Marc J. Poulin, PhD

• Professor, Department of Medicine and Department
• of Physiology and Biophysics, Faculty of Medicine,
• University of Calgary, Calgary, Canada

Positive feedback: Instead of maintaining homeostasis blood pressure calculator cheap lasix 100mg on-line, a hormone can perpetuate an increase or decrease of its own release away from the normal range via reinforcement along its endocrine axis blood pressure medication upset stomach 40 mg lasix with amex. Feedback can occur via alterations in gene transcription blood pressure normal range buy discount lasix 100 mg line, posttransla tional processing blood pressure medication classifications buy lasix 40mg mastercard, or hormone release hypertension remedies discount lasix 40 mg fast delivery. Each of its nuclei contributes to main taining homeostasis: water balance arrhythmia heart beats purchase cheapest lasix, body temperature, hunger, thirst, and even emotions. The hypothalamus exerts direct control over anterior pituitary hormone secre tion via releasing/inhibiting factors (Table 2-4). These factors are synthesized by neural cell bodies in the hypothalamus, stored in granules at axon termi nals, and released into the hypothalamo-hypophyseal circulation. Pituitary the pituitary, or hypophysis, is composed of two embryologically and mor phologically distinct glands (anterior and posterior) connected to the hypo thalamus by the pituitary stalk. It is composed of five different hormone-producing cell populations, all of which are regulated by hypothalamic releasing and inhibiting hormones. The neurons that secrete these releasing hormones converge in the median eminence of the hypothala mus and act on the anterior pituitary via the hypophyseal circulation (a portal system). The posterior pituitary, composed of neural tissue, releases hormones in response to neu rotransmission (not circulating hormones). Anterior Pituitary Cell Types and Regulation the adenohypophysis is composed of five major cell types, each of which pro duces one or more peptide hormones (Table 2-5). Cortisol (-) Peptide lnhibin (-), estrogen (-), progesterone (-) Testosterone (-), estrogen (+/-), progesterone (-) Somatomedins (-) Thyroid hormones (-) Peptide Promotes testosterone synthesis in testes; promotes estrogen/ progesterone synthesis in ovaries; surge causes ovulation and maintains the corpus luteum. Stimulates growth of thyroid gland and synthesis and secretion of thyroid hormones. Damage to the pituitary stalk can lead to decreased secretion of pituitary hormones secondary to disruption of the hypophyseal portal system (anterior pituitary) and hypothalamic neurons (posterior pituitary). After adolescence, overall production decreases and continues at a lower rate during adult life. Counterregulatory hor mones increase serum glucose levels by promoting glycogenolysis, gluco neogenesis, lipolysis, and ketogenesis. The anterior pituitary gland produces six major hormones that can be classi fied into three groups based on structural homology. Exogenous stimuli drive oxytocin secretion; signals include suckling of infant on breast and dilation of cervix (as in childbirth). Special vesicles containing aquaporins (permeable water pores) are inserted into the luminal aspect of the cell membrane. Secretion is stimulated by signals from atrial stretch receptors and baroreceptors. Signs and symptoms of a pituitary tumor can be due to the effect of excess hormone if present, suppression of other hormone production due to mechanical compression, and/or elevated intracranial pressure due to mass effect. Bitemporal hemianopsia due to superior growth of tumor, leading to com pression of the optic chiasm. Rule out secondary causes by screen ing for hypothyrodism, pregnancy, confounding antiemetic/antipsychotic medications, renal failure, and cirrhosis. Dopamine agonists (bromocriptine, cabergoline) are first-line treatment for any patient with hyperprolactinemia and are known to reduce the size and secretion of more than 90% of lactotroph adenomas. Gigantism can be a secondary feature of McCune-Albright syndrome and multiple endocrine neoplasia syndrome type I. Glucose intolerance and diabetes mellitus in one-sixth of cases; also amen orrhea and impotence. I l eadache due to mass effect, and bitemporal hemianopsia due to superior growth of tumor leading to compression of the optic chiasm. The onset of acro megaly is insidious, as opposed to the dramatic presentation of gigantism. Bromocriptine, a dopamine agonist, can work synergistically with octreo tide therapy. This is due to the increase in size and blood demand of the pituitary during pregnancy. This reduction in the release of all pituitary hormones may result from both primary and secondary causes. Primary causes directly affect the pituitary and include surgery, radiation, tumors, apoplexy (sudden hemorrhage into the gland, usually from adenoma), infection, infiltration by sarcoidosis or hemo chromatosis, ischemia (Sheehan syndrome), carotid aneurysm, cavernous sinus thrombosis, and trauma. Secondary causes disrupt the hypothalamus or pituitary stalk and include hypothalamic tumors, hypothalamic hormone defi ciency, surgery, infection, infiltration, and trauma. Because most of the anterior pituitary hormones are proteins or glycoproteins that induce the secretion of other hormones, the target gland hormone is often used as replacement rather than the pituitary hormone (ie, Primary polydipsia is a condition characterized by a marked increase in water intake, often seen in patients with psychiatric comorbidities, such as schizophrenia. It can also develop in patients with lesions affecting the hypothalamic thirst center. I L ypernatremia is usually not significant if the patient has free access to water, but is often a problem in hospitalized or debilitated patients with unrecognized or and reduced access to water. Meanwhile, U osm and P osm are both low in primary polydipsia, since the medullary gradient of the kidneys is washed out and dilute urine is produced. When water is not readily available, the rising serum sodium concen tration can cause weakness, fever, obtundation, and eventually death. There is a net gain in free water over sodium, resulting in euvolemic hyponatremia. If onset is acute, brain swelling can result, leading to lethargy, weakness, seizures, and coma/death. When given in a continuous fashion, leuprolide sup presses the growth of prostate cancer, leiomyomas, and endometriosis, and also halts precocious puberty. More effect on V2 receptors, which act on the renal collecting tubules to increase water reabsorption. Also, the parafollicular (C) cells of the thyroid gland produce calcitonin, a hormone that lowers serum calcium levels; however, in humans, it is not usually signifi cant in maintaining calcium homeostasis. Anatomy Situated anterior to the trachea, the thyroid is a butterfly-shaped structure below the larynx extending from C 5 to T l. It receives a disproportionately large share of cardiac output per gram of tissue. The rich blood supply of the thyroid is derived from two pairs of vessels: the superior and inferior thyroid arteries. Inferior thyroid artery: Stems from the thyrocervical trunk, which is a branch of the subclavian artery. Three sets of veins drain the thyroid: Superior, middle, and inferior thy roid veins. The superior and middle veins drain into the internal jugular veins, whereas the inferior thyroid veins empty into the brachiocephalic veins. The thyroid is formed from an epithelial outpouching, the thyroid diverticu lum, which develops in the floor of the foregut at 3-4 weeks of gestation. The thyroglossal duct progenitor migrates caudally, and the thyroid gland even tually assumes its normal position below the larynx unless migration is dis rupted. This duct remains patent during development, maintaining a connec tion between the foregut and thyroid. Ultimately, the thyroglossal duct closes, leaving the foramen cecum as an adult remnant. The thyroid begins secreting hormone as early as the 1 8th week of fetal development. Histology At the microscopic level, the thyroid gland is made up of spherical, closed fol licles that are lined with cuboidal epithelial cells. Interspersed within the walls of thyroid follicles are small collections of parafollicular C cells that synthesize and secrete calcitonin. Intracellular iodide rapidly diffuses across the apical membranes of folli cular cells and into the colloidal lumen. Thyroid hormones are synthe sized from tyrosine residues in the protein structure of thyroglobulin. Thyroglobulin is synthesized by thyroid follicular cells and is secreted across the apical membrane. Thyroid peroxidase, an apical membrane enzyme, binds an iodide atom and a tyrosine moiety, brings them into close apposition, and promotes free radicals that enable the reaction between iodide and tyrosine residues on thyroglobulin. Within the follicular cells, lysosomes fuse with pinocytic vesicles, and thyroglobulin is proteolytically digested. Products of protein breakdown include T4 and T3, both of which are transported across the basal mem brane and into the circulation. T4 is the major hormone secreted by the thyroid and carried in the circulation; however, T 3 is the physiologi cally active form of the hormone. Inactivation: A separate deiodinase enzyme targets another site on the T4 molecule, forming biologically inactive reverse T 3 (rT). In contrast, the Jod-Basedow effect is the overproduction of thyroid hormone, causing overt hyperthyroidism in the presence of large amounts of iodine in persons who fail to manifest the Wolff-Chaikoff effect. Thyroid hormone also stimulates calcification and closure of cartilaginous growth plates through out the body. As part of normal development, neuroblasts proliferate into the second trimester, after which they begin to differentiate into neurons. Thyroid hormone promotes this transition to neuronal differentiation and, ultimately, synapse formation. Contractility, stroke vol ume, and heart rate are all increased, thereby increasing cardiac output. Increased risk of atrial fibrillation, isolated systolic hypertension, and high output cardiac failure. Causes of Hyperthyroidism Thyroid storm is a life-threatening form of thyrotoxicosis characterized by high fever, tachyarrhythmia, psychosis, confusion, diarrhea, and liver dysfunction. It is managed with intensive care unit-level support, antithyroid medications, and! I nflammation of thyroid gland -> spilling of preformed thyroid hormones -> transient hyperthyroidism. Pituitary inhibition causes transient hypothyroidism before return to euthyroid state. Toxic multinodular goiter (Plummer disease) Subacute thyroiditis (de Quervain thyroiditis) Thyroid gland firm, painful, tender. Struma ovarii this is a very rare condition in which ectopic thyroid tissue develops as part of an ovarian tumor, causing hyperthyroidism. P-Blockers such as propranolol: Control of adrenergic symptoms (sweat ing, tachycardia, tremor). Endemic goiter, caused by iodine deficiency, is the most common cause of goiter worldwide. Over 9 5 % of cases of hypothyroidism result from failure of the thyroid gland itself (primary hypothyroidism). The most common cause of primary hypo thyroidism in the United States is Hashimoto thyroiditis (in the developing world, iodine deficiency is most common). Lymphocytic infiltrate with germinal centers seen on histology, as well as Hurthle cells. Sheehan syndrome Postpartum pituitary necrosis secondary to postpartum hemorrhage. Myxedema coma: Stupor, coma, and hypoventilation coupled with hypo thermia, bradycardia, and hypotension. A life-threatening hypothyroid con dition that results from long-standing, untreated hypothyroidism. May be helpful for diagnosing and distinguishing among primary, secondary, and tertiary causes. Thyroid hormone deficiency during fetal development may be due to a failure of thyroid gland formation, inability to synthesize hormone (T3/T4), lack of iodine, radioiodine taken by the mother, or untreated hypothyroidism in the mother. Thyroid Neoplasms Thyroid cancer is the most common endocrine malignancy in the United States, with an annual incidence of approximately 2 cases per 1 00,000. Risk factors include childhood head and neck radiation exposure, male gender, young age, and positive family history. Dyspnea, coughing/choking spells, dysphagia, and hoarseness may occur due to compression of the trachea or esophagus. Radioactive iodine thy roid scintiscanning is not used to determine whether a nodule should be biopsied. Fine-needle aspiration: Provides cytopathologic diagnosis of four varieties of cancer (Table 2- 1 5). Fifteen percent of nodules are suspicious or malig nant, yet most biopsies are benign or indeterminate. Tends to invade into blood vessels -> spreads to bone, lung, and liver (lymph node involvement rare). Liothyronine (T3) is not used routinely for the treatment of hypothyroid ism because it is arrhythmogenic and can precipitate heart failure, although it may be used to treat myxedema coma. Leads to increased protein synthesis, increased metabolic rate, and increased -receptors, increased sensitivity to catecholamines. Excess iodine reduces thyroid synthesis and release (via the Wolff-Chaikoff effect) and radioiodine ablates cells that make thyroid hormone. Methimazole is used during the second and third trimes ters to reduce potential teratogenic effects. Radioiodine is used for hyperthyroidism and adjunc tive treatment for some thyroid cancers. Clinical manifestations include hypocalcemia secondary to absence of the parathyroid glands, immune deficiency secondary to absence of thymic tissue leading to abnormal T-cel l maturation, and congenital cardiac malformations. Vitamin D and calcitonin also play important roles in calcium homeosta sis, as discussed later.

Therefore hypertension kidney discount lasix 40mg amex, once it is present in food arteria digitalis palmaris communis discount lasix 100 mg without prescription, reheating or even boiling will not prevent illness arteria latin order discount lasix on-line. Typically blood pressure medication safe for pregnancy buy generic lasix line, the food is cooked more than 24 hours before consumption heart attack zine archive discount generic lasix canada, allowed to cool slowly at room temperature blood pressure chart different ages order lasix with american express, and then served either cool or rewarmed. During this period of incubation, spores that survived cooking germinate, and clostridia multiply to reach sufficient numbers to constitute an infectious inoculum. A dilated transverse colon >12 cm indicates imminent perforation, causing peritonitis and septicaemia with subsequent high mortality rate. Other common sonographic findings include gallbladder wall thickening and pericholecystic fluid. The anterior wall of the gallbladder should be measured, as the acoustic enhancement artifact will obscure an accurate picture of the posterior wall. The urea breath test is one such test that is highly sensitive and specific and is also useful in assessing eradication. The patient can then be referred to their primary care provider for further testing and, if positive, eradication therapy commenced. Not all patients with dyspepsia require endoscopy but those with alarm features do, as they raise the index of suspicion for gastric or oesophageal cancer. It is classically associated with repeated retching or vomiting; however, repeated vomiting is only present in one-third of cases. The remaining cases include rare causes like angiodysplasia and aortoenteric fistulae. One should have a high index of suspicion in patients with previous abdominal vascular surgery, as a herald bleed precedes massive haemorrhage, which is difficult to control and often fatal. In patients presenting with haematemesis, it may help to assess the presence of ongoing bleeding as well as prepare the patient for endoscopy. The black, tarry stool is produced as result of bacterial degradation of haemoglobin in the gut. The ligament of Treitz is a fold of peritoneum that suspends the fourth part of the duodenum. Haematochezia is the passage of bright red or maroon-coloured blood per rectum and suggests a source distal to the ligament of Treitz. Approximately 14% of bleeds presenting with hematochezia are caused by a brisk upper source with rapid transit. Haematochezia due to an upper tract source of bleeding has been associated with a higher transfusion requirement, need for surgery and mortality rate. Additionally, it has not been found to alter clinical outcomes or management decisions in the absence of pulmonary examination findings or known pulmonary disease. A haemoglobin level of <100 g/L has been associated with increased rebleeding and mortality rates. Early endoscopy allows the prediction of likelihood of rebleeding and mortality, according to the nature and location of lesion and stigmata of recent haemorrhage. Risk stratification using a combination of clinical and endoscopic findings has been well validated as a means of predicting the risk of rebleeding and in-hospital mortality. The Rockall score is an example of such a scoring tool and frequently used for risk stratification. However, only a small number of studies looked at risk stratifying patients solely on clinical features without including endoscopy findings. Although promising, clinical predictive scores are not yet widely accepted and still need further validation to make a graded recommendation. A positive guaiac test is dependant on the time of onset of the bleeding in relation to gastrointestinal transit time. It is therefore possible that in some acute bleeds, the blood may not have traversed the bowel by the time testing is done. Falsepositive guaiac tests can be caused by certain bacterial and vegetable peroxidases, such as bananas and horseradish. Therapeutic iron intake is commonly believed to cause false-positive guaiac testing. Most studies in vivo, however, have shown that this is not a common cause of false-positive testing. Answer: C Traditionally, gastric lavage was thought to decrease bleeding or rebleeding, particularly if cold water was used, but the evidence does not support this. Gastric lavage is now mainly used to allow better visualisation during endoscopy and room-temperature water is recommended. Answer: B Variceal bleeding may be catastrophic, with 30% mortality for a first bleed. Significant advances in the treatment of acute variceal bleeding have been made since the era of balloon tamponade with the Sengstaken-Blakemore tube. This is now rarely used due to significant complications and rebleeding upon balloon deflation but should still be considered as a temporising measure if bleeding is uncontrolled and pharmacological options and endoscopy are not immediately available. After insertion of the tube, the gastric balloon is inflated first with air and the tube pulled until resistance is felt, at which point the balloon is tamponading the gastro-oesophageal junction. If bleeding continues despite inflation of the gastric balloon, the oesophageal balloon should be inflated, taking care not to overinflate the oesophageal balloon as it may cause oesophageal necrosis or rupture. Advances include endoscopic techniques, mainly sclerotherapy or band ligation, and vasoactive pharmacological options like octreotide. It is effective in controlling bleeding and reduces rebleeding and the need for blood transfusion. It is, however, associated with significant complications including deep oesophageal ulcerations, strictures, mediastinitis, pleural effusions, sepsis and death. Endoscopic band ligation appears to be more effective and associated with fewer complications and is the preferred endoscopic treatment in most cases. Pharmacological therapy with octreotide is comparable to injection sclerotherapy in terms of bleeding control and with the advantage of fewer side effects. Additionally, combination endoscopic and pharmacological therapy improves initial haemostasis and early rebleeding rates. It is therefore imperative that octreotide infusion be initiated as soon as possible to all patients with suspected varices. Not only does it carry the risk of sepsis but concurrent infection also impairs coagulation, thereby increasing the risk or rebleeding. Fluoroquinolones have been traditionally used in the past but recent resistance patterns have encouraged the use of third-generation cephalosporins. Measurement of the liver span is more important than the presence of a palpable liver edge to detect hepatomegaly, as 80% of people have some palpable extension of the liver beyond the costal margin. Palpation of the liver edge may be normal, due to enlargement or due to lung hyperinflation. Extension of the liver >2 cm beyond the rib margin is, however, most likely due to hepatomegaly. The presence of ascites is suspected in patients with abdominal distension, bulging flanks, flank dullness to percussion, shifting dullness to percussion, and/or a fluid thrill. Bulging flanks are 80% sensitive in the detection of ascites but only 50% specific, whereas a fluid thrill is only 60% sensitive but 90% specific. They may occur on normal individuals but the presence of >5 are abnormal and chronic liver disease should be suspected. A cell count and differential should be performed in all patients undergoing abdominal paracentesis. Lymphocytes should predominate, and clinical signs or symptoms of peritoneal infection should be absent. Answer: D In a cirrhotic patient, ascites is caused by a combination of portal hypertension, hypoalbuminaemia, and poor renal management of sodium and water. These patients are usually responsive to salt restriction and diuretics and therefore the mainstay of treatment of patients with cirrhosis and ascites includes education regarding dietary sodium restriction and oral diuretics. Fluid restriction is not necessary in treating most patients with cirrhosis and ascites. Similarly, it is sodium restriction, not fluid restriction, that results in weight loss as fluid follows sodium passively. The usual diuretic regimen consists of a combination of a single morning dose of oral spironolactone and frusemide, beginning with 100 mg of the former and 40 mg of the latter. Answer: A the accuracy of physical findings to detect ascites is variable and depends in part upon the amount of fluid present, the technique used to examine the patient, and the clinical setting. Approximately 1500 mL of fluid has to be present for flank dullness to be detected; therefore, lesser degrees of ascites can be missed. Ascitic fluid had been classified as an exudate if the total protein concentration is 30 g/L and a transudate, if it is <30 g/L. Usual maximum doses are 400 mg/day of spironolactone and 160 mg/day of furosemide. Spironolactone can be used as a single agent; however, hyperkalaemia and its long half-life limit its use. Single-agent furosemide has been shown to be less efficacious than spironolactone. Starting with both drugs appears to be the preferred approach in achieving rapid natriuresis and maintainig normokalemia. In the largest, multicentre, randomised controlled trial performed in patients with ascites, dietary sodium restriction and a dual diuretic regimen has been shown to be effective in more than 90% of patients in achieving reduction in the volume of ascites to acceptable levels. Serial paracentesis remains an alternative for patients refractory to medical therapy. Outpatient treatment can be attempted initially if no precipitants are identified. However, some patients with cirrhosis and ascites also have gastrointestinal haemorrhage, hepatic encephalopathy, bacterial infection, and/or hepatocellular carcinoma, and may require hospitalisation for definitive diagnosis and management of their liver disease as well as management of their fluid overload. One site is approximately 2 cm below the umbilicus in the midline where the fasciae of the rectus abdominis join to form the fibrous, thin, avascular linea alba. This is also the preferred site by many clinicians as abdominal obesity increases the midline thickness. It is important to remain lateral to the rectus sheath at all times to avoid the inferior epigastric arteries; these vessels are located midway between the pubis and anterior superior iliac spines and then run cephalad in the rectus sheath. One controversial issue regarding therapeutic paracentesis is the role of colloid replacement. So far, studies have failed to show more clinical morbidity and mortality in patients not receiving colloids. However, there has been no study large enough to demonstrate decrease survival in patients who are given no plasma expander compared with patients given albumin. Current recommendations do not recommend colloid replacement for a single paracentesis of <5 L, but it remains optional, due to lack of evidence, if larger volumes are removed. As many as two-thirds to three-quarters of patients undergoing paracentesis will have a coagulopathy. Because transfusion-requiring haematoma is so unlikely, even in this population, prophylactic administration of fresh frozen plasma or platelets is not standard and is associated with considerable cost, in addition to the risk of transfusion-related complications, with little net gain. Furthermore, routine tests of coagulation do not reflect the bleeding risk in patients with cirrhosis. Serial paracentesis should preferably be reserved for the 10% of patients who truly fail medical therapy. An 18-gauge needle is preferred for large-volume therapeutic paracenteses because this permits expeditious outflow, whereas a smaller-gauge (20- to 22-gauge) needle may be sufficient for diagnostic taps and lessen the likelihood of post-procedural ascitic fluid leak through the wound site. Plastic sheath cannulas tend to kink and run the risk of being sheared off into the peritoneal cavity. The needle should be inserted slowly in 5-mm increments to detect undesired entry of a vessel and to help prevent unnecessary puncture of the small bowel. Continuous manual aspiration should be avoided because it may attract bowel or omentum to the end of the paracentesis needle with resultant occlusion. Clinical assessment for detection of spontaneous bacterial peritonitis by emergency clinicians is only 75% sensitive. However, treatment should commence immediately and one should not wait until the ascitic fluid culture grows bacteria as it may result in the death of the patient from overwhelming infection. Therefore, in a clinical setting compatible with ascitic fluid infection (fever, abdominal pain or unexplained encephalopathy), all patients should receive empiric antibiotic therapy awaiting culture results. When ascitic fluid is collected in a syringe or tube, positive cultures are obtained in about 50% of cases compared with 80% if inoculated into a blood culture bottle prior to administration of antibiotics. Answer: C Lactulose, a nonabsorbable disaccharide, is the first-line treatment in patients with hepatic encehalopathy.

Cauda equina syndrome A prolapsed intervertebral disc or fracture can cause compression of the cauda equina prehypertension vegetarian cheap lasix 40mg visa. The symptoms of this include pain in the nerve distribution of the root affected prehypertension symptoms discount 40mg lasix with amex, saddle anaesthesia (around the anus) and disturbance of bladder/ bowel function heart attack young cheap 100 mg lasix. It is a neurosurgical emergency and the pressure must be relieved to preserve the function of the nerves arteria mesenterica inferior purchase cheap lasix. Before the 5th week of gestation hypertension 2 torrent order lasix cheap, the first and third vesicles divide in two: week 6 roof plate dorsal root ganglion cell from migrating neural crest tissue alar plate outgoing motor neurons floor plate basal plate the forebrain vesicle forms the telencephalon and diencephalon digital blood pressure monitor order generic lasix online. The central canal of the neural tube enlarges to form: Lateral ventricles in the primitive cerebral hemispheres Third ventricle in the diencephalon Cerebral aqueduct (of Sylvius) in the midbrain Fourth ventricle in the hindbrain. The neural tube bends to form: the cervical flexure (between the primitive spinal cord and the third vesicle) the cephalic flexure (between the first and second vesicles). Pons and cerebellum the pons is formed by the anterior part of the metencephalon and part of the alar plate of the medulla. It contains a thick band of fibres (important in motor processing) which connect the forebrain with the cerebellum. The medulla Initially, the myelencephalon or medulla is organized like the primitive spinal cord with alar and basal plates. As it flattens out further up, forming the floor of the fourth ventricle, the alar plates (sensory cell groups) move outwards until they lie lateral to the basal plates (motor cell groups). Other cells from the alar plate migrate ventrolaterally to form the olivary nuclei. The cerebellum develops from the most posterior parts of the alar plates, above the level of the medulla. Cerebellar growths project over the top of the fourth ventricle and fuse in the midline, with migrating cells from the alar plates becoming the cerebellar cortex. The telencephalon (hemispheres) expands much more than the other parts of the brain and ultimately covers the diencephalon and midbrain. The two swellings meet in the midline, trapping a small amount of mesenchymal tissue which forms the falx cerebri. Similarly, the occipital lobes of the hemispheres are separated from the cerebellum by mesenchyme (which becomes the tentorium cerebelli). Grooves gradually appear on the smooth surface of the hemispheres and become the sulci. The gyri thus formed allow a much greater volume of cortex (folded up) to be packed into the cranium. The cortex that covers part of the corpus striatum (lentiform nucleus) is called the insula. It remains fixed while the temporal, parietal and frontal lobes grow rapidly to bury it within the lateral sulcus. It passes through the developing sphenoid bone to reach the downgrowth from the hypothalamus. Development of the cranial nerves There are three developmentally distinct groups of cranial nerves: Somatic efferents. These innervate muscles that develop from the parts of the rostral somites which become the head myotomes. These supply motor and sensory innervation to the embryological pharyngeal arches that formed the primitive oral cavity and pharynx. These afferent nerves relay information from special sense receptors to the appropriate central pathway. Development of the choroid plexi the cerebrospinal fluid producing choroid plexus is formed from two layers (the pia mater and the ependymal lining of the cavities of the ventricles) which together are called the tela choroidea. The brainstem is displaced downwards, with the cerebellar tonsils and medulla herniating through the foramen magnum. It is associated with hydrocephalus, especially dilatation of the third and fourth ventricles. Defects may include mental retardation, lower (ocular) cranial nerve palsies and cerebellar/brainstem signs. Forebrain disorders Neural tube defects are caused by varying degrees of failure of fusion of the posterior neural arch. Holoprosencephaly Holoprosencephaly is a congenital disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres. Genes, called Hox genes, that normally guide the placement of embryonic structures, fail to activate along the midline of the brain. In most cases of holoprosencephaly, the malformations are so severe that babies die before birth. In less severe cases, babies are born with normal or near-normal brain development and facial deformities that may affect the eyes, nose and upper lip. Spina bifida is caused by local defects in the development and closure of the neural tube and vertebral arches. The spinal cord may be tethered by a fibrous band or tight filum terminale, associated with increasing deficit as the child grows and the cord stretches. In the developing brain, neurons must migrate from their place of origin adjacent to the ventricles to the areas where they will finally settle into their correct neural circuits. Neuronal migration, which occurs as early as the 2nd month of gestation, is guided by a complex assortment of chemical signals. When these signals are absent or incorrect, neurons do not end up where they belong. This can result in structurally abnormal or missing areas of Rachischisis this is the most severe defect in which the entire neural tube fails to close. Symptoms vary according to the abnormality, but often feature poor muscle tone and motor function, seizures, developmental delays, mental retardation, failure to thrive, feeding difficulties, swelling in the extremities and microcephaly. Treatment is symptomatic, and may include anti-seizure medication and physical, occupational, and speech therapies. Usually asymptomatic until adulthood when it expands, sometimes after provocation by a sudden increase in intracranial pressure. Sensory loss is described as dissociated, because pain and temperature sensations are affected, but not joint position and vibration senses. If the cavity extends to the brainstem (syringobulbia), dysarthria, dysphagia, tongue wasting, ataxia and nystagmus may occur. Cerebral palsy Cerebral palsy is a heterogeneous group of childhood disorders in which injury to the brain early in life results in a non-progressive neurological disorder of movement and tone. Birth trauma, although the most widely known cause, actually only accounts for approximately 10% of cases. Spastic diplegia is the most common presentation, sometimes with ataxia, hemiplegia, tetraplegia and dyskinetic syndrome. Other modalities may also be affected, and there may be associated learning difficulties (although intelligence is preserved in up to 70% of patients), visual problems and epilepsy (30%). Understanding these concepts is the first stage in appreciating the way in which the whole system works. They communicate with other excitable cells via specialized junctions called synapses. The cell body (soma) has a series of branching processes called dendrites which collect information from surrounding excitable cells and conduct it to the cell body. The principal role of dendrites is to increase the potential for synapse formation. Accordingly, the number of dendrites reflects the way information is processed in that pathway. A cell with many inputs may condense information from several pathways, whereas a cell with few inputs may be part of a highly conserved parallel pathway. The output of the nerve cell is a binary signal (meaning that it is an all-or-nothing impulse or train of impulses). In contrast to dendrites, there is only one axon per neuron (although the axon may divide into numerous branches). The axon transmits the output of the neuron (the action potential) to the terminal boutons (presynaptic swellings containing vesicles of neurotransmitter). Neurons are surrounded by a lipid bilayer (cell membrane) within which proteins are embedded. Some proteins form ion channels, some form receptors to specific chemicals and others function as ion pumps. Ion channels within the axolemma (axonal surface membrane) enable the axon to conduct action potentials. The axoplasm (cytoplasm within the axon) contains microtubules, mitochondria and neurofilaments. These organelles play a key role in maintaining the ionic gradients necessary for action potential production and also enable the transport and recycling of proteins away from and, to a lesser extent, towards the cell body. These include the herpes simplex viruses, herpes zoster, rabies and the polio virus. This mechanism is also being evaluated as a possible means of delivering therapeutic interventions in diseases such as motor neuron disease. Arrangement of neurons According to the function of the area, neurons can be arranged as: Layers. Note that, although only anterograde transmitter transport is shown, retrograde movement of molecules also occurs. There are two classes of neuron: Projection neurons (Golgi type-1 neurons) influence cells located in a different part of the nervous system and so have long axons. The long axons often project small collateral branches that help to spread information further in the central nervous system. These are distinct from projection neurons which have connections outside the nervous system. They provide more opportunities for cells within a group or circuit to communicate with one another. Humans possess far larger numbers of these neurons compared with their closest evolutionary relatives. Ion channels Ion channels are protein macromolecules which span the lipid bilayer and allow ions to move from one side of the cell membrane to the other. It is ion channels which imbue the neuron with the fundamental quality of electrical excitability. The electrochemical gradient across the membrane determines the direction of ion movement. Generally ions flow from regions of high concentration to regions of low concentration. However, in the presence of a voltage gradient, there may be no flow of ions even with non-equilibrated concentrations. Their status in this respect is determined either by altering the voltage across the membrane (voltage-gated ion channels) or by the binding of a chemical messenger (ligand-gated ion 32 Neuronal excitation and inhibition. In addition, some ion channels respond not to voltage changes or chemical messengers, but to mechanical stretch or pressure. Ionic basis of resting potentials In the resting neuron there is far more potassium within the cell than outside and far less sodium. If there were no active channels at work, and no other ions crossed the membrane, potassium ions would tend to move out of the cell (down their concentration gradient) leaving a relatively negative charge behind. The signal to alter permeability comes either from neurotransmitter interaction with receptors at the synapse or direct electrical excitation of the neuron. It takes into account the relative permeabilities of all the ions involved in generating the membrane potential. Many of these pumps are found in the membranes of all excitable cells and they are largely responsible for the high metabolic requirements of neurons. Generation and propagation of the action potential In the 1950s Hodgkin and Huxley discovered the ionic mechanism of action potential propagation by studying the squid giant axon. A neuronal action potential may be induced by inputs from other nerve cells or inputs from sensory neurons. The predictions made by the Goldman equation are more accurate because it takes into account more of the ions involved than the Nernst equation does. The sodium channels are only open briefly and will not reopen until the membrane potential is restored to its resting level.

Severe alkalosis can cause neuromuscular irritability heart attack is purchase lasix 100mg with mastercard, including seizures blood pressure monitor walgreens generic lasix 40mg on-line, paresthesias blood pressure chart athlete cheap 100 mg lasix overnight delivery, confusion blood pressure medication causes nightmares order lasix overnight, and ventricular arrhythmias blood pressure chart with age generic 40mg lasix otc. When severe arrhythmia foods to eat lasix 40mg line, anorexia, nausea, malaise, metallic taste, itching, confusion, fluid retention, and hypertension. Recognition of high-risk patient, avoidance of nephrotoxins, and maintenance of intravascular volume is important. Prerenal azotemia: reversal of decreased effective renal blood flow (fluids, inotropes). Reference Bridoux F et al: Acute renal failure after the use of angiotensin-convertingenzyme inhibitors in patients without renal artery stenosis. This extensive vacuolation of the proximal tubules is consistent with osmotic nephrosis. Differential Diagnosis Osmotic nephrosis caused by administration of hydroxyethylstarch and other sucrose-containing solutions. Pearl Prevention of direct myoglobin-induced tubular toxicity in rhabdomyolysis is possible by early hydration and alkalinization of urine. Differential Diagnosis Acute and chronic tubulointerstitial nephritis of other etiologies. Acute interstitial nephritis (drugs or infections, eosinophiluria, and eosinophilia in some cases and, less commonly, rash and fever). Risk factors include old age, preexisting renal impairment, intravascular volume depletion, hepatorenal syndrome, sepsis. Differential Diagnosis Acute tubular necrosis caused by other nephrotoxic drugs or ischemia. Oliguria and need for dialysis are unusual and are primarily seen in patients with diabetes with severe chronic kidney disease. Differential Diagnosis Renal atheroembolism seen in patients receiving contrast arterially (may be accompanied by livedo reticularis, digital ischemia, retinal embolization). Steroids, fresh frozen plasma, hemodilaysis, plasmapheresis, alone or in combination. Characterized by circulatory instability with systemic arterial vasodilation and activation of vasoactive systems. Serum creatinine may only mildly increase despite severe renal failure due to muscle wasting in cirrhotic patients. Effective pharmacotherapies include: vasopressin analogues, midodrine, octreotide. Chapter 2 Acute Kidney Injury 107 Obstructive Uropathy Essentials of Diagnosis An anatomical or functional problem causes obstruction to the flow of urine in the urinary tract. Potential causes include neurogenic bladder, benign prostatic hypertrophy, nephrolithiasis, prostate cancer, cervical cancer, bladder tumors, retroperitoneal fibrosis, retroperitoneal lymphoma, metastatic tumors, and blood clots within the urinary tract. Acute interstitial nephritis (drugs or infections, high urine eosinophil count, peripheral eosinophilia in some cases and less commonly rash and fever). High postvoid residual urine volume in the bladder suggests neurogenic bladder or bladder outlet obstruction. Chapter 2 Acute Kidney Injury 109 Tumor Lysis Syndrome Essentials of Diagnosis Caused by the rapid release of intracellular contents of tumor cells into the systemic circulation. Most commonly seen following treatment of hematologic malignancies with high cellular burden (lymphomas, leukemias). Presents with hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, often accompanied by azotemia, and acute renal failure. Etiology of renal failure due to acute obstruction of urine flow by precipitated uric acid crystals, as well as acute nephrocalcinosis with interstitial and tubular damage from calcium-phosphorus depostion. Nephrotoxic or ischemic acute tubular necrosis (other medications or contrast agents, sepsis, hypotension). This page intentionally left blank 3 Chronic Kidney Disease Adynamic Bone Disease. Dilated renal pelvis and calyces might be present if renal atrophy is due to chronic ureteral obstruction. Chronic unilateral ureteral obstruction from stone, papillary necrosis, blood clot, or malignancy. Control blood pressure if renal artery stenosis is present using medications; sometimes nephrectomy is required. Rarely occurs in patients without kidney disease (primary hyperparathyroidism, malignancy, chemotherapy, inflammatory bowel disease, connective tissue disease, rapid weight loss). Skin biopsy is gold standard for diagnosis but can also precipitate ulcer formation and expansion. Pearl Prognosis is poor; up to 80% mortality most often associated with sepsis and wound infection. Ultrasound waves are formed in the transducer, and reflect from tissue interfaces that they pass through back to the transducer. Echogenicity reflects the characteristic ability of a tissue or substance to reflect sound waves and produce echoes. Each tissue type, such as liver, spleen, or kidney, has a particular echogenicity in its normal state. Echogenicity can be used to mean different than the normal echogenicity or compared to another tissue (kidney vs liver). For example, the medulla of the kidney is darker, or less echogenic than the cortex of the kidney on ultrasound. In diseased states, echogenicity of an organ can be altered, either more echogenic (whiter) or less echogenic than usual. Kidney diseases are more often seen as echogenic (ie, more echogenic rather than less echogenic). Pearl the term "medical renal disease" is nonspecific and generally is used by radiologists to describe "increased echogenicity" of the kidneys with loss of the corticomedullary differentiation (cortex whiter than medulla) normally seen on renal ultrasound. Symptoms include fatigue, pruritis, weight loss, nausea, loss of appetite, drowsiness, confusion, skin color, and nail changes. If peritoneal dialysis is the modality of choice, a Tenchkoff catheter is placed approximately 2 weeks prior to dialysis. Treatment It is essential to closely monitor these individuals for timely initiation of dialysis. Pearl Consider bone biopsy for establishing the type of renal bone disease, since no combination of biochemical parameters is sufficiently accurate. Cardiovascular abnormalities: uremic pericarditis, pericardial effusions, coronary and valvular calcification, left ventricular hypertrophy, arrhythmias and atherosclerosis. Nonuremic metabolic disturbances: hypocalcemia, hyperkalemia, hyperphosphatemia, and metabolic acidosis. Chapter 3 Chronic Kidney Disease 123 Uremic Pericarditis Essentials of Diagnosis Two types of pericarditis are associated with renal failure. Uremic pericarditis, which occurs in patients with uremia before or within 8 weeks of initiation of maintenance dialysis. Dialysis-associated pericarditis, occurs more than 8 weeks after dialytic therapy is begun (chronic dialysis patient). Tachycardia, hypotension, jugular venous distension, Kussmaul sign, elevated pulsus paradoxus, and Ewart sign may indicate impending cardiac tamponade. Echocardiogram is used to monitor effusion size and cardiac tamponade (reflected by right ventricular diastolic collapse). Histology shows organized fibrinous exudate attached to the thickened pericardium with lymphocyte infiltration. Differential Diagnosis Pericarditis from infection, connective tissue disorders, malignancy, or drugs. Large (>2 cm) effusions in dialysis-associated pericarditis should be referred immediately for surgery, whereas a trial of intensive dialysis should be employed in uremic pericarditis. Pearl Failure to rapidly diagnose uremic pericarditis could result in significant morbidity and increased risk for mortality. Renal biopsy is confirmatory, but is often not necessary as the diagnosis can be made on clinical grounds alone. Histologic changes include diffuse glomerular basement membrane thickening, mesangial expansion, Kimmelstiel-Wilson nodules, glomerular sclerosis, vascular disease, and chronic tubulointerstitial disease. Systemic symptoms: arthritis, arthralgia, malar rash, oral ulcers, serositis, alopecia, photosensitivity, cerebritis. Other complications may include protein malnutrition, acute renal failure, volume depletion. Renal biopsy is required to determine the etiology and subsequent treatment of nephrotic syndrome. Diagnosis is made presumptively in children based on the high prevalence, and by renal biopsy in adults. Chapter 5 Glomerular Disorders 133 IgM Nephropathy Essentials of Diagnosis An idiopathic proteinuric glomerular disease with mesangial hypercellularity and diffuse IgM deposits seen on immunofluorescence. Presents with proteinuria (often nephrotic range), microscopic hematuria, and hypertension. Approximately one-third of patients develop end-stage renal disease at up to 15 years post-diagnosis. Presents with variable degree of proteinuria, hypertension, microscopic hematuria, and decreased glomerular filtrate rate. Tip lesion is most responsive and collapsing variety is least responsive to treatment. Secondline therapy includes other cytotoxic agents such as cyclosporine, cyclophosphamide. Presents with nephrotic syndrome (heavy proteinuria, edema, and hypoalbuminemia), usually with preserved kidney function. Patients with severe nephrotic syndrome are at risk for renal vein and deep vein thrombosis and pulmonary embolism. Often have hyperlipidemia and vascular disease but no evidence of diabetes mellitus. Pearl Occurs in smokers and resembles diabetic nephropathy on biopsy though patients do not have glucose intolerance. Chapter 5 Glomerular Disorders 137 C1q Nephropathy Essentials of Diagnosis A rare proteinuric disease characterized by mesangial proliferation and prominent C1q deposits on immunofluorescence. Light microscopic findings vary from no lesion to focal segmental sclerosing lesions to proliferative glomerulonephritis. Electron microscopy shows tubuloreticular inclusions in the glomerular endothelial cells. Other causes include interventions on the renal vein, trauma, retroperitoneal fibrosis, and acute vascular rejection post transplant. Acute thrombosis presents with loin pain and hematuria, and less commonly, fever, worsening of proteinuria, and acute renal failure if bilateral or in a single kidney. Chronic thrombosis is often asymptomatic and may be discovered incidentally in a patient with a pulmonary embolism. Treatment Nephrotic patients with serum albumin less than 2 g/dL and proteinuria greater than 5 g may warrant prophylaxis if other risk factors for embolic events are present. Reference Kanjanabuch T, et al: An update of acute postinfectious glomerulonephritis worldwide. Chapter 5 Glomerular Disorders 141 Post-infectious Glomerulonephritis Essentials of Diagnosis Immunologic response of the kidneys that follows a nonrenal infection, most commonly streptococci. Patholologic patterns seen include: Endocapillary exudative glomerulonephritis (Group A streptococci). Labs may show hypocomplementemia and streptozyme test may be positive in patients with group A -hemolytic streptococcus. Differential Diagnosis Treatment Eradication of offending infection with appropriate antimicrobials and/or surgical drainage or excision. Kidney biopsy reveals membranoproliferative glomerulonephritis type I with granular deposits of IgG, IgM, and C3 on immunofluorescence and subendothelial and mesangial deposits on electron microscopy. Reference Kiryluk K et al: A young man with Proprionibacterium acnes-induced shunt nephritis. Renal manifestations include proteinuria (nephrotic or subnephrotic), microscopic hematuria, and decreased kidney function. Chapter 5 Glomerular Disorders 145 Cryoglobulinemic Glomerulonephritis Essentials of Diagnosis Cryoglobulins are circulating immunoglobulins (Ig) that precipitate upon cooling. Type I: High levels of monoclonal Ig, mostly IgM or IgG, often due to Waldenstrom macroglobulinemia or multiple myeloma.

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