Theodore P. Abraham, MD, FACC, FASE

• Associate Professor of Medicine
• Johns Hopkins University
• Vice-Chief of Cardiology
• Co-Director, Echocardiography
• Director, Johns Hopkins Hypertrophic Cardiomyopathy Clinic
• Director, Translational Cardiovascular Ultrasound Laboratory
• Baltimore, Maryland

Opposing the effects of insulin are growth hormone and leptin (described later), which inhibit lipogenesis symptoms 8 dpo betoptic 5 ml discount. The balance between lipogenesis and lipolysis followed by fatty acid oxidation determines the overall accumulation of body fat medications known to cause nightmares purchase betoptic with american express. Protein the balance between protein synthesis and degradation is regulated by interactions among hormonal, nutritional, neural, and inflammatory mediators treatment 0 rapid linear progression betoptic 5ml without prescription. Lipolysis in adipose tissue is mostly dependent on the concentrations of hormones (epinephrine stimulates lipolysis, and insulin inhibits lipolysis) medications rights purchase betoptic uk. In the periphery, increased production and release of cortisol, glucagon, and catecholamines and suppressed release of insulin favor an overall catabolic response premonitory symptoms cheap betoptic 5 ml mastercard. Stimulation of hepatic glycogenolysis and gluconeogenesis, muscle glycogenolysis, and adipose tissue lipolysis ensures the production and mobilization of energy stores to meet the enhanced metabolic demands of the individual 606 treatment syphilis order generic betoptic from india. Reproductive and growth functions are inhibited, conserving energy to sustain fundamental processes that ensure survival. Stimulation of hepatic glycogenolysis and gluconeogenesis, muscle glycogenolysis and adipose tissue lipolysis ensure the production and mobilization of energy stores to sustain the enhanced metabolic demands of the individual as shown in the metabolic pathway. Unlike most other tissues, the brain cannot utilize fatty acids for energy when blood glucose levels become compromised. The release of glycerol and free fatty acids from adipose tissue is inhibited by insulin and stimulated primarily by catecholamines. For example, an adult with 15 kg of body fat has enough energy to support the whole body energy requirements (8. Cortisol, epinephrine, and glucagon together favor muscle protein breakdown and hepatic amino acid uptake, some of which can be utilized for gluconeogenesis. An imbalance in either energy intake or expenditure leads to one of the following two extremes: loss of lean body mass or wasting syndrome and obesity. In the absence of chronic physical or psychiatric illness, development of a wasting syndrome is infrequent. Obesity is an important health problem that increases the risk of several diseases. Because of the rising incidence of obesity in our society, a brief discussion follows on the endocrine physiologic responses implicated in the development of this condition. Their effects are not immediate; thus, they are mostly involved in defense against prolonged hypoglycemia. In addition, cortisol induces hepatic enzymatic gene expression required for enhanced gluconeogenic rates and exerts permissive effects on the stimulation of gluconeogenesis in the liver by glucagon and epinephrine. Epinephrine stimulates hepatic glycogenolysis and hepatic and renal gluconeogenesis, largely by mobilizing gluconeogenic precursors including lactate, alanine, glutamine, and glycerol. Together, glucagon and epinephrine act within minutes to raise plasma glucose concentrations. The contribution of the activation of the autonomic nervous system is more easily understood when described in the context of acute and severe hypoglycemia. As plasma glucose levels are restored, peripheral glucose sensors in the portal vein, small intestine, and liver decrease firing. This afferent signal is transmitted to the hypothalamus and to the nucleus solitarius in the medulla through the vagus nerve, conveying information on the prevailing peripheral glucose levels. In the hypothalamus, glucose sensors contribute to the central nervous system integration of these signals. This initiates an appropriate response through the inhibition of hepatic and adrenal nerve activity, with consequently decreased release of adrenomedullary catecholamines. The decreased sympathetic activation allows hyperglycemia to induce pancreatic insulin secretion. Thus, glucose acts as a feedback signal contributing to integration of the neuroendocrine mechanisms that regulate its homeostasis. Obesity is associated with an increased risk of type 2 diabetes mellitus, dyslipidemia, hypertension, heart disease, and cancer. Body weight and the excess weight gain leading to obesity are determined by interactions among genetic, environmental, and psychosocial factors that affect the physiologic mediators of energy intake and expenditure, several of which pertain to the endocrine system. Energy expended by the individual can be in the form of work (physical activity) or heat production (thermogenesis), which can be affected by environmental temperature, diet, and the neuroendocrine system (catecholamines and thyroid hormone). The expression of proteins involved in this process (uncoupling protein-1 expressed in brown adipose tissue and uncoupling protein-3 in skeletal muscle) is modulated by catecholamines, thyroid hormones, and leptin. The role of genetics in the predisposition to obesity has been demonstrated convincingly. Susceptibility genes have been identified that increase the risk of developing obesity, and their relevance has been shown in studies in which pairs of twins were exposed to periods of positive and negative energy balance. The differences in the rate of weight gain, the proportion of weight gained, and the sites of fat deposition showed greater similarity within pairs than between pairs, indicating a close genetic relationship. Environmental factors are also thought to unmask genetic tendencies toward obesity. The responsiveness to hormones that regulate lipolysis varies according to the distribution of fat depots. The lipolytic response to norepinephrine is greater in abdominal than in gluteal or femoral adipose tissue in both men and women. The exaggerated release of free fatty acids from abdominal adipocytes directly into the portal system, an increased hepatic gluconeogenesis, and hepatic glucose release, and hyperinsulinemia are hallmarks of patients with upper-body obesity. The endocrine properties of the different fat depots may be more important than the anatomic location. The severity of medical complications is more closely related to body fat distribution, being greater in individuals with abdominal (visceral) obesity than those with an excess total body fat. The presence of visceral obesity, insulin resistance, dyslipidemia, and hypertension is collectively termed the metabolic syndrome. Excess energy intake in relation to the energy expended by the organism leads to the accumulation of fat. The fat mass itself is determined by the balance between breakdown (lipolysis) and synthesis (lipogenesis). The sympathetic nervous system is the principal stimulator of lipolysis, particularly when the energy demands of the individual are increased. When intake exceeds energy utilization, lipogenesis occurs in liver and adipose tissue. Other hormones involved in the regulation of body fat stores include testosterone, dehydroepiandrosterone, and thyroid hormone. Hypothalamic Integration the hypothalamus receives innervation from several areas, notably the nucleus tractus solitarius and area postrema in the brainstem. These areas relay many neural and hormonal signals from the gastrointestinal tract. Mechanical stretch receptors sense stretch of the stomach and other areas of the intestine. The nucleus tractus solitarius also relays taste information to the hypothalamus and other centers. Other signals regarding smell, sight, memory of food, and the social context under which it is ingested are also integrated and may also influence energy intake by modulating output from the hypothalamus. Integration of these signals results in the activation of gene expression of mediators implicated in the regulation of satiety and development of obesity. The relative contributions of these mediators to the regulation of caloric intake, energy expenditure, body weight, and fat mass are not completely understood. However, important new discoveries, such as the secretory function of adipose tissue, have provided new insight into potential factors contributing to obesity. Adipose tissue is an endocrine tissue participating in a complex network regulating energy homeostasis, glucose and lipid metabolism, vascular homeostasis, immune response, and even reproduction. Secretion of almost all of these hormones and cytokines is dysregulated as a consequence of both excess and deficiency in the mass of adipose tissue, suggesting that they are involved in the pathophysiology of both obesity and cachexia. Regulation of Energy Intake Regulation of energy intake is mediated by several factors. Central integration of peripheral signals, including those mediated by mechanoreceptors and chemoreceptors, signals the presence and energy density of food in the gastrointestinal tract. Hypothalamic glucose sensors monitor fluctuations in circulating glucose concentrations. Hormones signal the central release of peptides that regulate appetite and satiety. Two hormones that have been identified as crucial in the long-term regulation of energy balance are insulin and leptin, the product of the ob gene (discussed later). Additional signals regarding smell, sight, memory of food, and the social context under which it is ingested are also integrated and may also influence energy intake by modulating output from the hypothalamus. These include hypothalamic areas such as the ventromedial nucleus, dorsomedial nucleus, and the lateral hypothalamic area, which modulate this control system. Integration of these signals results in regulation of energy intake, satiety, control of thermogenesis, and energy expenditure. Mediator Gastrointestinal tract Cholecystokinin Ghrelin Released in the duodenum during a meal. Stimulates growth hormone release, decreases fat oxidation, increases food intake and adiposity. Overall has antileptin action Member of the neuropeptide Y family, released in the distal small intestine and colon in response to food. Inhibits neuronal melanocortin-4 receptors and increases food intake Produced by neurons in the lateral hypothalamus perifornical area. They stimulate food intake Produced by adipose tissue (decreased in obese patients; plasma levels correlate negatively with triglycerides). Increases insulin sensitivity and tissue fat oxidation, resulting in reduced circulating fatty acid levels and reduced intramyocellular and liver triglyceride content Produced by adipose tissue. Paracrine signal increases efficiency of triacylglycerol synthesis in adipocytes, resulting in more rapid postprandial lipid clearance Produced in adipose tissue. Leptin produced by white adipose tissue functions as a signal that provides information about the level of energy stores (adipose tissue mass). The signal is integrated by hypothalamic neurons, and an effector response, most likely involving modulation of appetite centers and sympathetic nervous system activity, regulates the two main determinants of energy balance: intake and expenditure. Leptin secretion exhibits a circadian rhythm, with a nocturnal rise over daytime secretion. These changes in leptin plasma concentrations are not influenced by meal ingestion and meal-induced increases in the circulating insulin concentration. The effects of leptin are mediated through the leptin receptor, a member of the gp130 family of cytokine receptors, which activates a gene transcription factor on two populations of hypothalamic neurons. The role of leptin in humans appears to be mostly one of the adaptations to low energy intake rather than a brake on overconsumption and obesity. Leptin concentrations decrease during fasting and energy-restricted diets, independent of body fat changes, stimulating an increase in food intake before body energy stores become depleted. Because leptin levels do not increase in response to individual meals, it is not thought to serve as a meal-related satiety signal. Finally, it is notable that obese individuals have high plasma leptin concentrations that do not result in the expected reduction in food intake and increase in energy expenditure, suggesting that obesity is related to leptin resistance. Ghrelin Ghrelin is a hormone produced by the enteroendocrine cells of the stomach, and to a lesser extent by the pituitary, and hypothalamus. Circulating levels of ghrelin decrease during meals and are highest in the fasted state. Ghrelin levels are decreased in obese individuals and increased in individuals consuming low calorie diets, chronic strenuous exercise, cancer anorexia, and anorexia nervosa. In humans, ghrelin has been shown to be a potent growth hormone secretagogue and appetite stimulant. Aldosterone Aldosterone increases sodium reabsorption and potassium excretion in the distal tubule and the collecting duct of the nephron, playing a central role in determining total body Na+ mass, and thus long-term blood pressure regulation. Atrial natriuretic factor Atrial natriuretic factor is a peptide hormone produced in atrial myocardial cells and released in response to increased stretch, usually resulting from increased intravascular volume. It increases renal Na+ excretion and water loss through an increase in glomerular filtration rate and a decrease in Na+ reabsorption in the medullary collecting duct. The system works primarily to maintain intravascular volume and to a lesser extent to maintain tonicity. Low blood pressure results in decreased renal perfusion pressure and lower glomerular filtration rates, which Abnormalities in Sodium and Water Balance Abnormalities in sodium and water balance can be classified into four categories. Water deficit is due to lack of intake or excess loss (renal and nonrenal) and is manifested by hypernatremia and hyperosmolarity. Small losses (1%, or 35 mmol) of total body potassium content can seriously disturb the delicate balance between intracellular and extracellular potassium and can result in profound physiologic changes. The tissues most severely affected by potassium imbalance are muscle and renal tubular cells. Manifestations of hypokalemia include generalized muscle weakness, paralytic ileus, and cardiac arrhythmias. Only a small fraction (10%) of potassium is excreted through the gastrointestinal tract and the majority is excreted by the kidney. Thus, the kidney is responsible for long-term potassium homeostasis, as well as for regulating the serum potassium concentration.

Presynaptic inhibition of norepinephrine and somatostatin release facilitates secretion by removing the braking action of sympathetic and intrinsic nerves, which may also contribute to diarrheal symptoms top medicine purchase betoptic 5ml on line. Suppression of mucosal secretion is the physiological effect of inhibiting secretomotor firing medicine 75 yellow buy betoptic pills in toronto. Postganglionic neurons of the sympathetic nervous system are an important source of inhibitory input to the secretomotor neurons symptoms jaw pain buy betoptic with american express. Norepinephrine released from sympathetic axons acts at 2a noradrenergic receptors to inhibit firing of the secretomotor neurons in treatment 1-3 buy discount betoptic 5ml on line. Suppression of secretion in this manner is part of the mechanism involved in sympathetic nervous "shutdown" of gut function in homeostatic states symptoms 3 days before period betoptic 5 ml mastercard. In general, elevated activity is associated with elevated secretion that is manifested as neurogenic secretory diarrhea when secretomotor neuronal firing is sufficiently intense medicine 3604 betoptic 5 ml. Suppression of secretomotor firing is associated with decreased secretion, reduced liquidity of the luminal contents, and a constipated state, if severe. The discovery of purinergic inhibitory motor neurons was highly significant because prior to 1970, all neurally mediated inhibition was assumed to be mediated by catecholamines released from sympathetic postganglionic neurons. Inhibitory musculomotor neurons appear as an evolutionary adaptation for neural control of the specialized self-excitatory properties of the musculature (see Chapter 18). Like cardiac muscle, action potentials and pacemaker potentials spread from muscle fiber to muscle fiber in three dimensions and trigger a contraction as they enter each successive muscle fiber. The physiological characteristics of the musculature as a self-excitable electrical syncytium suggests that the pacemaker network should continuously evoke contractions that spread in three dimensions throughout the extent of the syncytium, which in effect is the entire length and circumference of the intestine. Nevertheless, in the normal bowel, long stretches of intestine can exhibit no contractile 21. The receptors for acetylcholine on the musculature belong to the muscarinic M1, M2, and M3 receptor subtypes. Ongoing firing of impulses by enteric inhibitory motor neurons accounts for the occurrence of contractile silence. The circular muscle is able to respond to a pacemaker potential only when the inhibitory musculomotor neurons in a segment of intestine are switched to an inactive state by input from other neurons in the interneuronal control circuits. Likewise, action potentials and associated contractions can only propagate into regions of the musculature where the inhibitory innervation is "turned-off. Consequently, action potentials and contractions in the muscle can occur only when the inhibitory neurons are switched-off by inhibitory input from interneurons in the control circuits. In the various smooth muscle sphincters found along the digestive tract, the inhibitory motor neurons are normally quiescent and are switched to an active state with timing appropriate for coordination of the opening of the sphincter with physiological events in adjacent regions. In non-sphincteric circular muscle, the state of activity of inhibitory motor neurons determines the length of a contracting segment by controlling the distance of spread of action potentials within the three-dimensional electrical geometry of the syncytium. Contraction can occur in segments in which ongoing inhibition has been switched-off, while adjacent segments with continuing inhibitory neuronal input cannot contract. The boundaries of the contracted segment reflect the transition zone from inactive to active inhibitory musculomotor neurons. The directional sequence in which the inhibitory motor neurons are switched-off establishes the direction of propagation of the contraction within the smooth muscle syncytium. Normally, they are switched-off in the aboral direction, resulting in contractile activity that propagates in the aboral direction. In the abnormal conditions associated with emesis, the interneuronal microcircuitry must switchoff the inhibitory musculomotor neurons in a reversed sequence to account for small intestinal propulsion that travels in the retrograde direction toward the stomach. After neural blockade, evoked action potentials and associated contraction of the circular muscle propagate over distances of several centimeters. Several circumstances that involve functional ablation of the intrinsic inhibitory neurons are associated with conversion from a hypo-irritable condition of the circular muscle to a hyperirritable state. The behavior of the muscle in these cases is tonic contracture and disorganized phasic contractile activity reminiscent of fibrillation in cardiac muscle, which like the smooth muscle behaves as a functional electrical syncytium. Without inhibitory control, the self-excitable syncytium of non-sphincteric regions will contract continuously and behave as an obstruction. Contractions spreading in the uncontrolled syncytium collide randomly resulting in fibrillation-like behavior in the affected intestinal segment. Loss or malfunction of inhibitory musculomotor neurons is the pathophysiological basis of disinhibitory motor disease. It underlies several forms of chronic intestinal pseudo-obstruction and sphincteric achalasia. In the former, the neuropathologic findings include a marked reduction in the number of neurons in both myenteric and submucosal plexuses, and the presence of round, eosinophilic intranuclear inclusions in about 30% of the residual neurons. Histochemical and ultrastructural evaluations reveal the inclusions are proteinaceous material-forming filaments, not viral particles. Paraneoplastic syndrome, Chagas disease, and idiopathic degenerative disease are recognizable forms of pseudo-obstruction related to inflammatory neuropathies. Both myopathic and neuropathic forms of chronic intestinal pseudo-obstruction are recognized. Failure of propulsive motility in the affected length of bowel reflects loss of the enteric neural microcircuits that program and control the repertoire of motility patterns required for the necessary functions of that region of bowel. Pseudo-obstruction occurs in part because contractile behavior of the circular muscle is hyperactive but disorganized in the denervated regions. The hyperactive and disorganized contractile behavior reflects the absence of inhibitory nervous control of the muscles that are self-excitable. Chronic pseudoobstruction is therefore symptomatic of the advanced stage of a progressive enteric neuropathy. Immunostaining with sera from paraneoplastic patients shows a characteristic pattern of staining in enteric neurons. The association of enteric neuronal loss and symptoms of pseudo-obstruction in Chagas disease also reflects autoimmune attack on the neurons with accompanying symptoms that mimic the situation in lower esophageal sphincter achalasia and paraneoplastic syndrome. Smooth muscle sphincters separate the various specialized compartments of the digestive tract. The lower esophageal sphincter isolates the esophagus from the acidic environment of the stomach. The sphincter of Oddi guards against reflux from the duodenum into the biliary and pancreatic ducts. Tonic contracture, that is an inherent myogenic property of the sphincteric musculature, maintains closure of the orifices that separate the compartments. Enteric inhibitory musculomotor neurons innervate the smooth musculature that forms the sphincters. Inhibitory musculomotor neurons are the motor component of lower esophageal sphincter relaxation during swallowing, relaxation of the sphincter of Oddi to admit bile and pancreatic secretions into the duodenum, and internal anal sphincter relaxation for defecation and passing of flatus. Inhibitory enteric neural control of the sphincteric musculature differs from the tonically active inhibitory outflow to the intestinal musculature. Inhibitory musculomotor neurons to the sphincters are normally silent and are transiently activated with appropriate timing for opening of the sphincter and passage of luminal contents from one compartment to another. Reclosure of the sphincter occurs when the excitatory input to the inhibitory neurons is halted and inhibitory firing stops. Achalasia in the lower esophageal sphincter leads to dilatation of the esophageal body and dysphagia. This is a form of synaptic connectivity in which the neurons of the circuit make recurrent excitatory synaptic connections one with another. A feed-forward circuit is one in which the synaptic connectivity causes excitation to build rapidly to firing threshold in each of the members of the driver circuit. Rapid buildup of firing in individual neurons in the circuit ensures simultaneous activation of the entire network around the circumference and along the length of a segment of bowel. Output of the circuit is excitatory synaptic input to pools of motor neurons around the circumference and along the length of the intestinal segment. Driver circuit output to a pool of secretomotor neurons synchronizes mucosal secretion within a segment of intestine. Neural connections between myenteric and submucosal plexuses coordinate mucosal secretion with contractile behavior of the musculature. Neurons in the circuit make recurrent excitatory synaptic connections one with another resulting in positive feed-forward flow of synaptic excitation that leads to rapid buildup of firing within the population of driver neurons. Slow synaptic excitation accounts for escalation of excitation in the individual neurons and prolonged firing in the circuit, the output of which simultaneously activates pools of motor neurons. Inhibitory synaptic input to the neurons, which form the circuit (not shown), is postulated to stop neuronal firing and halt excitatory output from the circuit to the motor neuronal pool. At the opposite extreme, the gates are closed when the cell somas are in their inexcitable state. Slow excitatory events, which are discussed later, are an integral part of the gating mechanism (see Section 21. The state of somal inexcitability reflects the absence of stimulation by slow excitatory mediators. Downward deflections are electrotonic potentials evoked by repetitive intraneuronal injection of hyperpolarizing current pulses. Twin extracellular stimulus pulses were applied to an interganglionic connective (see inset). The time interval between the two stimulus pulses was progressively shortened until first the somal action potential and then the electrotonic invasions from the projection in the fiber tract were not evoked by the second stimulus pulse. The superimposed traces show that the refractory period for the somal action potential was longer than for the spike conducted in the neurite in the fiber tract. Each inbound neurite spike fires the cell soma when it is in a hyperexcitable state. This occurs because excitability of the somal membrane is enhanced, membrane resistance and space constant are increased, and after-spike hyperpolarizing potentials are suppressed during slow synaptic or paracrine excitation, as will be discussed later (see Section 21. Inbound spike Chapter 21 Cellular Neurophysiology of Enteric Neurons 645 information from the mucosa does not cross the cell soma when it is in the inexcitable state and synaptic output from the cell body to neighboring neurons does not occur. Intermediate levels of excitability permit only a fraction of the inbound spikes to fire the cell soma, transferring differently encoded information to neighboring neurons in the circuit. They do not meet the traditionally rigorous criteria for sensory afferent function as applied for spinal, cranial, and vagal sensory neurons in all textbooks of sensory neurophysiology (see Chapter 24). Potassium conductance is the main ionic determinant of the resting membrane potential. In enteric neurons, inhibitory signal substances such as opioid peptides, galanin, and adenosine decrease neuronal excitability by increasing K conductance and hyperpolarizing the membrane. This shoulder reflects activation of voltage-gated Ca2 conductance in N-type, high-voltage-activated Ca2 channels180 as the membrane is depolarized by inward Na current. The Na channels are typical of tetrodotoxin-sensitive channels found in neurons elsewhere. The rate of rise of the spike in tetrodotoxin is increased by elevation of external Ca2, and the pure Ca2 spike in this case is abolished by multivalent ions that block Ca2 entry. These include an A-type, delayed rectifier, hyperpolarization-activated cation current (Ih), and inwardly rectifying currents. The after-hyperpolarization activates slowly from 45 to 80 ms after termination of the spike and lasts for up to 30 s. An increase in membrane conductance reflected by a decrease in the input resistance occurs during the hyperpolarizing after-potentials. The amplitude of the after-potential is increased by elevation of extracellular Ca2 and is suppressed by multivalent ions that block Ca2 entry. The amplitude is reduced and the duration of the hyperpolarizing after-potential is shortened in bathing media with reduced Ca2. These early findings were evidence that an outward current carried by K ions generated the hyperpolarizing after-potential. Further evidence for the Ca2 dependence of K current activation is the suppression of the current and the associated hyperpolarization produced by application of multivalent cations that block Ca2 entry. This is consistent with the results, obtained with optical imaging of intraneuronal Ca2, which show elevations of intraneuronal free Ca2 during the hyperpolarizing after-potential. During slow synaptic excitation, as discussed in the following section, the neurotransmitter or paracrine modulator acts to reduce the hyperpolarizing after-potential and allows the somal membrane to fire repetitively at higher frequency. Synaptic transmitters are released by Ca2-triggered exocytosis from stores localized in vesicles at axonal terminals or transaxonal varicosities. Release is triggered by the depolarizing effects of action potentials when they arrive at the release site and open voltageactivated Ca2 channels. Once released, enteric neurotransmitters bind to their specific postsynaptic receptors to evoke ionotropic or metabotropic synaptic events. When the receptors are directly coupled to the ionic channel, they are classified as "ionotropic. An enteric neuron may express mechanisms for both slow and fast synaptic neurotransmission. Fast synaptic potentials have durations in the millisecond range; slow synaptic potentials last for several seconds, minutes, or longer. The spikes are nearly always abolished by sufficient concentrations of tetrodotoxin and the rate of rise and amplitude are reduced in depleted Na. They appear to be the sole mechanism of transmission between vagal efferents and enteric neurons. The properties of a specific nicotinic receptor are determined by the kinds of subunits that form the pentameric receptor. Calbindin-immunoreactive enteric neurons do not express P2X3 receptor immunoreactivity. Rundown of this nature does not occur at the synapses in the stomach208,209 or gallbladder.

A) Kupffer cells B) hepatocytes C) colonocytes D) vascular endothelial cells E) stellate cells 5 medicine 93 7338 betoptic 5 ml free shipping. A patient with severe portal hypertension is noted to have bulging veins that protrude into his esophagus (esophageal varices) on endoscopic examination medicine zolpidem cheap 5 ml betoptic with amex. He is treated surgically by the placement of a shunt connecting the portal vein to the vena cava medicine 8 pill buy betoptic australia. A newborn infant is noted to be suffering from mild jaundice, but no bilirubin is found in the urine medications known to cause pill-induced esophagitis cheap betoptic express. Describe dietary sources of carbohydrates, and the pathways involved in the digestion and absorption of carbohydrate polymers, dietary disaccharides, and monosaccharides medications epilepsy generic 5 ml betoptic mastercard. Identify essential amino acids, and understand why they must be provided in the diet new medicine purchase betoptic 5ml overnight delivery. Describe pathways involved in the digestion and absorption of proteins, peptides, and amino acids. Together with lipids, discussed in the next chapter, they represent the major sources of calories in the diet, and each supplies specific building blocks for molecules needed for the physiologic function of the body as a whole. Dietary carbohydrates are the major exogenous source of glucose, which is utilized by cells as an energy source. Proteins supply amino acids, which are resynthesized into new proteins needed by the body. Starch Amylose Amylopectin Disaccharides Sucrose Lactose Monosaccharides Glucose Galactose Fructose Dietary fiber While the body can synthesize glucose de novo from a variety of substrates, some amino acids (essential amino acids) cannot be synthesized by the body. These reactions generate short-chain fatty acids, which are important energy sources for colonocytes. However, neither they nor the water-soluble end products of their digestion can readily traverse the membranes of the epithelial cells that line the small intestine. Thus, an ordered series of chemical reactions breaks down both proteins and carbohydrate polymers to their component monomers or short oligomers. Second, membrane-bound hydrolases localized to the microvillous membrane ("brush border") of the epithelial cells lining the villus tips in the small intestine mediate the next stage of digestion. The epithelium is only capable of transporting monosaccharides, so even dietary disaccharides must be digested at the brush border before they can be absorbed. For proteins, on the other hand, the epithelium expresses transporters that can take up short peptides, as well as those specific for monomeric amino acids. Thus, peptides taken up into the enterocytes undergo a third stage of digestion in the cytosol, mediated by intracellular hydrolases. Saliva contains a 56-kd amylase enzyme that is closely related to the 55-kd amylase that is secreted into the pancreatic juice. As its name implies, salivary amylase is capable of digesting amylose, the straight-chain component of starch. Salivary amylase is not essential for the normal digestion of carbohydrates, since all of the enzymes in the pancreatic juice are present in considerable excess of requirements. However, the salivary enzyme likely does assume an important role in infants, where there is a developmental delay in the production of pancreatic enzymes, and as a backup in patients with pancreatic insufficiency, such as in those with cystic fibrosis. However, its activity can be protected if its substrate occupies the active site of the enzyme. Thus, while starch is present in the gastric lumen, it is likely that its digestion mediated by salivary amylase can continue, until the task is assumed by pancreatic amylase. The latter is also sensitive to acid, but acts in an environment where gastric juices have been neutralized by duodenal, pancreatic, and biliary bicarbonate secretion. The synthesis and secretion of salivary amylase in the serous cells of the salivary glands are regulated by neurohumoral signals coincident with ingestion of a meal. Interestingly, in common with the pancreatic isoform, the synthesis of salivary amylase is upregulated by carbohydrate ingestion. There are three main forms of carbohydrate that have nutritional significance-starch, sucrose, and lactose. Starch is the name given to a complex mixture of dietary polymers of glucose derived from plant sources, such as cereals and starchy vegetables. There are two different types of glucose polymers in starch, which is significant because they require different enzymes to digest them fully. Sources of starch also supply other carbohydrate polymers, as well as noncarbohydrate polymers, that collectively are known as dietary fiber. Fiber is characterized by the fact that constituent polymers cannot be degraded by mammalian digestive enzymes. It is critical for intestinal health because, being indigestible in the small intestine, it remains in the lumen and provides bulk to the stool, retaining fluid and aiding passage of the fecal material through the colon. Fiber has additional nutritional significance in that, although it is not Intestinal Digestion In health, the majority of starch digestion likely involves the 55-kd amylase that is secreted as an active enzyme into the pancreatic juice by pancreatic acinar cells (see Chapter 51). Both the pancreatic and salivary enzymes act rapidly to cleave starch into a mixture of products, depending on whether amylose or amylopectin is the substrate. This means that while the action of amylase is rapid, none of the products it generates can immediately be absorbed by the enterocytes, since the epithelium can only transport monosaccharides. By the time the meal reaches the proximal small intestine, therefore, digestion of starch will generate a mixture of maltose (a dimer of glucose), maltotriose (a trimer of glucose), and -limit dextrins, which are the simplest structures that can be derived from the branch points in amylopectin. These molecules are partially digested by the enzyme amylase, yielding the products shown at the bottom of the figure. B) Brush border hydrolases responsible for the sequential digestion of the products of luminal starch digestion. Panel 1 depicts the digestion of linear oligomers of glucose; panel 2 shows the final steps in digestion of -limit dextrins. Brush border digestion is an essential component of the pathways leading to assimilation of all dietary carbohydrates, with the exception of glucose. Brush border hydrolysis of carbohydrates, as well as other dietary components, likely increases the efficiency of carbohydrate absorption because the monosaccharides generated are produced in close proximity to the transporters that are then required for their uptake. Likewise, this may also sequester digested monosaccharides from the limited numbers of small intestinal bacteria. The enzymes are trafficked specifically to the apical membrane of the cells in these sites and anchored in the membrane by a single transmembrane segment. The enzymatic activities involved in brush border hydrolysis include sucrase, isomaltase, glucoamylase, and lactase. Sucrase and isomaltase activities are actually encoded in a single polypeptide chain with two distinct active sites, and thus the complete protein is referred to as sucrase-isomaltase. Overall, the brush border hydrolases cooperate to facilitate the complete digestion of dietary carbohydrates and the products derived from their luminal digestion. However, isomaltase is critical for the full digestion of starch, since it is unique among the listed activities in being able to cleave not only the -1,4 bonds of linear glucose oligomers, but also the -1,6 bonds of the -limit dextrins. Lactose Lactose is an important nutrient in those who consume large quantities of milk, such as infants. It is a disaccharide that consists of glucose and galactose and is broken down at the brush border by lactase, an enzyme that contains two identical active sites within a single polypeptide chain. First, there is a developmental decline in lactase expression, meaning that levels of this enzyme in adulthood may be inadequate to hydrolyze all of the substrate presented to them. Thus, lactose hydrolysis, rather than transport of the products of this reaction, is usually rate limiting for assimilation. Second, the activity of lactase is inhibited by glucose, in a process known as "endproduct inhibition. Sucrose Sucrose (table sugar) is a prominent carbohydrate in many Western diets and requires no luminal digestion because it is a simple disaccharide consisting of glucose and fructose. Expression of sucrase-isomaltase is usually in excess of the requirements for this enzyme, at least in Western populations that emphasize sucrose in the diet. It exists in the membrane as a homotetramer, which appears to be important for its function. The protein mediates the ordered transfer of both sodium and glucose across the membrane. Sodium binds first to an extracellular site on the transporter, followed by glucose, which triggers a conformational change in the protein. This transfers these substrates to the cytoplasmic face of the membrane, where first glucose, and then sodium, can dissociate into the cytosol. It is also expressed in many other cell types throughout the body, where it participates in glucose uptake. Acutely, brush border hydrolases on the surface of enterocytes are degraded at the end of the meal, when dietary protein is no longer available to compete for the activity of pancreatic proteases. These enzymes are then resynthesized by the enterocyte to ready the epithelium to handle carbohydrates in the next meal. This cycle of degradation and resynthesis is not specific for the enzymes involved in carbohydrate digestion, but occurs for the entire complement of brush border proteins needed for nutrient assimilation. On the other hand, and on a longer time scale, if carbohydrates are specifically withheld from the diet, there is a gradual decline in the expression of the hydrolases and transporters that are involved in the assimilation of this class of nutrients, and likely also in the expression of amylase. All of these components are, in turn, upregulated if carbohydrate is then returned to the diet. Insulin, in particular, appears to suppress the levels of these molecules, meaning that glucose assimilation can be enhanced in the setting of type I diabetes mellitus. First, the 20 naturally occurring amino acids, compared with the 3 nutritionally significant monosaccharides, mean that proteins represent a significantly more diverse set of substrates and require a broader spectrum of peptidases and transporters to mediate their digestion and uptake. Second, the intestine is capable of transporting not only single amino acids, but also short oligomers, encompassing dipeptides, tripeptides, and perhaps even tetrapeptides. In fact, some amino acids are absorbed much more efficiently in the form of peptides than as the single molecules. Finally, the existence of peptide transport in the intestine implies that these molecules must eventually be digested to their component amino acids in order for them to be useful to other body tissues. This final stage of protein digestion takes place in the cytosol of the enterocyte. However, the capacity for luminal digestion of carbohydrates is regulated in the postnatal period. Expression of pancreatic amylase is low in infants below the age of 1 and is gradually induced as starch is added to the diet. However, both of these responses likely do not reflect strict developmental regulation, but rather are appropriate adaptive responses to the appearance or disappearance of the relevant substrates in the normal diet. Dietary the various components of the systems involved in carbohydrate assimilation are regulated by the diet in both the short Essential Amino Acids Another important concept when considering protein assimilation is that of the essential amino acid. Residues that are boxed are essential amino acids that must be obtained from dietary sources by humans. However, proteins from vegetable sources are "incomplete," meaning that they lack one or more of the essential amino acids. As we learned in Chapter 50, on the other hand, the chief cells of the gastric glands synthesize and store pepsinogens, inactive precursors of pepsins, which are a group of related proteolytic enzymes especially suited to action in the stomach. At low pH, there is autocatalytic cleavage of an N-terminal peptide from pepsinogen that yields the active form. Pepsins preferentially cleave dietary proteins at neutral amino acids, with a preference for large aliphatic or aromatic side chains. They are also sensitive to the pH of their environment, and are inactivated above a pH of 4. This means that gastric pepsins are quickly inactivated once they enter the small intestine, which may be important to prevent digestion of the epithelium. Because of the relatively limited specificity of pepsins, gastric proteolysis results in incomplete digestion with only a few free amino acids; the products are mostly large, nonabsorbable peptides. And in common with other aspects of the gastrointestinal system that are either redundant or present in excess, gastric proteolysis does not appear to be essential for normal levels of protein assimilation. Despite their various specificities, however, all of the pancreatic peptidases have one important feature in common. They are all stored in the pancreatic acinar cells as inactive precursors, which apparently is important to prevent autodigestion of the pancreas. How then are these inactive enzymes converted to their active forms only when they are in small intestinal lumen The answer lies in yet another proteolytic enzyme-enterokinase- expressed on the apical membrane of small intestinal epithelial cells. When the pancreatic juice is secreted into the intestine, it comes into contact with enterokinase, which cleaves an N-terminal hexapeptide from trypsinogen, yielding active trypsin. Large peptides derived from gastric proteolysis are sequentially cleaved by the endopeptidases (trypsin, chymotrypsin, and elastase). These reactions yield shorter peptides with either neutral or basic amino acids at their C-termini, which can be acted on in turn by carboxypeptidase A or carboxypeptidase B, respectively. Thus, the products of proteolysis in the intestinal lumen consist of free basic and neutral amino acids as well as short peptides that cannot be cleaved further due to the lack of an appropriate amino acid at their C-terminus. However, because of the diversity of possible substrates, there is the requirement for a much larger number of brush border hydrolases. These membrane-bound enzymes comprise both endopeptidases and ectopeptidases, and are expressed by villus, but not crypt, enterocytes. The activity of these enzymes yields free amino acids in the vicinity of the enterocyte apical membrane, although some peptides remain relatively resistant to hydrolysis, and are taken up in their unhydrolyzed form. This is a highly ordered process mediated by two families of pancreatic proteases, the secretion of which we discussed in Chapter 51.

In industrialized countries, toxigenic strains of Corynebacterium ulcerans are emerging as an important cause of a diphtherialike illness 5 medications for hypertension purchase betoptic 5 ml free shipping. C diphtheriae is an irregularly staining, gram-positive, nonsporeforming, nonmotile, pleomorphic bacillus with 4 biotypes (mitis, intermedius, gravis, and belfanti) treatment alternatives boca raton purchase betoptic 5ml on line. The toxin inhibits protein synthesis in all cells, resulting in myocarditis, acute tubular necrosis, and delayed peripheral nerve conduction treatment 2 buy betoptic with a mastercard. Nontoxigenic strains of C diphtheriae can cause sore throat and, rarely, other invasive infections, including endocarditis and foreign body infections medications overactive bladder 5ml betoptic mastercard. Organisms are spread by respiratory tract droplets and by contact with discharges from skin lesions medications going generic in 2016 buy cheap betoptic. Patients treated with an appropriate antimicrobial agent usually are not communicable 48 hours after treatment is initiated symptoms rectal cancer betoptic 5 ml. People who travel to areas where diphtheria is endemic or people who come into contact with infected travelers from such areas are at increased risk of being infected with the organism; rarely, fomites and raw milk or milk products can serve as vehicles of transmission. Severe disease occurs more often in people who are unimmunized or inadequately immunized. The incidence of respiratory diphtheria is greatest during autumn and winter, but summer epidemics can occur in warm climates in which skin infections are prevalent. During the 1990s, epidemic diphtheria occurred throughout independent states of the former Soviet Union, with case-fatality rates ranging from 3% to 23%. During 2012, one probable case of diphtheria was reported in the United States, representing the first case since 2003. Cases of cutaneous diphtheria likely still occur in the United States, but only respiratory tract cases are included for national notification. Diagnostic Tests Specimens for culture should be obtained from the nose or throat and any mucosal or cutaneous lesion. Material should be obtained from beneath the membrane, or a portion of the membrane itself should be submitted for culture. Because special medium is required for isolation, laboratory personnel should be notified that C diphtheriae is suspected. Because the condition of patients with diphtheria can deteriorate rapidly, a single dose of equine antitoxin should be administered on the basis of clinical diagnosis, even before culture results are available. Antitoxin and its indications for use and instructions for administration are available through the Centers for Disease Control and Prevention. To neutralize toxin from the organism as rapidly as possible, intravenous administration of the antitoxin is preferred. Before intravenous administration of antitoxin, tests for sensitivity to horse serum should be performed, initially with a scratch test. Allergic reactions of variable severity to horse serum can be expected in 5% to 20% of patients. The dose of antitoxin depends on the site and size of the diphtheria membrane, duration of illness, and degree of toxic effects; presence of soft, diffuse cervical lymphadenitis suggests moderate to severe toxin absorption. Erythromycin administered orally or parenterally for 14 days, aqueous penicillin G administered intravenously for 14 days, or penicillin G procaine administered intramuscularly for 14 days constitutes acceptable therapy. Antimicrobial therapy is required to stop toxin production, to eradicate the C diphtheriae organism, and to prevent transmission, but it is not a substitute for antitoxin, which is the primary therapy. Active immunization against diphtheria should be undertaken during convalescence from diphtheria; disease does not necessarily confer immunity. Tonsillar and pharyngeal diphtheria may need to be differentiated from group A streptococcal pharyngitis, infectious mononucleosis, vincent angina, acute toxoplasmosis, thrush, and leukemia, as well as other, less common entities, including tularemia and acute cytomegalovirus infection. Diphtheria pneumonia (hemorrhagic) with bronchiolar membranes (hematoxylin-eosin stain). Corynebacterium diphtheriae can not only affect the respiratory, cardiovascular, renal, and neurologic systems, but the cutaneous system as well, where it sometimes manifests as an open, isolated wound. Diphtheria was a common cause of these infant deaths prior to the introduction of a toxoid vaccine around 1921. However, reluctance to immunize children sets the stage for another generation of rows of tiny memories. All are acute, systemic, febrile illnesses, with common systemic manifestations, including fever, headache, chills, malaise, myalgia, and nausea. More variable symptoms include arthralgia, vomiting, diarrhea, cough, and confusion. Rash is more common in Ehrlichia infections than Anaplasma infections and is more common in children (up to 60% of cases). More severe manifestations of these diseases can include acute respiratory distress syndrome, encephalopathy, meningitis, disseminated intravascular coagulation, spontaneous hemorrhage, and renal failure. Significant laboratory findings in Anaplasma and Ehrlichia infections may include leukopenia, lymphopenia, thrombocytopenia, hyponatremia, and elevated serum hepatic transaminase concentrations. Neorickettsiosis is characterized by lymphadenopathy, a sign that is not commonly seen with infections by other members of this bacterial family. As with ehrlichiosis and anaplasmosis, patients with neoehrlichiosis often have had leukocytosis and elevated C-reactive protein concentrations, but liver transaminase levels are usually within normal ranges. Most cases of neoehrlichiosis have been in people with underlying immunosuppressive conditions. Without treatment, symptoms typically last 1 to 2 weeks, but prompt antimicrobial therapy will shorten the duration and reduce the risk of serious manifestations and sequelae. Following infection, fatigue may last several weeks; some reports suggest the occurrence of neurologic complications in some children after severe disease, and more commonly with Ehrlichia infections. Typically, E chaffeensis presents with more severe disease than does Anaplasma phagocytophilum. Ehrlichia and Anaplasma species do not cause vasculitis or endothelial cell damage characteristic of some other rickettsial diseases. However, because of the nonspecific presenting symptoms, Rocky Mountain spotted fever should be considered. Ehrlichia and Anaplasma species are gram-negative cocci with tropisms for different white blood cell types. Neorickettsia sennetsu may cause illness in Asia, while the organism designated as Neoehrlichia mikurensis has been found in various European and Asian countries. Epidemiology the reported incidences of E chaffeensis and A phagocytophilum infections during 2012 were 3. These diseases are underrecognized, and selected active surveillance programs have shown the incidence to be substantially higher in some areas with endemic infection. Most cases of E chaffeensis and E ewingii infection are reported from the south central and southeastern United States, as well as East Coast states. Most cases of human anaplasmosis have been reported from the upper Midwest and northeast United States (eg, Wisconsin, Minnesota, Connecticut, New York) and northern California. In most of the United States, A phagocyto philum is transmitted by the black-legged tick (Ixodes scapularis), which is also the vector for Lyme disease (Borrelia burgdorferi) and babesiosis (Babesia microti). In the western United States, the western blacklegged tick (Ixodes pacificus) is the main vector for A phagocytophilum. Various mammalian wildlife reservoirs for the agents of human ehrlichiosis and anaplasmosis have been identified, including white-tailed deer and wild rodents. In other parts of the world, other bacterial species of this family are transmitted by the endemic tick vectors for that area. An exception is N sennetsu, which occurs in Asia and is transmitted through ingestion of infected trematodes residing in fish. Reported cases of symptomatic ehrlichiosis and anaplasmosis are characteristically in older people, with age-specific incidences greatest in people older than 40 years. However, seroprevalence data indicate that exposure to E chaffeensis may be common in children. In the United States, most human infections occur between April and September, and the peak occurrence is from May through July. Coinfections of anaplasmosis with other tick-borne diseases, including babesiosis and Lyme disease, may cause illnesses that are more severe or of longer duration than a single infection. Whole blood anticoagulated with ethylenediaminetetraacetic acid should be collected at the first presentation before antibiotic therapy has been initiated. Polymerase chain reaction assays for anaplasmosis and ehrlichiosis are available commercially. Identification of stained peripheral blood smears to look for classic clusters of organism known as morulae may occasionally indicate infection with Anaplasmataceae, but this method is generally insensitive and is not recommended as a first-line diagnostic tool. Crossreactivity between species can make it difficult to interpret the causative agent in areas where geographic distributions overlap. Detection of IgG antibodies in acute and convalescent sera is recommended when assessing acutely infected patients. Treatment Doxycycline is the drug of choice for treatment of human ehrlichiosis and anaplasmosis, regardless of patient age, and has also been shown to be effective for the other Anaplasmataceae infections. Ehrlichiosis and anaplasmosis can be severe or fatal in untreated patients or patients with predisposing conditions; initiation of therapy early in the course of disease helps minimize complications of illness. Most patients begin to respond within 48 hours of initiating doxycycline treatment. Treatment with trimethoprim-sulfamethoxazole has been linked to more severe outcome and is contraindicated. Treatment should continue for at least 3 days after defervescence; the standard course of treatment is 5 to 10 days. Unequivocal evidence of clinical improvement is generally within 7 days, although some symptoms (eg, headache, malaise) can persist for weeks. The HmE polymerase chain reaction and serologic test results were positive for HmE. The differential diagnosis of this rash includes rocky mountain spotted fever, meningococcemia, and Stevens-Johnson syndrome. Other tick-borne diseases, such as Lyme disease, babesiosis, Colorado tick fever, relapsing fever, and tularemia, may need to be considered. Photomicrographs of human white blood cells infected with the agent of human granulocytic ehrlichiosis (Anaplasma phagocytophilum, formerly Ehrlichia phago cytophila) and the agent of human monocytic ehrlichiosis (Ehrlichia chaffeensis). This tick is a vector of several zoonotic diseases, including human monocytic ehrlichiosis, southern tick-associated rash illness, tularemia, and rocky mountain spotted fever. The most common manifestation is nonspecific febrile illness, which, in young infants, may lead to evaluation for bacterial sepsis. Other manifestations can include (1) respiratory: coryza, pharyngitis, herpangina, stomatitis, bronchiolitis, pneumonia, and pleurodynia; (2) skin: hand-footand-mouth disease, onychomadesis (periodic shedding of nails), and nonspecific exanthems; (3) neurologic: aseptic meningitis, encephalitis, and motor paralysis (acute flaccid paralysis); (4) gastrointestinal/genitourinary: vomiting, diarrhea, abdominal pain, hepatitis, pancreatitis, and orchitis; (5) eye: acute hemorrhagic conjunctivitis and uveitis; (6) heart: myopericarditis; and (7) muscle: pleurodynia and other skeletal myositis. Neonates, especially those who acquire infection in the absence of serotype-specific maternal antibody, are at risk of severe disease, including viral sepsis, meningoencephalitis, myocarditis, hepatitis, coagulopathy, and pneumonitis. Almost all confirmed cases were among children, many of whom had asthma or a history of wheezing. Illness consisted of spinal fluid pleocytosis and acute onset of limb weakness and changes on magnetic resonance imaging of the spinal cord demonstrating nonenhancing lesions restricted to the gray matter. As of December 2014, 94 children with acute flaccid myelitis have been reported in 33 states. Patients with humoral and combined immune deficiencies can develop persistent central nervous system infections, a dermatomyositis-like syndrome, or disseminated infection. Echoviruses 22 and 23 have been reclassified as human parechoviruses 1 and 2, respectively. They are spread by fecal-oral and respiratory routes and from mother to newborn prenatally, in the peripartum period, and, possibly, via breastfeeding. Infection incidence, clinical attack rates, and disease severity are typically greatest in young children, and infections occur more frequently in tropical areas and where poor sanitation, poor hygiene, and overcrowding are present. Fecal viral shedding can persist for several weeks or months after onset of infection, but respiratory tract shedding is usually limited to 1 to 3 weeks or less. Incubation Period 3 to 6 days for all except acute hemorrhagic conjunctivitis, which is 24 to 72 hours. Sensitivity of culture ranges from 0% to 80% depending on serotype and cell lines used. Courtesy of Centers for Disease Control and Prevention/ Emerging Infectious Diseases. Hand-foot-and-mouth disease lesions are caused by coxsackievirus A16 and enterovirus 71. This rash, commonly seen over the buttocks, often appears macular, maculopapular, or papulovesicular and may be petechial. Herpangina (coxsackievirus) lesions on the posterior palate of a young adult male. Coxsackievirus lesions are usually found in the posterior aspect of the oropharynx and may progress rapidly to painful ulceration. Echoviruses comprise 1 of 5 serotypes, which make up the genus Enterovirus, and are associated with illnesses, including aseptic meningitis, nonspecific rashes, encephalitides, and myositis. She also had approximately 10 maculopapular lesions on each buttock and a few on each foot.

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