u t t i n g o f f the i r b l o o d s u p p l y a n d p r o d u c i n g a n i n f a r c t i o n. G a s t r o s c h i s i s i s n o t a s s o c i a t e d w i t h g e n e t i c a b n o r ma l i t i e s o r w i t h o the r ma l f o r ma t i o n s. T h e r e f o r e, i f d a ma g e t o the b o w e l i s n o t t o o e xt e n s i v e, survival rates are good. A f o u r - c h a mb e r e d v i e w i s s o u g h t i n u l t r a s o u n d s c a n s o f the h e a r t. T h e c h a mb e r s a r e d i v i d e d b y the a t r i a l s e p t u m s u p e r i o r l y, the v e n t r i c u l a r s e p t u m i n f e r i o r l y, a n d the e n d o c a r d i a l c u s h i o n s s u r r o u n d i n g the a t r i o v e n t r i c u l a r c a n a l s l a t e r a l l y. To g e the r, the s e s t r u c t u r e s f o r m a c r o s s w h o s e i n t e g r i t y i s r e a d i l y v i s u a l i ze d b y u l t r a s o u n d. In t h i s c a s e, h o w e v e r, the f e t u s p r o b a b l y h a s a v e n t r i c u l a r s e p t a l d e f e c t, the mo s t c o mmo n l y o c c u r r i n g h e a r t ma l f o r ma t i o n, i n the me mb r a n o u s p o r t i o n o f the s e p t u m. T h e i n t e g r i t y o f the g r e a t v e s s e l s s h o u l d a l s o b e c h e c k e d c a r e f u l l y, s i n c e the c o n o t r u n c a l s e p t u m d i v i d i n g the a o r t i c a n d p u l mo n a r y c h a n n e l s mu s t c o me i n t o c o n t a c t w i t h the me mb r a n o u s p o r t i o n o f the i n t e r v e n t r i c u l a r s e p t u m f o r t h i s s t r u c t u r e t o d e v e l o p n o r ma l l y. S i n c e n e u r a l c r e s t c e l l s c o n t r i b u t e t o mu c h o f the d e v e l o p me n t o f the f a c e a n d t o the t r u n c a l p o r t i o n o f the c o n o t r u n c a l s e p t u m, the s e c e l l s h a v e p r o b a b l y b e e n d i s r u p t e d. C r e s t c e l l s ma y h a v e f a i l e d t o mi g r a t e t o the s e r e g i o n s, f a i l e d t o p r o l i f e r a t e, o r b e e n k i l l e d. R e t i n o i c a c i d (v i t a mi n A) i s a p o t e n t t e r a t o g e n t h a t t a r g e t s n e u r a l c r e s t c e l l s a mo n g o the r c e l l p o p u l a t i o n s. E n d o c a r d i a l c u s h i o n t i s s u e i s e s s e n t i a l f o r p r o p e r d e v e l o p me n t o f the s e s t r u c t u r e s. In the c o mmo n a t r i o v e n t r i c u l a r c a n a l, the s u p e r i o r, the i n f e r i o r, a n d t w o l a t e r a l e n d o c a r d i a l c u s h i o n s d i v i d e the o p e n i n g a n d c o n t r i b u t e t o the mi t r a a n d t r i c u s p i d v a l v e s i n the l e f t a n d r i g h t a t r i o v e n t r i c u l a r c a n a l s. In a d d i t i o n, t h s u p e r i o r a n d i n f e r i o r c u s h i o n s a r e e s s e n t i a l f o r c o mp l e t e s e p t a t i o n o f the a t r i a b y f u s i o n w i t h the s e p t u m p r i mu m a n d o f the v e n t r i c l e s b y f o r mi n g the me mb r a n o u s p a r t o f the i n t e r v e n t r i c u l a r s e p t u m. C u s h i o n t i s s u e i n the c o n u s a n d t r u n c u s f o r ms the c o n o t r u n c a l s e p t u m, w h i c h s p i r a l s d o w n t o s e p a r a t e the a o r t a a n d p u l mo n a r y c h a n n e l s a n d t o f u s e w i t h the i n f e r i o r e n d o c a r d i a l c u s h i o n t o c o mp l e t e the i n t e r v e n t r i c u l a r s e p t u m. T h e r e f o r e, a n y a b n o r ma l i t y o f c u s h i o n t i s s u e ma y r e s u l t i n a n u mb e r o f c a r d i a c d e f e c t s, i n c l u d i n g a t r i a l a n d ventricular septal defects, transposition of the great vessels, and other a b n o r ma l i t i e s o f the o u t f l o w t r a c t. In the d e v e l o p me n t o f the v a s c u l a r s y s t e m f o r the h e a d a n d n e c k, a s e r i e s o f a r t e r i a l a r c h e s f o r ms a r o u n d the p h a r y n x. M o s t o f the s e a r c h e s u n d e r g o a l t e r a t i o n s, i n c l u d i n g r e g r e s s i o n, a s the o r i g i n a l p a t t e r n s a r e mo d i f i e d. T w o s u c h a l t e r a t i o n s t h a t p r o d u c e d i f f i c u l t y s w a l l oa) i n g ua rle (a o r t i c a r c h, w do b e i n w h i c h a p o r t i o n o f the r i g h t d o r s a l a o r t a (t h a t n o r ma l l y r e g r e s s e s) p e r s i s t s b e t w e e n the s e v e n t h i n t e r s e g me n t a l a r t e r y a n d i t s j u n c t i o n w i t h the l e f t d o r s a l a o r t a, c r e a t i n g a v a s c u l a r r i n g a r o u n d the e s o p h a g urs g h tna o(r t i c a r c h, b) i; a d i n w h i c h the a s c e n d i n g a o r t a a n d the a r c h f o r m o n the r i g h t. If i n s u c h c a s e s the l i g a me n t u m a r t e r i o s u m r e ma i n s o n the l e f t, i t p a s s e s b e h i n d the e s o p h a g u s a n d ma y c o n s t r i c t i t. T h i s i n f a n t mo s t l i k e l y h a s s o me t y p e o f t r a c h e o e s o p h a g e a l a t r e s i a w i t h o r w i t h o u t a t r a c h e o e s o p h a g e a l f i s t u l a. T h e b a b y c a n n o t s w a l l o w, a n d t h i s r e s u l t s i n p o l y h y d r a mn i o s. B a b i e s b o r n p r i o r t o 7 mo n t h s o f g e s t a t i o n d o n o t p r o d u c e s u f f i c i e n t a mo u n t s o f s u r f a c t a n t t o r e d u c e s u r f a c e t e n s i o n i n the a l v e o l i t o p e r mi t n o r ma l l u n g f u n c t i o n. C o n s e q u e n t l y, a l v e o l i c o l l a p s e, r e s u l t i n g i n r e s p i r a t o r y d i s t r e s s s y n d r o me. R e c e n t i mp r o v e me n t s i n a r t i f i c i a l s u r f a c t a n t s h a v e i mp r o v e d the prognosis for these infants. T h e b a b y mo s t l i k e l y h a s s o me t y p e o f e s o p h a g e a l a t r e s i a a n d / o r t r a c h e o e s o p h a g e a l f i s t u l a. P o l y h y d r a mn i o s r e s u l t s b e c a u s e the b a b y c a n n o t s w a l l o w a mn i o t i c f l u i d. T h e d e f e c t i s c a u s e d b y a n a b n o r ma l p a r t i t i o n i n g o f the r e s p i r a t o r y d i v e r t i c u l u m f r o m the f o r e g u t b y the t r a c h e o e s o p h a g e a l s e p t u m. T h e mo s t l i k e l y d i a g n o s i s i s a n o mp h a l o c e l e r e s u l t i n g f r o m a f a i l u r e o f h e r n i a t e d b o w e l t o r e t u r n t o the a b d o mi n a l c a v i t y a t 1 0 t o 1 2 w e e k s o f g e s t a t i o n. S i n c e the b o w e l n o r ma l l y h e r n i a t e s i n t o the u mb i l i c a l c o r d, i t i s c o v e r e d b y a mn i o n. T h i s s i t u a t i o n i s i n c o n t r a s t t o g a s t r o s c h i s i s, i n w h i c h l o o p s o f b o w e l h e r n i a t e t h r o u g h a n a b d o mi n a l w a l l d e f e c t a n d a r e n o t c o v e r e d b y a mn i o n. T h e p r o g n o s i s i s n o t g o o d, s i n c e 2 5 % o f i n f a n t s w i t h o mp h a l o c e l e d i e b e f o r e b i r t h, 4 0 % t o 8 8 % h a v e a s s o c i a t e d a n o ma l i e s, a n d a p p r o xi ma t e l y 1 5 % s h o w c h r o mo s o ma l a b n o r ma l i t i e s. If n o o the r d e f e c t s a r e p r e s e n t, s u r g i c a l r e p a i r i s p o s s i b l e, a n d i n e xp e r i e n c e d h a n d s, s u r v i v a l i s 1 0 0 %. T h i s i n f a n t h a s a n i mp e r f o r a t e a n u s w i t h a r e c t o v a g i n a l f i s t u l a, p a r t o f a n a n o r e c t a l a t r e s i a c o mp l e x. S h e a p p e a r s t o h a v e a h i g h a n o r e c t a l a t r e s i a, s i n c e the f i s t u l a c o n n e c t s the r e c t u m t o the v a g i n a, a c c o u n t i n g f o r me c o n i u m (intestinal contents) in this structure. The defect was probably caused by a c l o a c a t h a t w a s t o o s ma l l, s o t h a t the c l o a c a l me mb r a n e w a s s h o r t e n e d p o s t e r i o r l y.

All shares of Preferred Stock which shall have been surrendered for conversion as provided in this Section 4 shall no longer be deemed to be outstanding and all rights with respect to such shares shall immediately cease and terminate at the Conversion Time erectile dysfunction test video buy generic levitra 10mg on line, except only the right of the holders thereof to receive the items provided for in the last sentence of Subsection 4 muse erectile dysfunction medication reviews buy levitra 20 mg with amex. Any shares of Preferred Stock so converted shall be retired and cancelled and may not be reissued as shares of such series erectile dysfunction heart attack cheap 20mg levitra amex, and the Corporation may thereafter take such appropriate action (without the need for stockholder action) as may be necessary to reduce the authorized number of shares of Preferred Stock accordingly erectile dysfunction protocol free buy cheap levitra 10 mg line. Upon any such conversion erectile dysfunction nutrition order levitra 20 mg amex, no adjustment to the Conversion Price shall be made for any declared but unpaid dividends on the relevant series of Preferred Stock surrendered for conversion or on Common Stock delivered upon conversion erectile dysfunction journal articles purchase levitra 20mg without prescription. The Corporation shall pay any and all issue and other similar taxes that may be payable in respect of any issuance or delivery of shares of Common Stock upon conversion of shares of Preferred Stock pursuant to this Section 4. The Corporation shall not, however, be required to pay any tax which may be payable in respect of any transfer involved in the issuance and delivery of shares of Common Stock in a name other than that in which the shares of Preferred Stock so converted were registered, and no such issuance or delivery shall be made unless and until the person or entity requesting such issuance has paid to the Corporation the amount of any such tax or has established, to the satisfaction of the Corporation, that such tax has been paid. Notwithstanding anything herein to the contrary, no adjustment of the Conversion Price with respect to any series of Preferred Stock shall be made as the result of the issuance or deemed issuance of Additional Shares of Common Stock if the Corporation receives written notice from the holders of a majority of the then outstanding shares of Preferred Stock, with all series voting together as a single class, agreeing that no such adjustment shall be made as the result of the issuance or deemed issuance of such Additional Shares of Common Stock; provided, however, that the waiver of any adjustment of the Conversion Price applicable to the Series B Preferred Stock shall require the consent of the holders of a majority of the shares of Series B Preferred Stock then outstanding. Notwithstanding the foregoing, no readjustment pursuant to this clause (b) shall have the effect of increasing the relevant Conversion Price to an amount which exceeds the lower of (1) the relevant Conversion Price in effect immediately prior to the original adjustment made as a result of the issuance of such Option or Convertible Security (or the occurrence of a record date with respect thereto) or (2) the Conversion Price that would have resulted from any issuances of Additional Shares of Common Stock (other than deemed issuances of Additional Shares of Common Stock as a result of the issuance of such Option or Convertible Security) between the original adjustment date and such readjustment date. Please Consider the Environment Before Printing this Document (c) If the terms of any Option or Convertible Security (excluding Options or Convertible Securities which are themselves Exempted Securities), the issuance of which did not result in an adjustment to any Conversion Price pursuant to the terms of Subsection 4. If, at any time after the applicable Original Series B Issue Date, the Corporation issues Additional Shares of Common Stock (including Additional Shares of Common Stock deemed to be issued pursuant to Subsection 4. Please Consider the Environment Before Printing this Document (b) Options and Convertible Securities. Such consideration shall, in the event that Additional Shares of Common Stock are deemed to have been issued pursuant to Subsection 4. If the Corporation issues, on more than one date, Additional Shares of Common Stock that are a part of one transaction or a series of related transactions and that would result in an adjustment to any Conversion Price pursuant to the terms of Subsection 4. If the Corporation at any time or from time to time after the Original Series B Issue Date effects a subdivision of the outstanding shares of Common Stock into a greater number of shares of Common Stock, the relevant Conversion Price in effect immediately before the subdivision shall be proportionately decreased so that the number of shares of Common Stock issuable on conversion of each share of such series shall be increased in proportion to such increase in the aggregate number of shares of Common Stock outstanding. Please Consider the Environment Before Printing this Document number of shares of Common Stock, the relevant Conversion Price in effect immediately before the combination shall be proportionately increased so that the number of shares of Common Stock issuable on conversion of each share of such series shall be decreased in proportion to such decrease in the aggregate number of shares of Common Stock outstanding. The relevant Conversion Price shall be readjusted in the same manner upon the happening of each subsequent subdivision or combination of the outstanding shares of Common Stock. If the Corporation at any time or from time to time after the Original Series B Issue Date makes or issues, or fixes a record date for the determination of holders of Common Stock entitled to receive, a Common Stock Dividend, then in each such event the relevant Conversion Price in effect immediately before such event shall be decreased as of the time of such issuance or, in the event such a record date shall have been fixed, as of the close of business on such record date, by multiplying the such Conversion Price then in effect by a fraction: (1) the numerator of which shall be the total number of shares of Common Stock issued and outstanding immediately prior to the time of such issuance or the close of business on such record date; and (2) the denominator of which shall be the sum of (a) the total number of shares of Common Stock issued and outstanding immediately prior to the time of such issuance or the close of business on such record date and (b) the total number of shares of Common Stock issuable in payment of such Common Stock Dividend. Notwithstanding the foregoing, (i) if such record date shall have been fixed and such Common Stock Dividend is not fully paid or made on the date fixed therefor, the relevant Conversion Price shall be recomputed accordingly as of the close of business on such record date and thereafter such Conversion Price shall be adjusted pursuant to this Subsection 4. The relevant Conversion Price shall be readjusted in the same manner upon the happening of each subsequent Common Stock Dividend. Please Consider the Environment Before Printing this Document Stock on the date of such event or such record date, as applicable, and had they thereafter, during the period from the date of such event or such record date, as applicable, to and including the conversion date, retained such securities during such period, giving application to all adjustments called for during such period under this Section 4 with respect to the rights of the holders of Preferred Stock or with respect to such other securities by their terms; provided, however, that no such provision shall be made if the holders of Preferred Stock receive, simultaneously with the dividend or distribution to the holders of Common Stock, a dividend or other distribution of such securities, cash or other property in an amount equal to the amount of such securities, cash or other property as they would have received if all outstanding shares of Preferred Stock had been converted into Common Stock on the date of such event or such record date, as applicable. Upon the occurrence of each adjustment or readjustment of any Conversion Price pursuant to this Section 4, the Corporation, at its expense, shall promptly (but in any event not later than ten days thereafter) compute such adjustment or readjustment in accordance with the terms hereof and furnish, or cause to be furnished, to each holder of the relevant series of Preferred Stock a certificate setting forth such adjustment or readjustment (including the kind and amount of securities, cash or other property into which such series of Preferred Stock is convertible) and showing in detail the facts upon which such adjustment or readjustment is based. Please Consider the Environment Before Printing this Document holder of any Preferred Stock, the Corporation shall promptly (but in any event not later than ten days thereafter) furnish, or cause to be furnished, to such holder a certificate setting forth (i) the Conversion Price then in effect and (ii) the number of shares of Common Stock and the amount, if any, of other securities, cash or property which then would be received upon the conversion of such series of Preferred Stock. In the event (x) the Corporation takes a record of the holders of any class of securities for the purpose of determining the holders thereof who are entitled to receive any dividend or other distribution, or to receive any right to subscribe for or purchase any shares of capital stock of any class or any other securities, (y) of any capital reorganization of the Corporation, any reclassification of Common Stock or any Deemed Liquidation Event, or (z) of the voluntary or involuntary liquidation, dissolution or winding up of the Corporation (the events described in the foregoing clauses (y) and (z), Other Events), then in each such case the Corporation shall send, or cause to be sent, to the holders of record of Preferred Stock, a notice specifying, as the case may be, (i) the date on which any such record is to be taken for the purpose of such dividend, distribution or right and (ii) the effective date on which such Other Event is proposed to take place and the time, if any is to be fixed, as of which the holders of record of Common Stock (or such other capital stock or securities at the time issuable upon the conversion of Preferred Stock) shall be entitled to exchange their shares of Common Stock (or such other capital stock or securities at the time issuable upon the conversion of the relevant series of Preferred Stock) for securities or other property deliverable upon such Other Event, and the amount per share and character of such exchange applicable to Common Stock and the relevant series of Preferred Stock. Each notice described in the foregoing sentence shall be sent at least ten days prior to the record date or effective date, as applicable, for the event specified in such notice. All outstanding shares of Preferred Stock shall automatically, and without any further action on the part of the holders thereof, be converted into shares of Common Stock at the then effective Conversion Price, upon either (a) the closing of the sale of shares of Common Stock to the public in a firm-commitment underwritten public offering pursuant to an effective registration statement filed under the Securities Act of 1933, as amended, (i) with a price of at least 1. The Corporation shall send, or cause to be sent, to all holders of record of shares of Preferred Stock, written notice of the Mandatory Conversion Time and the place designated for mandatory conversion of all such shares of Preferred Stock pursuant to this Section 5. Such notice need not be sent in advance of the occurrence of the Mandatory Conversion Time. Upon receipt of such notice, each holder of shares of Preferred Stock shall surrender his, her or its certificate or certificates for all such shares (or, if such holder alleges that such certificate has been lost, stolen or destroyed, a lost certificate affidavit and agreement reasonably acceptable to the Corporation to indemnify the Corporation against any claim that may be made against the Corporation on account of the alleged loss, theft or destruction of such certificate) to the Corporation, in the manner and at the place designated in such notice. All shares of Preferred Stock shall no longer be deemed to be outstanding and all rights with respect to such shares, including the rights, if any, to receive notices and to vote (other than as a holder of Common Stock), shall immediately cease and terminate at the Mandatory Conversion Time (notwithstanding the failure of the registered holder or holders thereof to surrender the certificates for such shares at or prior to such time), except only the right of the registered holders thereof, upon surrender of their certificate or certificates therefor (or lost certificate affidavit and agreement), to receive the items provided for in the next sentence of this Subsection 5. The Corporation shall, as soon as practicable after the Mandatory Conversion Time and the surrender of the certificate or certificates (or lost certificate affidavit and agreement) for shares of Preferred Stock so converted, (i) issue and deliver to such holder of Preferred Stock, or to his, her or its nominees, a certificate or certificates for the number of full shares of Common Stock issuable upon such conversion in accordance with the provisions hereof, (ii) pay in cash such amount as provided in Subsection 4. Such converted shares of Preferred Stock shall be retired and cancelled and may not be reissued as shares of such series, and the Corporation may thereafter take such appropriate action (without the need for stockholder action) as may be necessary to reduce the authorized number of shares of Preferred Stock accordingly. Neither the Corporation nor the holders of Preferred Stock shall have the unilateral right to call or redeem, or cause to have called or redeemed, any shares of Preferred Stock. Any shares of Preferred Stock that are acquired by the Corporation or any of its subsidiaries by reason of redemption, purchase, conversion or otherwise shall be automatically and immediately retired and cancelled and shall not be reissued, sold or transferred. Neither the Corporation nor any of its subsidiaries may exercise any voting or other rights granted to the holders of Preferred Stock following redemption. Any of the rights, powers, preferences and other terms of Series A Preferred Stock set forth herein may be waived on behalf of all holders of Series A Preferred Stock by the affirmative written consent or vote of the holders of a majority of the shares of Series A Preferred Stock then outstanding. Any of the rights, powers, preferences and other terms of Series A-1 Preferred Stock set forth herein may be waived on behalf of all holders of Series A-1 Preferred Stock by the affirmative written consent or vote of the holders of at least a majority of the shares of Series A-1 Preferred Stock then outstanding. Any of the rights, powers, preferences and other terms of Series B Preferred Stock set forth herein may be waived on behalf of all holders of Series B Preferred Stock by the affirmative written consent or vote of the holders of at least a majority of the shares of Series B Preferred Stock then outstanding. Any such notice shall be deemed given upon such mailing, delivery or electronic transmission, as applicable. The books of the Corporation may be kept (subject to any provision contained in applicable statutes) outside the State of Delaware at such place or places as may be designated from time to time by the Board or in the Bylaws of the Corporation. An Excluded Opportunity is any matter, transaction or interest that is presented to , or acquired, created or developed by, or which otherwise comes into the possession of (i) any director of the Corporation who is not an officer or employee of the Corporation or any of its subsidiaries, or (ii) any holder of Preferred Stock or Common Stock issued upon the conversion of the Preferred Stock, or any partner, member, director, stockholder, employee or agent of any such holder, excluding (A) any holder that is affiliated with someone who is an officer or employee of the Corporation or any of its subsidiaries, and (B) anyone who is an officer or employee of the Corporation or any of its subsidiaries (the persons and entities being referred to in clauses (i) and (ii), collectively, Covered Persons), unless such matter, transaction or interest is presented to , or acquired, created or developed by, or otherwise comes into the possession of, a Covered Person expressly and solely in such Covered Persons capacity as a director of the Corporation. Accordingly, for purposes of making any calculation under Section 500 of the California Corporations Code in connection with such repurchase, the amount of any preferential dividends arrears amount or preferential rights amount (as those terms are defined therein) shall be deemed to be zero (0). In the absence of any such determination by the Board, meetings of stockholders shall be held at the Companys principal executive office. Any other proper business may be transacted at the annual meeting of stockholders. Notwithstanding the foregoing, the Company shall not be required to hold an annual meeting of stockholders, provided that (i) the stockholders are permitted to act by written consent under the Companys certificate of incorporation and these bylaws, (ii) the stockholders take action by written consent to elect directors, and (iii) the stockholders unanimously consent to such action or, if such consent is less than unanimous, all of the directorships to which directors could be elected at an annual meeting held at the effective time of such action are vacant and are filled by such action. If any person(s) other than the Board calls a special meeting, the request shall: (i) be in writing; (ii) specify the general nature of the business proposed to be transacted; and (iii) be delivered personally or sent by registered mail, return receipt requested, or by facsimile transmission to the Chairperson of the Board, Chief Executive Officer, President (in the absence of a Chief Executive Officer) or Secretary. Please Consider the Environment Before Printing this Document the officer(s) of the Company receiving the request shall cause notice to be promptly given to the stockholders entitled to vote at such meeting, in accordance with these bylaws, that a meeting will be held at the place and time determined by the Board, which shall not be fewer than 30 nor more than 120 days after the date of receipt of the request. No business may be transacted at such special meeting other than the business specified in such notice to stockholders. If, however, such quorum is not present or represented at any meeting of stockholders, then either (i) the Chairperson of the Meeting (as defined in Section 1. A quorum, once established, shall not be broken by the subsequent withdrawal of enough votes to leave less than a quorum. Please Consider the Environment Before Printing this Document any business which might have been transacted at the original meeting. If the adjournment is for more than 30 days, a notice of the adjourned meeting shall be given to each stockholder of record entitled to vote at the meeting. The Secretary shall act as secretary of each meeting, but in his or her absence the Chairperson of the Meeting may appoint any person to act as secretary of such meeting. The Chairperson of the Meeting shall determine the order of business and the procedure at the meeting, including such regulation of the manner of voting and the conduct of business. Unless otherwise provided in the certificate of incorporation and subject to Section 1. Elections of directors need not be by written ballot and, unless otherwise required by law, need not be conducted by inspectors of election unless so determined by the holders of shares of stock having a majority of the votes which could be cast by the holders of all outstanding shares of stock entitled to vote thereon which are present in person or by proxy at such meeting. If authorized by the Board, such requirement of a written ballot shall be satisfied by a ballot submitted by electronic transmission, provided that any such electronic transmission must either set forth or be submitted with information from which it can be determined that the electronic transmission was authorized by the stockholder or proxy holder. Please Consider the Environment Before Printing this Document to vote on the election of directors, and (iii) where a separate vote by a class or series or classes or series is required, in all matters other than the election of directors, the affirmative vote of the majority of shares of such class or series or classes or series present in person or represented by proxy at the meeting shall be the act of such class or series or classes or series. Every written consent (other than a written consent by electronic transmission) shall bear the date of signature of each stockholder who signs the consent, and no written consent shall be effective to take the corporate action referred to therein unless, within 60 days of the earliest dated consent delivered to the Company in the manner herein required, written consents signed by a sufficient number of stockholders to take action are delivered to the Company by delivery to its registered office in the State of Delaware, its principal place of business or an officer or agent of the Company having custody of the book in which proceedings of meetings of stockholders are recorded. Delivery made to the Companys registered office shall be by hand or by certified or registered mail, return receipt requested. An electronic transmission consenting to an action to be taken and transmitted by a stockholder or proxy holder, or by a person or persons authorized to act for a stockholder or proxy holder, shall be deemed to be written, signed and dated for purposes of this Section 1. The date on which such electronic transmission is transmitted shall be deemed to be the date on which such consent was signed. Notwithstanding the foregoing, in the event that the Board shall have instructed the officers of the Company to solicit the vote or written consent of the stockholders of the Company, an electronic transmission of a stockholder written consent given pursuant to such solicitation may be delivered to the Secretary or President (or to a person designated by the Secretary or President). The Secretary or President (or a person designated by the Secretary or President) shall cause any such written consent by electronic transmission to be reproduced in paper form and inserted into the Companys corporate records. A determination of stockholders of record entitled to notice of or to vote at a meeting of stockholders shall apply to any adjournment of the meeting, provided that the Board may fix a new record date for the determination of stockholders entitled to vote at the adjourned meeting, and in such case shall also fix as the record date for stockholders entitled to notice of such adjourned meeting the same or an earlier date as that fixed for determination of stockholders entitled to vote in accordance with the foregoing provisions of this Section 1. The Company shall not be required to include electronic mail addresses or other electronic contact information on such list. Such list shall be open to the examination of any stockholder for any purpose germane to the meeting for a period of at least 10 days prior to the meeting: (i) on a reasonably accessible electronic network, provided that the information required to gain access to such list is provided with the notice of the meeting, or (ii) during ordinary business hours, at the Companys principal place of business. In the event that the Company determines to make the list available on an electronic network, the Company may take reasonable steps to ensure that such information is available only to stockholders of the Company. If the meeting is to be held at a place, then a list of stockholders entitled to vote at the meeting shall be produced and kept at the time and place of the meeting during the whole time thereof and may be examined by any stockholder who is present. If the meeting is to be held solely by means of remote communication, then such list shall also be open to the examination of any stockholder during the whole time of the meeting on a reasonably accessible electronic network, and the information required to access such list shall be provided with the notice of the meeting. Unless the certificate of incorporation fixes the number of directors, the number of directors shall be determined from time to time by resolution of the Board. No reduction of the authorized number of directors shall have the effect of removing any director before that directors term of office expires. Directors need not be stockholders unless so required by the certificate of incorporation or these bylaws. The certificate of incorporation or these bylaws may prescribe other qualifications for directors. Each director shall hold office until such directors successor is elected and qualified or until such directors earlier death, resignation or removal. A resignation is effective when the resignation is delivered unless the resignation specifies a later effective date or an effective date determined upon the happening of an event or events. A resignation which is conditioned upon the director failing to receive a specified vote for reelection as a director may provide that it is irrevocable. Unless otherwise provided in the certificate of incorporation or these bylaws, when one or more directors shall resign from the Board, effective at a future date, a majority of the directors then in office, including those who have so resigned, shall have power to fill such vacancy or vacancies, the vote thereon to take effect when such resignation or resignations shall become effective. Unless otherwise provided in the certificate of incorporation or these bylaws, vacancies and newly created directorships resulting from any increase in the authorized number of directors may be filled by a majority of the directors then in office, although less than a quorum, or by a sole remaining director. A director elected to fill a vacancy shall be elected for the unexpired term of his or her predecessor in office and until such directors successor is elected and qualified or until such directors earlier death, resignation or removal. Unless otherwise restricted by the certificate of incorporation or these bylaws, members of the Board, or any committee designated by the Board, may participate in a meeting of the Board, or any committee, by means of conference telephone or other communications equipment by means of which all persons participating in the meeting can hear each other, and such participation in a meeting shall constitute presence in person at the meeting. The Secretary shall act as secretary of the meeting, but in his or her absence the chairperson of the meeting may appoint any person to act as secretary of such meeting. Please Consider the Environment Before Printing this Document Notice of the time and place of all special meetings shall be: (i) delivered personally by hand, by courier or by telephone (including a voice messaging system or other technology designed to record and communicate messages) during normal business hours at least 24 hours before the date and time of the meeting; (ii) sent by United States first-class mail, postage prepaid, deposited at least four days before the date and time of the meeting; (iii) sent by facsimile during normal business hours at least 24 hours before the date and time of the meeting; or (iv) sent by electronic mail during normal business hours at least 24 hours before the date and time of the meeting, directed to each director at that directors address, telephone number, facsimile number or electronic mail address, as the case may be, as shown on the Companys records. The notice need not specify the place of the meeting (if the meeting is to be held at the Companys principal executive office) nor the purpose of the meeting. If a quorum is not present at any meeting of the Board, then the directors present thereat may adjourn the meeting from time to time, without notice other than announcement at the meeting, until a quorum is present. A meeting at which a quorum is initially present may continue to transact business notwithstanding the withdrawal of directors if any action taken is approved by at least a majority of the required quorum for that meeting. The vote of the majority of the directors present at a meeting at which a quorum is present shall be the act of the Board, unless the certificate of incorporation or these bylaws requires a vote of a greater number. If the certificate of incorporation provides that one or more directors shall have greater or fewer than one vote per director on any matter, every reference in these bylaws to a majority or other proportion of the directors shall refer to a majority or other proportion of the votes of the directors. Please Consider the Environment Before Printing this Document Such filing shall be in paper form if the minutes are maintained in paper form and shall be in electronic form if the minutes are maintained in electronic form. Whenever the holders of any class or series are entitled to elect one or more directors by the certificate of incorporation, this Section 2. The Board may at any time increase or decrease the number of members of any committee or terminate the existence of any committee. The membership of a committee member shall terminate on the date of his or her death, resignation from such committee or the Board or removal from such committee or the Board. The Board may at any time and for any reason remove any individual committee member, and the Board may fill any committee vacancy created by a committee members death, resignation or removal. The Board may designate one or more directors as alternate members of any committee, who may replace any absent or disqualified member at any meeting of the committee. In the absence or disqualification of a member of a committee, the member or members present at any meeting and not disqualified from voting, whether or not such member or members constitute a quorum, may unanimously appoint another member of the Board to act at the meeting in the place of any such absent or disqualified member. However: (i) the time of regular meetings of a committee may be determined either by resolution of the Board or by resolution of such committee; (ii) special meetings of committees may also be called by resolution of the Board; and (iii) notice of special meetings of any committee shall also be given to all alternate members of such committee, who shall have the right to attend all meetings of such committee. The Board may adopt rules for the government of any committee not inconsistent with the provisions of these bylaws. Any provision in the certificate of incorporation providing that one or more directors shall have more or less than one vote per director on any matter shall apply to voting in any committee or subcommittee, unless otherwise provided in the certificate of incorporation or these bylaws.

Many of them travel within the same nerve sheath as peripheral nerves to reach the organs that they innervate erectile dysfunction doctor in pune buy levitra 20mg online. The autonomic nervous system is separated into two divisions: sympathetic (thoracolumbar outflow) parasympathetic (craniosacral outflow) erectile dysfunction after drug use buy generic levitra 10 mg. They normally work in an opposing manner impotence and age discount levitra 20 mg online, thereby maintaining balance of involuntary functions statistics for erectile dysfunction generic levitra 10 mg overnight delivery. Sympathetic activity tends to predominate in stressful situations and parasympathetic activity during rest erectile dysfunction doctor dallas best 10 mg levitra. Each division has two efferent neurones between the central nervous system and effector organs erectile dysfunction in your 20s levitra 20mg with amex. The preganglionic neurone this has its cell body in the lateral column of grey matter in the spinal cord between the levels of the 1st thoracic and 2nd or 3rd lumbar vertebrae. The nerve fibre of this cell leaves the cord by the anterior root and terminates at a synapse in one of the ganglia either in the lateral chain of sympathetic ganglia or passes through it to one of the prevertebral ganglia (see below). The postganglionic neurone this has its cell body in a ganglion and terminates in the organ or tissue supplied. Noradrenaline (norepinephrine) is usually the neurotransmitter at sympathetic effector organs. The major exception is that there is no parasympathetic supply to the sweat glands, the skin and blood vessels of skeletal muscles. These structures are supplied by only sympathetic postganglionic neurones, which are known as sympathetic cholinergic nerves and usually have acetylcholine as their neurotransmitter. Sympathetic ganglia the lateral chains of sympathetic ganglia these chains extend from the upper cervical level to the sacrum, one chain lying on each side of the vertebral bodies. Preganglionic neurones that emerge from the cord may synapse with the cell body of the postganglionic neurone at the same level or they may pass up or down the chain through one or more ganglia before synapsing. For example, the nerve that dilates the pupil of the eye leaves the cord at the level of the 1st thoracic vertebra and passes up the chain to the superior cervical ganglion before it synapses with the cell body of the postsynaptic neurone. The arrangement of the ganglia allows excitation of nerves at multiple levels very quickly, providing a rapid and widespread sympathetic response. Prevertebral ganglia There are three prevertebral ganglia situated in the abdominal cavity close to the origins of arteries of the same names: coeliac ganglion superior mesenteric ganglion inferior mesenteric ganglion. The ganglia consist of nerve cell bodies rather diffusely distributed among a network of nerve fibres that form plexuses. Preganglionic sympathetic fibres pass through the lateral chain to reach these ganglia. Parasympathetic nervous system Two neurones (preganglionic and postganglionic) are involved in the transmission of impulses from their source to the effector organ. The preganglionic neurone this is usually long in comparison to its counterpart in the sympathetic nervous system and has its cell body either in the brain or in the spinal cord. The cell bodies of the sacral outflow are in the lateral columns of grey matter at the distal end of the spinal cord. Their fibres leave the cord in sacral segments 2, 3 and 4 and synapse with postganglionic neurones in the walls of pelvic organs. The postganglionic neurone this is usually very short and has its cell body either in a ganglion or, more often, in the wall of the organ supplied. Functions of the autonomic nervous system the autonomic nervous system is involved in many complex involuntary reflex activities which, like the reflexes described previously, depend on sensory input to the brain or spinal cord, and on motor output. In this case the reflex action is rapid contraction, or inhibition of contraction, of involuntary (smooth and cardiac) muscle or glandular secretion. Some sensory input does reach consciousness and may result in temporary inhibition of the reflex action. The majority of the body organs are supplied by both sympathetic and parasympathetic nerves, which have opposite effects that are finely balanced to ensure their optimum functioning meets body needs at any moment. Sympathetic stimulation prepares the body to deal with exciting and stressful situations. The adrenal glands are stimulated to secrete the hormones adrenaline (epinephrine) and noradrenaline (norepinephrine) into the bloodstream. The effects of stimulation on the heart, blood vessels and lungs (see below) enable the body to respond by preparing it for exercise. Additional effects are an increase in the metabolic rate and increased conversion of glycogen to glucose. Parasympathetic stimulation has a tendency to slow down body processes except digestion and absorption of food and the functions of the genitourinary systems. Normally the two systems function together, maintaining a regular heartbeat, normal temperature and an internal environment compatible with the immediate external surroundings. Effects of autonomic stimulation Cardiovascular system Sympathetic stimulation Accelerates firing of the sinoatrial node in the heart, increasing the rate and force of the heartbeat. Dilates the blood vessels supplying skeletal muscle, increasing the supply of oxygen and nutritional materials and the removal of metabolic waste products, thus increasing the capacity of the muscle to work. Raises peripheral resistance and blood pressure by constricting the small arteries and arterioles in the skin. In this way an increased blood supply is available for highly active tissue, such as skeletal muscle, heart and brain. This raises the volume of blood available for circulation in dilated blood vessels. The parasympathetic nervous system exerts little or no effect on blood vessels except the coronary arteries. Respiratory system Sympathetic stimulation this causes smooth muscle relaxation and therefore dilation of the airways (bronchodilation), especially the bronchioles, allowing a greater amount of air to enter the lungs at each inspiration, and increases the respiratory rate. Parasympathetic stimulation this causes contraction of the smooth muscle in the airway walls, leading to bronchoconstriction. Digestive and urinary systems Sympathetic stimulation the liver increases conversion of glycogen to glucose, making more carbohydrate immediately available to provide energy. Smooth muscle contraction (peristalsis) and secretion of digestive juices are inhibited, delaying digestion, onward movement and absorption of food, and the tone of sphincter muscles is increased. The adrenal (suprarenal) glands are stimulated to secrete adrenaline (epinephrine) and noradrenaline (norepinephrine) which potentiate and sustain the effects of sympathetic stimulation throughout the body. The muscle tone of the sphincters is increased, inhibiting micturition and defecation. Motility and secretion are increased, together with the rate of digestion and absorption of food. Relaxation of the internal urethral sphincter is accompanied by contraction of the muscle of the bladder wall, and micturition occurs. Similar relaxation of the internal anal sphincter is accompanied by contraction of the muscle of the rectum, and defecation occurs. Eye Sympathetic stimulation this causes contraction of the radiating muscle fibres of the iris, dilating the pupil. Retraction of the levator palpebrae muscles occurs, opening the eyes wide and giving the appearance of alertness and excitement. The ciliary muscle that adjusts the thickness of the lens is slightly relaxed, facilitating distant vision. Parasympathetic stimulation this contracts the circular muscle fibres of the iris, constricting the pupil. Constricts the peripheral blood vessels, increasing blood supply available to active organs. Some sympathetic fibres are adrenergic, causing vasoconstriction, and some are cholinergic, causing vasodilation. Afferent impulses from viscera Sensory fibres from the viscera travel with autonomic fibres and are sometimes called autonomic afferents. The impulses they transmit are associated with: visceral reflexes, usually at an unconscious level. Visceral pain Normally the viscera are insensitive to cutting, burning and crushing. However, a sensation of dull, poorly located pain is experienced when: visceral nerves are stretched a large number of fibres are stimulated there is ischaemia and local accumulation of metabolites the sensitivity of nerve endings to painful stimuli is increased. This is because the peripheral spinal (somatic) nerves that innervate the superficial tissues also innervate the parietal layer of serous membrane. They transmit the impulses to the cerebral cortex where somatic pain is perceived and accurately located. As the condition progresses the parietal peritoneum becomes involved and acute pain is clearly located in the right iliac fossa, i. This occurs when sensory fibres from the affected organ enter the same segment of the spinal cord as somatic nerves, i. It is believed that the sensory nerve from the damaged organ stimulates the closely associated nerve in the spinal cord and it transmits the impulses to the sensory area in the cerebral cortex where the pain is perceived as originating in the area supplied by the somatic nerve. Ischaemic heart tissue generates impulses in nerve Y that then stimulate nerve X and pain is perceived in the shoulder. Increased intracranial pressure this is a serious complication of many conditions that affect the brain. As it reaches its limit a further small increase in pressure is followed by a sudden and usually serious reduction in the cerebral blood flow as autoregulation fails. This leads to progressive loss of functioning neurones, which exacerbates bradycardia and hypertension. Expanding lesions may occur in the brain or in the meninges and they can damage the brain in various ways. Obstruction of the flow of cerebrospinal fluid the ventricles or their ducts may be pushed out of position or a duct obstructed. Vascular damage There may be stretching or compression of blood vessels, causing: haemorrhage when stretched blood vessels rupture ischaemia and infarction due to compression of blood vessels papilloedema (oedema round the optic disc) due to compression of the retinal vein in the optic nerve sheath where it crosses the subarachnoid space. Cerebral oedema There is movement of fluid from its normal compartment when oedema develops (p. Cerebral oedema occurs when there is excess fluid in brain cells and/or in the interstitial spaces, causing increased intracranial pressure. It is associated with: traumatic injury haemorrhage infections, abscesses hypoxia, local ischaemia or infarcts tumours inflammation of the brain or meninges hypoglycaemia (p. Enlargement of the head occurs in children when ossification of the cranial bones is incomplete but, in spite of this, the ventricles dilate and cause stretching and thinning of the brain. Congenital primary hydrocephalus is due to malformation of the ventricles, foramina or ducts, usually at a narrow point. Head injuries Damage to the brain may be serious even when there is no outward sign of injury. At the site of injury there may be: a scalp wound, with haemorrhage between scalp and skull bones damage to the underlying meninges and/or brain with local haemorrhage inside the skull a depressed skull fracture, causing local damage to the underlying meninges and brain tissue fracture involving the air sinuses of the sphenoid, ethmoid or frontal bones, making an opening between the nose and the meninges. Other injuries include: nerve cell damage, usually to the frontal and parietal lobes, due to movement of the brain over the rough surface of bones of the base of the skull nerve fibre damage due to stretching, especially following rotational movement haemorrhage due to rupture of blood vessels in the subarachnoid space on the side opposite the impact or more diffuse small haemorrhages, following rotational movement. Complications of head injury If the individual survives the immediate effects, complications may develop hours or days later. Sometimes they are the first indication of serious damage caused by a seemingly trivial injury. Traumatic intracranial haemorrhage Haemorrhage may occur causing secondary brain damage at the site of injury, on the opposite side of the brain or diffusely throughout the brain. Extradural haemorrhage this may follow a direct blow that may or may not cause a fracture. In children there is rarely a fracture because the skull bones are still soft and the joints have not fused. Acute subdural haemorrhage this is due to haemorrhage from small veins in the dura mater or from larger veins between the layers of dura mater before they enter the venous sinuses. Chronic subdural haemorrhage this may occur weeks or months after minor injuries and sometimes there is no history of injury. The haematoma formed gradually increases in size owing to repeated small haemorrhages and causes mild chronic inflammation and accumulation of inflammatory exudate. Intracerebral haemorrhage and cerebral oedema these occur following contusions, lacerations and shearing injuries associated with acceleration and deceleration, especially rotational movements. Post-traumatic epilepsy this is usually characterised by seizures (fits) and may develop in the first week or several months after injury. Early development is most common after severe injuries, although in children the injury itself may have appeared trivial. Persistent vegetative state In this condition there is severe brain damage that results in unconsciousness but the vital centres that control homeostasis remain intact. When the mean blood pressure falls below about 60 mmHg, the autoregulating mechanisms that control the blood flow to the brain by adjusting the diameter of the arterioles fail. The consequent rapid decrease in the cerebral blood supply leads to hypoxia and lack of glucose. If severe hypoxia is sustained for more than a few minutes there is irreversible brain damage. The neurones are affected first, then the neuroglial cells and later the meninges and blood vessels. Conditions in which autoregulation breaks down include: cardiorespiratory arrest sudden severe hypotension carbon monoxide poisoning hypercapnia (excess blood carbon dioxide) drug overdosage with. Conditions affecting cerebral blood vessels that may lead to hypoxia include: occlusion of a cerebral artery by. If the individual survives the initial episode of ischaemia, then infarction, necrosis and loss of function of the affected area of brain may occur. Stroke (cerebrovascular disease) this condition is a common cause of death and disability, especially in older people.

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