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巨噬细胞极化在骨关节炎中的作用

巨噬细胞极化在骨关节炎中的作用引言巨噬细胞是免疫系统中的重要成分，它在多种疾病中扮演着重要角色。

在骨关节炎中，巨噬细胞的极化状态对于疾病的发展和治疗至关重要。

本文将就巨噬细胞极化在骨关节炎中的作用展开深入探讨。

什么是巨噬细胞极化？巨噬细胞极化是指巨噬细胞在不同的微环境中表现出的不同形态和功能。

根据所接受的刺激和细胞因子的调节，巨噬细胞可以分化为两种主要类型，即经典型巨噬细胞(M1型)和曲张型巨噬细胞(M2型)。

经典型巨噬细胞(M1型)经典型巨噬细胞主要参与机体的炎症反应，并具有促炎作用。

当组织受损或感染时，巨噬细胞被激活并释放一系列的炎性细胞因子，如白细胞介素1β(IL-1β)、肿瘤坏死因子α(TNF-α)等。

这些细胞因子可以引起炎症细胞的浸润和活化，促进炎症反应的发生。

曲张型巨噬细胞(M2型)曲张型巨噬细胞主要参与组织修复和再生，并具有抗炎作用。

在抗炎反应中，曲张型巨噬细胞释放的细胞因子，如白细胞介素10(IL-10)、转化生长因子β(TGF-β)等，可以抑制炎症反应的发生，并促进伤口愈合。

巨噬细胞极化在骨关节炎中的作用巨噬细胞极化在骨关节炎的发展和进程中起着重要作用。

下面将从多个方面探讨巨噬细胞极化在骨关节炎中的具体作用。

1. 炎症反应的调节在骨关节炎中，巨噬细胞极化状态的改变可以调节病变区域的炎症反应。

炎症反应是骨关节炎的基本特征之一，巨噬细胞的极化能够促进或抑制炎症反应的发生。

M1型巨噬细胞的活化会释放大量炎性细胞因子，导致关节炎炎症的进一步加剧。

而M2型巨噬细胞的活化则可以抑制炎症细胞因子的产生，从而减轻炎症反应和相关疼痛。

2. 软骨退化的影响巨噬细胞极化状态的改变也会影响软骨的退化过程。

在骨关节炎中，软骨的退化是疾病的关键因素之一。

研究发现，M1型巨噬细胞的活化会产生一系列的骨吸收相关因子，如骨吸收细胞趋化因子和金属蛋白酶等，这些因子会促进软骨组织的逐渐退化。

相反，M2型巨噬细胞的活化则可以释放一些抗骨吸收因子，如骨抑制细胞趋化因子和组织抑制蛋白等，从而保护软骨组织的完整性。

电解质钾稳定性

Then e w e ng l a n d j o u r na lofm e dic i n eReview ArticleDisorders of Fluids and ElectrolytesJulie R. Ingelfinger, M.D., EditorAn Integrated View of Potassium HomeostasisMichelle L. Gumz, Ph.D., Lawrence Rabinowitz, Ph.D., and Charles S. Wingo, M.D.From the Departments of Medicine (M.L.G., C.S.W.), Molecular Biology and Biochemistry (M.L.G.), and Physiology and Functional Genomics (C.S.W.), University of Florida, North Florida–South Georgia Veterans Health System (C.S.W.), and Malcom Randall Veterans Affairs (VA) Medical Center (C.S.W.) — all in Gainesville, FL; and the Department of Physiology and Membrane Biology, University of California School of Medicine at Davis, Davis (L.R.). Address reprint requests to Dr. Wingo at the Nephrology Section, 111G, Malcom Randall VA Medical Center, 1601 Archer Rd., Gainesville, FL, 32608-1197. This article was updated on July 2, 2015, at .N Engl J Med 2015;373:60-72. DOI: 10.1056/NEJMra1313341Copyright © 2015 Massachusetts Medical Society.he plasma potassium level is normally maintained within narrow limits (typically, 3.5 to 5.0 mmol per liter) by multiple mechanisms that collectively make up potassium homeostasis. Such strict regulation is essential for a broad array of vital physiologic processes, including the resting cellularmembrane potential and the propagation of action potentials in neuronal, muscular, and cardiac tissue, along with hormone secretion and action, vascular tone, systemic blood-pressure control, gastrointestinal motility, acid–base homeostasis, glucose and insulin metabolism, mineralocorticoid action, renal concentrating ability, and fluid and electrolyte balance.1-3 The importance of potassium homeostasis is underscored by the well-recognized finding that patients with hypokalemia or hyperkalemia have an increased rate of death from any cause.4,5 In addition, derangements of potassium homeostasis have been associated with pathophysiologic processes, such as progression of cardiac and kidney disease and interstitial fibrosis.1,3,6 The need for tight regulation of the extracellular level of potassium is illustrated by the potential for derangements in the level during the ingestion of a normal meal. An average adult has approximate levels of 60 to 80 mmol of total extracellular potassium and levels of 20 to 25 mmol of total plasma potassium. Meals may contain more potassium than the total plasma potassium content, but because of rapid clearance by renal and extrarenal mechanisms, the variations in the plasma potassium level during the course of a day are commonly no greater than 10%.7 Renal potassium excretion also has a circadian rhythm independent of food intake and modulates other mechanisms that control potassium excretion. Here we review the mechanisms that regulate potassium homeostasis and describe the important role that the circadian clock exerts on these processes. From a clinical perspective, the importance of the circadian clock is illustrated by the benefits of timed drug administration. For example, the time of drug administration can affect the therapeutic benefit.8,9 Aldosterone and cortisol have an endogenous circadian secretion pattern, so sampling at specific times will reduce variability and improve clinical assessment. Moreover, the action of these hormones is influenced by the circadian clock.10 The substantial daily variation in urinary potassium excretion justifies caution in the use of random urine sampling to evaluate hypokalemia or hyperkalemia. Without consideration of the time of collection, random measurement of urinary potassium may either underestimate or overestimate the 24-hour rate of potassium excretion. Finally, the time of day affects the adaptation to a potassium load and can be important in emergency potassium-replacement therapy.11TP o ta ssium Homeos ta sisPotassium homeostasis denotes the maintenance of the total body potassium content and plasma potassium level within narrow limits in the face of potentially60n engl j med 373;1 July 2, 2015The New England Journal of Medicine Downloaded from at MCMASTER UNIVERSITY HEALTH SCI LIB on July 10, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.an integr ated view of potassium homeostasiswide variations in dietary potassium intake. It involves two concurrent processes — external and internal. External potassium homeostasis regulates renal potassium excretion to balance potassium intake, minus extrarenal potassium loss and correction for any potassium deficits. Internal potassium regulation controls the asymmetric distribution of total body potassium with the greater part (approximately 98%) intracellular and only a small fraction (approximately 2%) extracellular.2 Much evidence supports the role of the circadian clock in external homeostasis, and some evidence indicates a role in internal homeostasis.7,12-14E x ter na l P o ta ssium B a l a nceExternal potassium balance involves three control systems (Fig. 1A). Two systems can be categorized as “reactive,” whereas a third system is considered to be “predictive.” A negative-feedback system reacts to changes in the plasma potassium level and regulates the potassium balance. Potassium excretion increases in response to increases in the plasma potassium level, leading to a decrease in the plasma level. A reactive feed-forward system that responds to potassium intake in a manner that is independent of changes in the systemic plasma potassium level has been recognized.2,15 Currently, the component mechanisms remain under study and are incompletely delineated. Because oral potassium intake was seen to produce a marked kaliuresis in the absence of effective increases in the plasma potassium level, investigators postulated that potassium receptors reside in the gut, hepatic portal vein, or liver.2,15 Experiments with the use of vagotomy and hypophysectomy support the role of vagal afferents and the pituitary as components of this system.16,17 Evidence in animal models shows that an oral potassium load leads to kaliuresis, but aldosterone, vasopressin, α-melanocyte–stimulating hormone (α-MSH), γ-MSH, and peptides such as glucagon-like peptide 1, guanylin, uroguanylin, and other candidate substances do not appear to be responsible.18 The nature of the kaliuretic factors requires further investigation. A predictive system appears to modulate the effect of reactive systems, enhancing physiologic mechanisms at the time of day when food intake characteristically occurs — typically, during the day in humans and at night in nocturnal ro-dents.7 This predictive system is driven by a circadian oscillator in the suprachiasmatic nucleus of the brain and is entrained to the ambient light–dark cycle. The central oscillator (clock) entrains intracellular clocks in the kidney that generate the cyclic changes in excretion. When food intake is evenly distributed over 24 hours, and physical activity and ambient light are held constant, this system produces a cyclic variation in potassium excretion.7,13,19 After the ingestion of a meal, the feed-forward system induces kaliuresis.20-22 If the quantity of potassium is sufficient to increase the plasma potassium level, the feedback system is activated.20-22 Intake can vary widely throughout the day. Although the circadian clock and potassium intake from meals alter potassium excretion rapidly (≤24 hours), potassium excretion responds appropriately with intake. For example, under normal conditions in persons who consume four equal meals at 6-hour intervals, meal-induced kaliuresis is greater during the day than at night.23 However, balance studies show that with large, prolonged step increases or decreases in potassium intake, potassium balance may not be fully achieved for several days.In ter na l P o ta ssium Homeos ta sisInternal potassium homeostasis is the maintenance of an asymmetric distribution of total body potassium between the intracellular and extracellular fluid. This occurs by the balance of active cellular uptake by sodium–potassium adenosine triphosphatase, an enzyme that pumps sodium out of cells while pumping potassium into cells (called the sodium–potassium pump rate), and passive potassium efflux (called the leak rate). Case 1 illustrates the dramatic effect of derangements in the proper coupling between potassium pump and leak rates (Box 1). Little increase in the plasma potassium level occurs during potassium absorption from the gut in normal persons owing to potassium excretion by the kidney and potassium sequestration by the liver and muscle (Fig. 1A). Between meals, the plasma potassium level is nearly constant, as potassium excretion is balanced by the release of sequestered intracellular potassium (Fig. 1B). Potassium depletion primarily involves a loss of potassium from muscle, although it may be reflected in reductions in the plasma potassium level. When the potassium loss is corrected,61n engl j med 373;1 July 2, 2015The New England Journal of Medicine Downloaded from at MCMASTER UNIVERSITY HEALTH SCI LIB on July 10, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.Then e w e ng l a n d j o u r na lofm e dic i n eA Meal-Driven Potassium ExcretionCircadian regulation Potassium intake ↑ Potassium sequestration in liver and skeletal muscle Ambient light–dark cycleBrain-originated circadian rhythm Splanchnic sensors activatedPlasma potassiumDecreased level Negative feedback regulation Increased levelBrain-to-kidney entrainment, creating tubule-cell circadian rhythmFeed-forward regulationSignals from vagus nerveSignals from gutGut kaliuretic factors? Brain kaliuretic factors?Meal-driven kidney potassium excretionB Fasting Potassium ExcretionCircadian regulation Potassium intake Release of sequestered potassium from liver and skeletal muscle Ambient light–dark cycleBrain-originated circadian rhythmSplanchnic sensors activatedPlasma potassiumBrain-to-kidney entrainment, creating tubule-cell circadian rhythmFeed-forward regulationSignals from vagus nerveSignals from gutGut kaliuretic factors? Brain kaliuretic factors?Between-meal fasting potassium excretionFigure 1. Overview of Potassium Homeostasis. Shown are the known mechanisms that regulate external potassium balance and the pathways for net potassium movement associated with meal-driven potassium intake (Panel A) and with between-meal fasting (Panel B). Mealdriven potassium intake initiates both an increase in potassium excretion and sequestration of potassium in liver and skeletal muscle. Increased excretion is driven by reactive mechanisms, which can be either dependent on the plasma potassium level (negative-feedback regulation) or independent of the plasma potassium level (feed-forward regulation) initiated at splanchnic receptors. The circadian rhythm drives a predictive regulation of the tubule mechanisms responsible for potassium excretion, generated by a central clock and transmitted to circadian clocks in the tubule cells responsible for variations in potassium excretion. This rhythm enhances excretion during the active daylight phase and diminishes it during the inactive nighttime phase. In combination, these components provide maintenance of total body potassium levels within narrow limits without appreciable changes in the plasma potassium level. Between periods of meal intake, potassium is released from intracellular stores (primarily liver and skeletal muscle) for excretion.62n engl j med 373;1July 2, 2015The New England Journal of Medicine Downloaded from at MCMASTER UNIVERSITY HEALTH SCI LIB on July 10, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.an integr ated view of potassium homeostasisBox 1. Case 1. Case 1 illustrates the dramatic effect of derangements in the proper coupling between potassium-pump rates and potassiumleak rates. An 11-year-old boy was admitted for evaluation of hypokalemia and muscle weakness. He awoke at 3:00 a.m. with paralysis of the lower limbs and severe weakness in both upper limbs, with a muscle-strength grade of 1, on a scale of 0 (lowest) to 5 (highest). His mother called for an ambulance. The patient had a history of having similar episodes approximately three to four times per year, frequently in the early morning. Most attacks were less severe than this one, but a recent episode had prompted admission for near paralysis and hypokalemia. The attacks were characterized by weakness, principally in the thighs with occasional involvement of the upper limbs. None were associated with loss of consciousness. On admission (5:00 a.m., 2 hours after the beginning of the episode), the patient’s plasma potassium level was 1.6 mmol per liter, and he promptly received 40 mmol of potassium chloride by mouth. After approximately 90 minutes without relief of the paralysis, 40 mmol per liter of potassium chloride was infused in 0.9% saline intravenously over 2 hours. However, this treatment did not substantially increase the plasma potassium level (1.7 mmol per liter). The patient received an additional 100 mmol of potassium chloride by mouth at the completion of the intravenous potassium chloride infusion. His muscle strength improved, and the plasma potassium level increased to 2.2 mmol per liter by 11:45 a.m. His strength improved progressively. The plasma potassium level increased to 5.4 mmol per liter at 2:40 p.m. but decreased to 4.0 mmol per liter by 4:15 p.m. Subsequent plasma potassium values remained between 3.7 and 4.8 mmol per liter, and by 11:00 p.m. (20 hours after the beginning of the episode), the patient had recovered most of his strength and his symptoms had largely abated. The results of subsequent laboratory testing for levels of triiodothyronine and free thyroxine were normal. The patient was prescribed acetazolamide and potassium chloride tablets and a high-potassium diet. This case illustrates one form of periodic paralysis with profound hypokalemia. Although quite rare, this disease provides substantial insight into the principal factors that dictate the plasma potassium level.24 In the absence of exogenous potassium administration, the plasma potassium level fell precipitously during an attack as cellular potassium uptake exceeded potassium leak from cells, principally skeletal muscle. In such cases, cautious use of potassium is generally recommended because the hypokalemia does not reflect potassium deficiency but rather transcellular potassium redistribution.25 During attacks, the balance between cellular pump potassium uptake and potassium efflux is shifted to an increase in cellular potassium uptake relative to potassium efflux. As this case illustrates, during the peak of the attack (between 3:00 a.m. and 8:00 a.m.), plasma potassium values may remain depressed despite substantial potassium administration. Periodic paralysis encompasses cases associated with episodic muscle weakness or paralysis.26,27 Many of these cases are hereditary, typically with an autosomal dominant inheritance pattern — hence the designation of familial periodic paralysis. Both hypokalemic and hyperkalemic forms of familial periodic paralysis exist, although the increase in the plasma potassium level is typically small and may not exceed the normal range in the latter. Hypokalemic familial periodic paralysis typically presents in the first two decades of life, with attacks typically lasting several hours; the attacks may be brief or last for several days. Factors that are implicated in the precipitation of attacks include stress, strenuous exercise, and carbohydrate-rich meals. Two genetically distinct mutations account for the majority of the familial cases and are due to a mutation in the gene encoding either skeletal muscle calcium channel α1 subunit (CACNA1) or skeletal muscle sodium channel voltage-gated type IV α subunit (SCN4A). Hyperkalemic familial periodic paralysis usually presents earlier in life than hypokalemic familial periodic paralysis, frequently in infancy or early childhood, with episodes of transient paralysis. Factors that are implicated in the precipitation of attacks include exposure to cold temperature, fasting, rest after exercise, and potassium ingestion. Mutations in SCN4A are known to produce this condition. Thyrotoxic hypokalemic periodic paralysis is an uncommon manifestation of thyrotoxicosis that is characterized by abrupt development of hypokalemia and episodes of muscular weakness. Its incidence is substantially greater in Asians than in non-Asians, and most patients present in their 20s or 30s.28 Although there is a higher incidence of hyperthyroidism in women than in men, the development of periodic paralysis associated with hyperthyroidism is more frequent in men. A recent study indicates that loss of function of the skeletal muscle–specific potassium channel Kir2.6 may contribute to this disorder.29 The differential diagnosis of hypokalemic paralysis should include nonperiodic paralysis and periodic paralysis that can be familial or sporadic. Other more common conditions should be considered in patients presenting with hypokalemia and paralysis, including renal tubular acidosis. In one series, renal tubular acidosis was the most frequent cause of hypokalemia with paralysis.30,31 This is particularly the case if there is substantial potassium depletion or if provoked by high-carbohydrate caloric sources.32 Autoimmune disorders such as Sjögren’s syndrome and pernicious anemia should also alert the clinician to the possibility of renal tubular acidosis and potassium depletion as potential causes of hypokalemic paralysis.31,33potassium retention from intake replaces the deficit.2,15 Insulin, catecholamines, and mineralocorticoids stimulate potassium uptake into muscle and other tissues. Absorption of meal-derived glucose stimulates insulin secretion with a consequent insulin-driven potassium uptake in muscle. The effectiveness of insulin in the treatment of hyperkalemia depends on its capacity to drivepotassium into skeletal muscle, thereby decreasing the plasma potassium level. In the absence of a change in the total body potassium content, severe hypokalemia may result from a minor increase in intracellular potassium as a result of a resetting of pump–leak kinetics.34 The pump– leak kinetics are not altered by short-term elevations in aldosterone but are reset by chronic mineralocorticoid stimulation, which reduces63n engl j med 373;1 July 2, 2015The New England Journal of Medicine Downloaded from at MCMASTER UNIVERSITY HEALTH SCI LIB on July 10, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.Then e w e ng l a n d j o u r na lofm e dic i n eBox 2. Case 2. Case 2 illustrates the importance of glucose and insulin to extrarenal potassium homeostasis and to maintenance of the plasma potassium level. A 35-year-old woman presented with nausea, vomiting, and muscle weakness for the past several days. Before this episode, she had had a good appetite. Her medical history was unremarkable except for a previous diagnosis of nephrolithiasis. She had a 15-year pack-history of smoking tobacco and reported taking no prescription medicines, diuretics, or nonprescription or other drugs, including laxatives. Her blood pressure was 108/88 mm Hg, and the heart rate was 110 beats per minute; respirations were unlabored, and she was afebrile. The chest and cardiovascular examination was normal. Muscle strength was initially judged to be modestly reduced, with a score of 3 out of 5. The results of initial laboratory tests were as follows: a normal differential blood count; sodium, 137 mmol per liter; potassium, 1.6 mmol per liter; chloride, 108 mmol per liter; bicarbonate, 16 mmol per liter; anion gap, 13; blood urea nitrogen, 10 mg per deciliter (3.6 mmol per liter); creatinine, 0.8 mg per deciliter (71 μmol per liter); arterial blood pH, 7.32; and partial pressure of carbon dioxide, 25 mm Hg. On urinalysis, the urine pH was 7.5, specific gravity 1.005, with no leukocytes, protein, blood, or nitrites. Electrocardiography revealed prominent U waves. Nephrocalcinosis was confirmed on renal ultrasonography and intravenous pyelography. She was treated with intravenous potassium (40 mmol per liter) in 5% glucose and oral potassium (40 mmol). Severe muscle weakness (grade 1 out of 5) ensued, and a repeat plasma potassium level was 1.2 mmol per liter. The patient was admitted to the intensive care unit for close observation and electrolyte replacement. Potassium replacement was continued intravenously as 40 to 60 mmol of potassium chloride per liter in normal saline, and the plasma potassium level increased to 3.6 mmol per liter. The patient’s muscle strength rapidly returned to normal. Subsequent evaluation confirmed the diagnosis of hypokalemic (type I) distal renal tubular acidosis. On hospital discharge, she was prescribed 25 ml of potassium citrate and citric acid oral solution four times daily. At a follow-up visit 2 weeks later, she had no symptoms and had normal plasma electrolytes. This case illustrates a potentially life-threatening complication that can ensue from administration of intravenous glucose solutions (despite potassium-replacement therapy) to patients with potassium depletion.32 The glucose-enhanced insulin secretion results in rapid stimulation of cellular potassium uptake. Life-threatening cardiac arrhythmias and worsening muscle weakness can develop during the infusion of potassium with glucose in the treatment of hypokalemia. The infusion of glucose reduces the plasma potassium level in both healthy persons and in those with hypokalemia, but the complications can be more serious when hypokalemia or potassium depletion is present. In the correction of potassium depletion, oral administration of potassium is recommended if practicable. If intravenous potassium repletion is used, it should be in glucose-free solutions, to avoid neuromuscular paralysis or cardiac arrhythmias.the plasma potassium level in the absence of discernable changes in the total body potassium content.34-36 Such actions contribute largely to the reductions in plasma potassium associated with increased secretion or administration of aldosterone. Nevertheless, supraphysiologic rates of aldosterone secretion, as in primary hyperaldosteronism, may be associated with potassium depletion. Case 2 illustrates the importance of extrarenal potassium homeostasis to the maintenance of the plasma potassium level (Box 2).action of diuretics, alterations in acid–base balance, or impaired kidney function) or limit the capacity of the kidney to compensate (e.g., in chronic kidney disease).R ena l P o ta ssium H a ndl ingThe healthy kidney has a robust capacity to excrete potassium, and under normal conditions, most persons can ingest very large quantities of potassium (400 mmol per day or more) without clinically significant hyperkalemia.23,37 Potassium that is filtered at the glomerulus is largely reabsorbed in the proximal tubule and the loop of Henle. Consequently, the rate of renal potassium excretion is determined mainly by the difference between potassium secretion and potassium reabsorption in the cortical distal nephron and collecting duct. Both of these processes are regulated — potassium ingestion stimulates potassium secretion and inhibits potassium reabsorption.2,38 Factors that regulate potassium secretion and reabsorption can be divided into those that serve to preserve potassium balance (homeostatic) and those that affect potassium excretion without intrinsically acting to preserveA ber r a n t P o ta ssium Homeos ta sisThe concurrent activities of the external and internal systems act to maintain the plasma potassium level within narrow limits. However, in clinical practice, clinicians often encounter deviations from normal levels when potassium intake is greatly altered. Hypokalemia and hyperkalemia frequently occur as the result of nonhomeostatic processes that are not regulated by changes in the potassium balance. These processes increase or decrease potassium excretion but not in response to changes in potassium intake (e.g.,64n engl j med 373;1 July 2, 2015The New England Journal of Medicine Downloaded from at MCMASTER UNIVERSITY HEALTH SCI LIB on July 10, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.an integr ated view of potassium homeostasisTable 1. Factors Regulating Potassium Secretion and Potassium Reabsorption. Change Homeostatic Increases effect Potassium loading Aldosterone in the presence of hyperkalemia Potassium Secretion Contra-homeostatic Increased luminal flow rate Increased luminal sodium delivery Decreased luminal chloride Exogenous mineralocorticoid agonists, fludrocortisone, diuretics Metabolic alkalosis Decreased luminal flow rate Decreased luminal sodium delivery Drugs that inhibit sodium absorption (e.g., amiloride, triamterene, trimethoprim, pentamidine, digitalis) Inhibitors of renin–angiotensin– aldosterone system (RAAS)* Potassium-channel inhibitors and other mechanisms, including metabolic acidosis, cyclooxygenase inhibitors (nonsteroidal antiinflammatory drugs), and calcineurin inhibitors Potassium Reabsorption Homeostatic Potassium restriction and depletion Progesterone Contra-homeostatic Acidosis Exogenous mineralocorticoid agonists (e.g., fludrocortisone)Decreases effectPotassium restriction and depletionPotassium loading Tissue kallikreinInhibitors of renin–angiotensin–aldosterone system (RAAS)* RAAS inhibitors include those that affect aldosterone synthesis (e.g., heparin); those that affect aldosterone regulation, including the inhibition of renin secretion (e.g., beta-blockers, cyclooxygenase inhibitors), direct renin inhibitors (e.g., aliskiren), angiotensin-converting–enzyme inhibitors (e.g., captopril), and angiotensin II–receptor blockers (e.g., losartan); and those that affect aldosterone action, including mineralocorticoid receptor blockers (e.g., spironolactone, eplerenone).potassium balance (contra-homeostatic) (Table 1). Examples of the latter include flow rate in the renal tubular lumen and the luminal sodium level. The acid–base balance also affects potassium excretion. The predominant effect of acidosis is to inhibit potassium clearance, whereas the predominant effect of alkalosis is to stimulate potassium clearance. Cases 3 and 4 illustrate the evaluation of hypokalemia from renal and extrarenal causes (Box 3). The mechanisms for potassium secretion and reabsorption in the collecting duct are shown in Figure 2. Apical cellular sodium entry through the amiloride-sensitive epithelial sodium channel (ENaC) promotes active basolateral cellular potassium uptake in exchange for sodium extrusion by the sodium–potassium pump. Apical sodium entry through ENaC depolarizes the apical membrane, which stimulates potassium secretion through apical potassium channels. Functional cotransport of potassium chloride also effects potassium secretion and is particularly important when the luminal chloride level is substantially reduced, as in the administration of a non-reabsorbable anion or during chloridedependent metabolic alkalosis.2Active potassium reabsorption is driven by an apical membrane proton–potassium pump (Fig. 2). The activity of this pump is pH-sensitive and activated by acidosis,42-44 potassium restriction,45 and mineralocorticoids.34 The mineralocorticoid effect may explain the lack of substantial renal potassium loss with chronic mineralocorticoid stimulation.34-36,46 Thus, mineralocorticoids can enhance potassium reabsorption or secretion depending on the potassium balance.The Circ a di a n Cl o ck in Cel lul a r Ph ysiol o gyIn vertebrates, a central clock in the suprachiasmatic nucleus of the brain and peripheral clocks that are present in virtually all cells regulate circadian rhythms.47 Although ablation of the suprachiasmatic nucleus disrupts many circadian rhythms, particularly those related to activity, the circadian rhythm of potassium excretion is preserved, presumably due to continued activity of renal-cell clocks. Indeed, this rhythm persists after adrenalectomy and requires no environmental stimuli.7,48,4965n engl j med 373;1 July 2, 2015The New England Journal of Medicine Downloaded from at MCMASTER UNIVERSITY HEALTH SCI LIB on July 10, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.。

海獭对世界的影响英语作文

Sea otters, though small in stature, have a significant impact on the world in various ways. As keystone species, they play a crucial role in maintaining the balance of their ecosystems. Heres how these charming marine mammals influence the world around them:1. Ecosystem Engineers: Sea otters are known as ecosystem engineers due to their ability to shape their environment. By preying on sea urchins, they prevent these creatures from overgrazing kelp forests. Healthy kelp forests are vital as they provide habitat and food for numerous marine species, thus supporting biodiversity.2. Biodiversity Enhancement: By controlling the population of sea urchins, sea otters indirectly protect a variety of marine life that depends on kelp forests. This includes fish, invertebrates, and other organisms that call these underwater forests home.3. Carbon Sequestration: Kelp forests are efficient at capturing and storing carbon dioxide from the atmosphere. By preserving these ecosystems, sea otters contribute to the mitigation of climate change through the process of carbon sequestration.4. Economic Impact: The presence of sea otters can have economic benefits for coastal communities. Healthy marine ecosystems support fisheries and tourism, both of which can be negatively impacted by the loss of kelp forests.5. Cultural Significance: Sea otters hold cultural importance for many indigenous communities. They are often featured in traditional stories, rituals, and crafts, contributing to the rich cultural heritage of these communities.6. Conservation Efforts: The protection of sea otters has led to increased awareness and conservation efforts for marine life in general. Their status as an endangered species has prompted research and protective measures that benefit the broader marine ecosystem.7. Educational Value: Sea otters are popular animals in educational settings. They serve as ambassadors for marine conservation, teaching people about the interconnectedness of ecosystems and the importance of protecting our oceans.8. Scientific Research: Studies on sea otters have contributed to our understanding of marine biology, predatorprey dynamics, and the effects of human activity on wildlife populations.In conclusion, sea otters are more than just adorable creatures they are vital contributors to the health and balance of marine ecosystems. Their presence or absence can havefarreaching effects on the biodiversity, climate, economy, and culture of our world. As stewards of the planet, it is our responsibility to protect and preserve these remarkable animals and their habitats.。

放射医学专业英语翻译

Unit 4 Section ADNA Strand Breaks and Chromosomal Abberations Inducedby Ionizing Radiation（1）1.What is the principal target for the biologic effects of radiation on the basis of strong circumstantial evidence?基于详细的证据，辐射生物效应的主要靶点是什么？2. What is the structure of a deoxyribonucleic acid molecule?脱氧核糖核酸分子的结构是什么?DNA Strand BreaksDNA链断裂There is strong circumstantial evidence to indicate that deoxyribonucleic acid (DNA) is the principal target for the biologic effects of radiation, including cell killing mutation, and carcinogenesis. A consideration of the biologic effects of radiation therefore must begin logically with a description of the breaks in DNA caused by charged-particle tracks and by the chemical species produced.有足够多且详细的证据表明脱氧核糖核酸是辐射生物效应的主要的靶，包括细胞杀伤性突变和致癌作用。

因此，从带电粒子和化学产物导致的DNA链断裂来考虑辐射生物效应是较合乎逻辑的。

心脏磁共振成像在急性ST段抬高心肌梗死中的应用新进展

心脏磁共振成像在急性ST段抬高心肌梗死中的应用新进展急性ST段抬高心肌梗死（ST-segment el evation myocardial infarction，STEMI）病人再灌注治疗明显降低了其死亡率[1]，然而，梗死后心力衰竭造成的死亡率仍明显增高[2]。

再灌注治疗过程会导致进一步的心肌损伤和心肌细胞死亡，即所谓的再灌注损伤。

因此，找到有效的新治疗方法减少心肌梗死（myocardial infarction，MI）大小和预防梗死后心力衰竭是当前研究热点[3]。

心脏磁共振（cardiac magentic resonance，CMR）是评价STEMI再灌注治疗后的新治疗方法能否减少MI面积、能否预防左心室负性重构的重要工具[4, 5]。

近年来，T1mapping和T2mapping等CMR新技术[6]，从更深的层面获得STEMI后的病理生理学过程，如STEMI后第一周心肌水肿的演变[7, 8]、心肌内出血（intramyocardial hemorrhage，IMH）的演变及其预后意义高于微血管梗阻（microvascular obstruction，MO）[9, 10]，STEMI后左心室负性重构病人对侧心肌间质间隙的变化[11, 12]。

本文综述了CMR在STEMI再灌注后病人的应用新进展。

一、STEMI再灌注后的相关病理生理学概念及其基本CMR表现（一）心肌梗死大小MI大小可通过CMR的延迟钆增强（late gad olinium enhancement，LGE）进行定量评估，通常表示为MI占左心室心肌总体积或质量的百分比[13]。

钆对比剂不能通过完整的细胞膜。

急性心肌坏死后，细胞膜破裂，对比剂可进入这些细胞。

在陈旧性心肌梗死，细胞外间隙扩大导致胶原沉积，残余完整心肌细胞数量相对少，对比剂从血管内进入间质间隙。

因此，急性和陈旧性MI内的对比剂分布浓度均高于正常心肌，从而表现为延迟强化。

哺乳动物的繁殖英文介绍

pengel@
2
Sexual Reproduction Review
• Few offspring • Genetic variation • 2 parents produce haploid gametes • Gametes fuse to produce offspring • Offspring have characteristics of both parents, but are not identical to each other or to parents • Uses meiosis to produce gametes
pengel@
/mammal/mammal.html
4
Monotremes
• Three living monotremes
– Duckbilled platypus – 2 species of Echidna (spiny anteater)
A few examples are: - Giraffe, Monkeys, Tiger, Cats, Dogs, Elephants, Humans, etc.
Yellow Baboon. Photo by H. Vannoy Davis, © 2002 California Academy of Sciences.
pengel@
10
Placental Special Structures
• Special structures – Uterus – Placenta – nipples
pengel@
11
Quick Review
• Mammals use sexual reproduction to produce offspring.

海马的结构及功能

• （ 2 ）杏仁腹侧传出通路 ventral amygdalofugal projection：进入外侧视前区与下丘脑外侧区、隔区和斜角带核等。
• （ 3 ）杏仁被盖束 amygdalo-tegmental tract：终止于下丘脑外侧区，黑质、蓝斑等。
• （ 4 ）杏仁皮质投射 amygdalo-cortical projection：投射至眶额回、颞上、中、下回。
• 根据细胞形态,不同皮质区发育旳差别以及多种纤维通路旳不同， Lorente do No{1934}把海马又提成CA1、CA2、CA3、 CA4 四个扇形区。 CA4 位于齿状回门内,CA3区内有最大旳锥体细胞,CA3区由大锥体细胞构成, CA1区是邻近下托旳部分,由小锥体细胞构成,CA2区是移行区，由大和小锥体细胞构成。
核等。外侧隔核接受大量从海马经穹窿来旳传
入纤维。
• 1.传入纤维
•
〈1〉发自海马旳纤维经穹隆止于外侧隔
核。
•
〈2〉发自杏仁体旳纤维经斜角带或终纹
止于隔核。
• 〈3〉发自中脑网状构造,黑质、蓝斑、中缝核与下丘脑核旳纤维终止于内侧隔核。
• 〈4〉前穿质发纤维经内侧嗅纹至隔。
• （5）额叶新皮质和扣带回发纤维至隔。
• 3.海马构造旳纤维联络
•
〈1〉传入
•
①丰富旳传入来自内嗅区。
•
②扣带回发纤维经扣带束直接终止
于海马和或经内嗅区中继后发纤维维(胆碱能纤维)经穹
窿、海马伞,终止于海马和齿状回。
•
• ④一侧海马发纤维经同侧海马伞、穹窿脚,经过海马连合至对侧穹窿脚与海马伞, 终止于对侧海马和齿状回。

1995-Demography and growth of Medicago minima and Erodium cicutarium-water stress effects

0140-1963/5/010075+07
$08.0010
0 1995 Academic Press Limited
76
D. V. PELiiEZ
ETA
Introduction are two naturalized annual Medicaao minima Grufb. and Erodium cicutarium L’Herit. species-widely distributed in Argentina (Marzocca, 1976). Their presence in the south of the Calden District (caldenal), a semi-arid phytogeographic region of about 10 1976), is associated with degraded, million ha in central Argentina (Cabrera, overgrazed areas. Nevertheless, these cool season species are also present in areas with a high cover of native grasses (Fresnillo Fedorenko et al., 1993). In spring, M. minima and E. cicutarium can produce a large amount of high quality forage (Caimie & Monesiglio, 1967; Distel & Pelaez, 1987; Fresnillo Fedorenko et al., 1993). During part of their growth cycle, both species can be exposed to soil water potentials lower than -2.0 MPa (Pelaez et al., 1992). Water stress may reduce the number of ramifications, leaf number and size, flower number and plant height in several plant species (Karamanos, 1978; Specht et al., 1986; Acosta Gallegos & Shibata, 1989; Fresnillo Fedorenko et al., 1995. However, there is no information on growth and demographic characteristics of M. minima and E. cicutarium under water stress conditions in the field. The objective of this work was to determine the effects of water stress on the demography and growth of M. minima and E. cicutarium under field conditions.

药物基因组学

应用
• 试验中失败的药物都有可能“推倒重来”。已被淘汰的或未被批准的药物中，可能存在对某些病人有很好疗效的药物。如果对这类药物配上基因标签，表明对某类人群有效，那么应用基因芯片技术对特定人群的前期基因诊断，可能有助于新药的开发。
• 另外，由于基因组学规模大、手段新、系统性强，药物基因组学可以直接加速新药的发现。
整合基因与药物基因组学的平台多样性分析
Epidauros Biotechnologie Janssen Pharmaceutica Nova Mollecular
目的基因多态性分析线粒体基因多样性分析中枢神经系统疾病图
基本原理
• 药物基因组学=基因功能学+分子药理学
• 不是以发现人体基因组基因为主要目的， • 而是相对简单地运用已知的基因理论改善病人的治疗。 • 也可以这么说，药物基因组学以药物效应及安全性为目标，
研究动态
实验室和（或）公司
Aeiveos Sciences Group （Seattle, WA）
Avitech Diagostics (Malvern, PA)
研究领域年龄相关的基因及基因作用
酶基因突变检测方法
Eurona Medical,AB (Upsala，SE) 药物效应与遗传学关系
Genome Therapeutics Crop (Waltham, MA)
药物疗效的个体差异性
• 药物基因组学（pharmacogenomics）是研究 DNA和RNA特征的变异与药物反应相关性的科学，即研究基因序列的多态性与药物效应多样性之间的关系。
它是一门研究影响药物吸收、转运、代谢、清除、效应等个体差异的基因特性，即决定药物行为和敏感性的全部基因的新学科。主要阐明药物代谢、药物转运、和药物靶分子的基因多态性与药物效应及不良反应之间的关系，并在此基础上研制新的药物或新的用药方法。

蒙特利尔认知评估替代版(MoCAv7.2)使用指导和评分手册

蒙特利尔认知评估替代版（MoCA v7.2）使用指导和评分手册蒙特利尔认知评估（the Montreal Cognitive Assessment, MoCA）旨在快速筛查轻度认知障碍。

MoCA评估不同的认知领域：注意与专注、执行功能、记忆、语言、视结构技能、概念思维、计算和定向。

完成MoCA测试约需要10分钟。

测试最高得分为30分，大于等于26分为正常水平。

[译者注：使用MoCA原版v7.1对同一受试者进行多次评定时，可能因学习效应而难以准确评估受试者认知功能的变化。

因此，MoCA作者设计了两个替代版本v7.2和v7.3。

本手册配合MoCA 替代版本v7.2使用。

除v7.1、v7.2和v7.3中不同的测试内容外，本版译文将3个评分手册中的其他部分保持一致，以保证良好的测试基准。

考虑到文化和语言差异，本次对原版中的5词记忆、词语流畅性、抽象三个部分做了少量调整。

本译文参考了之前各中译本，并由北京（国家康复辅具研究中心）-广州（中山大学附属第三医院）两地协作完成，以更好地符合不同地区的语言习惯。

]1．交替连线：使用指导：检查者对受试者介绍如下：“数字和汉字都有自己的顺序。

请您画一条线，从一个数字连到一个汉字，要按照数字和汉字的顺序来连接。

从这里开始[指着数字①]，画一条线连到汉字（甲），然后连到数字②，这样连下去。

最后连到这里[指着汉字（戊）]。

”评分：如果受试者能够按照“①−甲−②−乙−③−丙−④−丁−⑤−戊”的次序顺利完成画线，而且连线之间没有交叉，则评为1分。

如果出现任何错误，并且没有立即自行改正，则评为0分。

2．视结构技能（长方体）：使用指导：检查者指着MoCA测试表上的长方体图案，并进行如下介绍：“把这个图案画下来，要尽量画得一模一样。

请画在这个图案下面空白的地方。

”评分：如能正确完成图案绘制，则评为1分。

• 画出的图案必须是三维图形• 要画出长方体所有的线• 没有增加额外的线• 所有水平的线基本平行• 画出的图案必须明显地是一个长方体，也就是说，较短的垂直边的长度不能超过较长的水平边长度的3/4如果违反了上述标准的任何一条，则评为0分。

哺乳动物细胞膜成分

哺乳动物细胞膜成分英文回答：The cell membrane of mammalian cells is composed of various components that play essential roles in maintaining the structure and function of the cell. These components include lipids, proteins, and carbohydrates.Lipids are one of the major components of the cell membrane. They form a lipid bilayer, which provides a barrier between the inside and outside of the cell. The lipid bilayer is primarily composed of phospholipids, which have a hydrophilic (water-loving) head and a hydrophobic (water-fearing) tail. This arrangement allows the lipid bilayer to be selectively permeable, controlling the movement of substances in and out of the cell.Proteins are another important component of the cell membrane. They are embedded within the lipid bilayer and have various functions. Some proteins act as channels ortransporters, facilitating the movement of specific molecules across the membrane. Others serve as receptors, allowing the cell to communicate with its environment by binding to specific molecules or signaling molecules. Additionally, some proteins function as enzymes, catalyzing chemical reactions within the cell membrane.Carbohydrates are present on the outer surface of the cell membrane. They are attached to lipids or proteins, forming glycolipids or glycoproteins, respectively. These carbohydrate chains serve as recognition sites, allowing cells to interact with each other and with molecules in their environment. For example, the ABO blood group antigens on the surface of red blood cells are glycoproteins that determine blood compatibility.In addition to these major components, the cell membrane may also contain other molecules such as cholesterol, which helps regulate the fluidity andstability of the membrane, and various signaling molecules that are involved in cell signaling and communication.Overall, the composition of the mammalian cell membrane is crucial for maintaining the integrity and functionalityof the cell. It allows the cell to selectively transport molecules, interact with its environment, and communicate with other cells.中文回答：哺乳动物细胞的细胞膜由多种成分组成，这些成分在维持细胞的结构和功能方面起着重要作用。

Multimodality Image Registration by Maximization of Mutual Information

Multimodality Image Registration byMaximization of Mutual Information Frederik Maes,*Andr´e Collignon,Dirk Vandermeulen,Guy Marchal,and Paul Suetens,Member,IEEEAbstract—A new approach to the problem of multimodality medical image registration is proposed,using a basic concept from information theory,mutual information(MI),or relative entropy,as a new matching criterion.The method presented in this paper applies MI to measure the statistical dependence or information redundancy between the image intensities of corresponding voxels in both images,which is assumed to be maximal if the images are geometrically aligned.Maximization of MI is a very general and powerful criterion,because no assumptions are made regarding the nature of this dependence and no limiting constraints are imposed on the image content of the modalities involved.The accuracy of the MI criterion is validated for rigid body registration of computed tomog-raphy(CT),magnetic resonance(MR),and photon emission tomography(PET)images by comparison with the stereotactic registration solution,while robustness is evaluated with respect to implementation issues,such as interpolation and optimization, and image content,including partial overlap and image degra-dation.Our results demonstrate that subvoxel accuracy with respect to the stereotactic reference solution can be achieved completely automatically and without any prior segmentation, feature extraction,or other preprocessing steps which makes this method very well suited for clinical applications.Index Terms—Matching criterion,multimodality images,mu-tual information,registration.I.I NTRODUCTIONT HE geometric alignment or registration of multimodality images is a fundamental task in numerous applications in three-dimensional(3-D)medical image processing.Medical diagnosis,for instance,often beneﬁts from the complemen-tarity of the information in images of different modalities. In radiotherapy planning,dose calculation is based on the computed tomography(CT)data,while tumor outlining is of-ten better performed in the corresponding magnetic resonance (MR)scan.For brain function analysis,MR images provide anatomical information while functional information may beManuscript received February21,1996;revised July23,1996.This work was supported in part by IBM Belgium(Academic Joint Study)and by the Belgian National Fund for Scientiﬁc Research(NFWO)under Grants FGWO 3.0115.92,9.0033.93and G.3115.92.The Associate Editor responsible for coordinating the review of this paper and recommending its publication was N.Ayache.Asterisk indicates corresponding author.*F.Maes is with the Laboratory for Medical Imaging Research, Katholieke Universiteit Leuven,ESAT/Radiologie,Universitair Ziekenhuis Gasthuisberg,Herestraat49,B-3000Leuven,Belgium.He is an Aspirant of the Belgian National Fund for Scientiﬁc Research(NFWO)(e-mail: Frederik.Maes@uz.kuleuven.ac.be).A.Collingnon,D.Vandermeulen,G.Marchal,and P.Suetens are with the Laboratory for Medical Imaging Research,Katholieke Universiteit Leuven, ESAT/Radiologie,Universitair Ziekenhuis Gasthuisberg,Herestraat49,B-3000Leuven,Belgium.Publisher Item Identiﬁer S0278-0062(97)02397-5.obtained from positron emission tomography(PET)images, etc.The bulk of registration algorithms in medical imaging(see [3],[16],and[23]for an overview)can be classiﬁed as being either frame based,point landmark based,surface based,or voxel based.Stereotactic frame-based registration is very ac-curate,but inconvenient,and cannot be applied retrospectively, as with any external point landmark-based method,while anatomical point landmark-based methods are usually labor-intensive and their accuracy depends on the accurate indication of corresponding landmarks in all modalities.Surface-based registration requires delineation of corresponding surfaces in each of the images separately.But surface segmentation algorithms are generally highly data and application dependent and surfaces are not easily identiﬁed in functional modalities such as PET.Voxel-based(VSB)registration methods optimize a functional measuring the similarity of all geometrically cor-responding voxel pairs for some feature.The main advantage of VSB methods is that feature calculation is straightforward or even absent when only grey-values are used,such that the accuracy of these methods is not limited by segmentation errors as in surface based methods.For intramodality registration multiple VSB methods have been proposed that optimize some global measure of the absolute difference between image intensities of corresponding voxels within overlapping parts or in a region of interest(ROI) [5],[11],[19],[26].These criteria all rely on the assumption that the intensities of the two images are linearly correlated, which is generally not satisﬁed in the case of intermodality registration.Crosscorrelation of feature images derived from the original image data has been applied to CT/MR matching using geometrical features such as edges[15]and ridges[24] or using especially designed intensity transformations[25]. But feature extraction may introduce new geometrical errors and requires extra calculation time.Furthermore,correlation of sparse features like edges and ridges may have a very peaked optimum at the registration solution,but at the same time be rather insensitive to misregistration at larger distances,as all nonedge or nonridge voxels correlate equally well.A mul-tiresolution optimization strategy is therefore required,which is not necessarily a disadvantage,as it can be computationally attractive.In the approach of Woods et al.[30]and Hill et al.[12], [13],misregistration is measured by the dispersion of the two-dimensional(2-D)histogram of the image intensities of corresponding voxel pairs,which is assumed to be minimal in the registered position.But the dispersion measures they0278–0062/97$10.00©1997IEEEpropose are largely heuristic.Hill’s criterion requires seg-mentation of the images or delineation of speciﬁc histogram regions to make the method work [20],while Woods’criterion is based on additional assumptions concerning the relationship between the grey-values in the different modalities,which reduces its applicability to some very speciﬁc multimodality combinations (PET/MR).In this paper,we propose to use the much more general notion of mutual information (MI)or relative entropy [8],[22]to describe the dispersive behavior of the 2-D histogram.MI is a basic concept from information theory,measuring the statistical dependence between two random variables or the amount of information that one variable contains about the other.The MI registration criterion presented here states that the MI of the image intensity values of corresponding voxel pairs is maximal if the images are geometrically aligned.Because no assumptions are made regarding the nature of the relation between the image intensities in both modalities,this criterion is very general and powerful and can be applied automatically without prior segmentation on a large variety of applications.This paper expands on the ideas ﬁrst presented by Collignon et al .[7].Related work in this area includes the work by Viola and Wells et al .[27],[28]and by Studholme et al .[21].The theoretical concept of MI is presented in Section II,while the implementation of the registration algorithm is described in Section III.In Sections IV,V,and VI we evaluate the accuracy and the robustness of the MI matching criterion for rigid body CT/MR and PET/MR registration.Section VII summarizes our current ﬁndings,while Section VIII gives some directions for further work.In the Appendexes,we discuss the relationship of the MI registration criterion to other multimodality VSB criteria.II.T HEORYTwo randomvariables,,with marginal probabilitydistributions,and:.MI,and(1)MI is related to entropy by theequationsandgivengiven(5)(7)Theentropy,whilewhenknowingby the knowledge of another randomvariablecontainsaboutandandand.The MI registration criterion states that the images are geometrically aligned by thetransformation forwhichMAES et al.:MULTIMODALITY IMAGE REGISTRATION BY MAXIMIZATION OF MUTUAL INFORMATION189(a)(b)Fig.1.Joint histogram of the overlapping volume of the CT and MR brain images of dataset A in Tables II and III:(a)Initial position:I (CT;MR )=0:46,(b)registered position:I (CT;MR )=0:89.Misregistration was about 20mm and 10 (see the parameters in Table III).If both marginaldistributionsand,the MI criterion reduces to minimizing the jointentropyor ,which is the case if one of the images is always completely contained in the other,the MI criterion reduces to minimizing the conditionalentropyisvariedandand.The MI criterion takes this into accountexplicitly,as becomes clear in (2),which can be interpreted as follows [27]:“maximizing MI will tend to ﬁnd as much as possible of the complexity that is in the separate datasets (maximizing the ﬁrst two terms)so that at the same time they explain each other well (minimizing the last term).”For.Thisrequiresis varied,which will be the case if the image intensity values are spatially correlated.This is illustrated by the graphs in Fig.2,showing the behaviorofaxis along the row direction,theaxis along the plane direction.One of the images is selected to be the ﬂoatingimage,are taken and transformed intothe referenceimage,or a sub-or superset thereof.Subsampling of the ﬂoating image might be used to increase speed performance,while supersampling aims at increasing accuracy.For each value of the registrationparameterfalls inside the volumeofis a six-component vector consisting of three rotationanglestoimage(8)with3diagonal matrixes representing thevoxel sizes ofimages,respectively (inmillimeters),3rotation matrix,with thematrixes-,-axis,respectively,and190IEEE TRANSACTIONS ON MEDICAL IMAGING,VOL.16,NO.2,APRIL1997Fig.3.Graphical illustration of NN,TRI,and PV interpolation in 2-D.NN and TRI interpolation ﬁnd the reference image intensity value at position T s and update the corresponding joint histogram entry,while PV interpolation distributes the contribution of this sample over multiple histogram entries deﬁned by its NN intensities,using the same weights as for TRI interpolation.B.CriterionLetatposition.The joint image intensityhistogramis computed by binning the image intensitypairs forallbeing the total number of bins in the joint histogram.Typically,weusewill not coincide with a grid pointofis generally insufﬁcient to guaranteesubvoxel accuracy,as it is insensitive to translations up to one voxel.Other interpolation methods,such as trilinear (TRI)interpolation,may introduce new intensity values which are originally not present in the reference image,leading tounpredictable changes in the marginaldistributionof the reference image for small variationsof,the contribution of the imageintensityofon the gridofis varied.Estimations for the marginal and joint image intensitydistributionsis then evaluatedby(12)and the optimal registrationparameter is foundfrom,using Brent’s one-dimensional optimization algorithm for the line minimizations [18].The direction matrix is initialized with unit vectors in each of the parameter directions.An appropriate choice for the order in which the parameters are optimized needs to be speciﬁed,as this may inﬂuence optimization robustness.For instance,when matching images of the brain,the horizontal translation and the rotation around the vertical axis are more constrained by the shape of the head than the pitching rotation around the left-to-right horizontal axis.There-fore,ﬁrst aligning the images in the horizontal plane by ﬁrst optimizing the in-planeparameters may facilitate the optimization of the out-of-planeparametersMAES et al.:MULTIMODALITY IMAGE REGISTRATION BY MAXIMIZATION OF MUTUAL INFORMATION 191TABLE IID ATASETS U SEDIN THEE XPERIMENTS D ISCUSSED IN S ECTIONS VANDVIIV.E XPERIMENTSThe performance of the MI registration criterion was eval-uated for rigid-body registration of MR,CT,and PET images of the brain of the same patient.The rigid-body assumption is well satisﬁed inside the skull in 3-D scans of the head if patient related changes (due to for instance interscanning operations)can be neglected,provided that scanner calibration problems and problems of geometric distortions have been minimized by careful calibration and scan parameter selection,respectively.Registration accuracy is evaluated in Section V by comparison with external marker-based registration results and other retrospective registration methods,while the robust-ness of the method is evaluated in Section VI with respect to implementation issues,such as sampling,interpolation and op-timization,and image content,including image degradations,such as noise,intensity inhomogeneities and distortion,and partial image overlap.Four different datasets are used in the experiments described below (Table II).Dataset A 1contains high-resolution MR and CT images,while dataset B was obtained by smoothing and subsampling the images of dataset A to simulate lower resolution data.Dataset C 2contains stereotactically acquired MR,CT,and PET images,which have been edited to remove stereotactic markers.Dataset D contains an MR image only and is used to illustrate the effect of various image degradations on the registration criterion.All images consist of axial slices and in all casestheaxis is directedhorizontally front to back,andthedirection.In all experiments,the joint histogram size is256axis (0.7direction due to an offset inthedirection for the solution obtainedusing PV interpolation due to a 1rotation parameter.For MR to PET as well as for PET to MR registration,PV interpolation yields the smallest differences with the stereotactic reference solution,especially inthedirection due to offsets inthe192IEEE TRANSACTIONS ON MEDICAL IMAGING,VOL.16,NO.2,APRIL 1997TABLE IIIR EFERENCE AND MI R EGISTRATION P ARAMETERS FOR D ATASETS A,B,AND C AND THE M EAN AND M AXIMAL A BSOLUTE D IFFERENCE E V ALUATED AT E IGHT P OINTS N EAR THE B RAIN SURFACEvolume as the ﬂoating image and using different interpolation methods.For each combination,various optimization strate-gies were tried by changing the order in which the parameters were optimized,each starting from the same initial position with all parameters set to zero.The results are summarized in Fig.5.These scatter plots compare each of the solutions found (represented by their registrationparameterson the horizontal axis (using mm and degreesfor the translation and rotation parameters,respectively)and by the difference in the value of the MI criterion(MI)on the vertical axis.Although the differences are small for each of the interpolation methods used,MR to CT registration seems to be somewhat more robust than CT to MR registration.More importantly,the solutions obtained using PV interpolation are much more clustered than those obtained using NN or TRI interpolation,indicating that the use of PV interpolation results in a much smoother behavior of the registration criterion.This is also apparent from traces in registration space computed around the optimal solution for NN,TRI,and PV interpolation (Fig.6).These traces look very similar when a large parameter range is considered,but in the neighborhood of the registration solution,traces obtained with NN and TRI interpolation are noisy and show manylocal maxima,while traces obtained with PV interpolation are almost quadratic around the optimum.Remark that the MI values obtained using TRI interpolation are larger than those obtained using NN or PV interpolation,which can be interpreted according to (2):The TRI averaging and noise reduction of the reference image intensities resulted in a larger reduction of the complexity of the joint histogram than the corresponding reduction in the complexity of the reference image histogram itself.B.SubsamplingThe computational complexity of the MI criterion is pro-portional to the number of samples that is taken from the ﬂoating image to compute the joint histogram.Subsampling of the ﬂoating image can be applied to increase speed perfor-mance,as long as this does not deteriorate the optimization behavior.This was investigated for dataset A by registration of the subsampled MR image with the original CT image using PV interpolation.Subsampling was performed by takingsamples on a regular grid at sample intervalsofand direction,respectively,using NNinterpolation.No averaging or smoothing of the MR image before subsampling was applied.Weused,and .The same optimization strategy was used in each case.RegistrationsolutionsandMAES et al.:MULTIMODALITY IMAGE REGISTRATION BY MAXIMIZATION OF MUTUAL INFORMATION193(a)(b)Fig.5.Evaluation of the MI registration robustness for dataset A.Horizontal axis:norm of the difference vector j 0 3j for different optimization strategies,using NN,TRI,and PV interpolation. 3corresponds to the registration solution with the best value for the registration criterion for each of the interpolation schemes applied.Vertical axis:difference in the registration criterion between each solution and the optimal one.(a)Using the CT image as the ﬂoating image.(b)Using the MR image as the ﬂoatingimage.(a)(b)(c)(d)Fig.6.MI traces around the optimal registration position for dataset A:Rotation around the x axis in the range from 0180to +180 (a)and from 00.5to +0.5 (bottom row),using NN (b),TRI (c),and PV (d)interpolation.intheand 0.2mm off from the solutionfound without subsampling.C.Partial OverlapClinically acquired images typically only partially overlap,as CT scanning is often conﬁned to a speciﬁc region to minimize the radiation dose while MR protocols frequently image larger volumes.The inﬂuence of partial overlap on the registration robustness was evaluated for dataset A for CT to MR registration using PV interpolation.The images were initially aligned as in the experiment in Section V and the same optimization strategy was applied,but only part of the CT data was considered when computing the MI criterion.More speciﬁcally,three 50-slice slabs were selected at the bottom (the skull basis),the middle,and the top part of the dataset.The results are summarized in Table IV and compared with the solution found using the full dataset by the mean and194IEEE TRANSACTIONS ON MEDICAL IMAGING,VOL.16,NO.2,APRIL 1997TABLE IVI NFLUENCEOFP ARTIAL O VERLAPONTHE R EGISTRATION R OBUSTNESSFORCTTOMR R EGISTRATIONOFD ATASETAFig.7.Effect of subsampling the MR ﬂoating image of dataset A on the registration solution.Horizontal axis:subsampling factor f ,indicating that only one out of f voxels was considered when evaluating the MI criterion.Vertical axis:norm of the difference vector j 0 3j . 3corresponds to the registration solution obtained when no subsampling is applied.maximal absolute difference evaluated over the full image at the same eight points as in Section V.The largest parameter differences occur for rotation aroundthedirection,resulting in maximal coordinate differencesup to 1.5CT voxel inthe direction,but on average all differences are subvoxel with respect to the CT voxel sizes.D.Image DegradationVarious MR image degradation effects,such as noise,in-tensity inhomogeneity,and geometric distortion,alter the intensity distribution of the image which may affect the MI registration criterion.This was evaluated for the MR image of dataset D by comparing MI registration traces obtained for the original image and itself with similar traces obtained for the original image and its degraded version (Fig.8).Such traces computed for translation inthewas alteredinto(15)(a)(b)(c)(d)Fig.8.(a)Slice 15of the original MR image of dataset D,(b)zero mean noise added with variance of 500grey-value units,(c)quadratic inhomogeneity (k =0:004),and (d)geometric distortion (k =0:00075).with being the image coordinates of the point around which the inhomogeneity is centeredand.All traces for all param-eters reach their maximum at the same position and the MI criterion is not affected by the presence of the inhomogeneity.3)Geometric Distortion:Geometricdistortions(16)(17)(18)withthe image coordinates of the center of each image planeandtranslation parameter proportionalto the averagedistortionMAES et al.:MULTIMODALITY IMAGE REGISTRATION BY MAXIMIZATION OF MUTUAL INFORMATION195(a)(b)(c)(d)Fig.9.MI traces using PV interpolation for translation in the x direction of the original MR image of dataset D over its degraded version in the range from 010to +10mm:(a)original,(b)noise,(c)intensity inhomogeneity,and (d)geometric distortion.VII.D ISCUSSIONThe MI registration criterion presented in this paper assumes that the statistical dependence between corresponding voxel intensities is maximal if both images are geometrically aligned.Because no assumptions are made regarding the nature of this dependence,the MI criterion is highly data independent and allows for robust and completely automatic registration of multimodality images in various applications with min-imal tuning and without any prior segmentation or other preprocessing steps.The results of Section V demonstrate that subvoxel registration differences with respect to the stereo-tactic registration solution can be obtained for CT/MR and PET/MR matching without using any prior knowledge about the grey-value content of both images and the correspondence between them.Additional experiments on nine other datasets similar to dataset C within the Retrospective Registration Evaluation Project by Fitzpatrick et al .[10]have veriﬁed these results [29],[14].Moreover,Section VI-C demonstrated the robustness of the method with respect to partial over-lap,while it was shown in Section VI-D that large image degradations,such as noise and intensity inhomogeneities,have no signiﬁcant inﬂuence on the MI registration crite-rion.Estimations of the image intensity distributions were ob-tained by simple normalization of the joint histogram.In all experiments discussed in this paper,the joint histogram was computed from the entire overlapping part of both images,using the original image data and a ﬁxed number of bins of256andand .For low-resolutionimages,the optimization often did not converge to the global optimum if a different parameter order was speciﬁed,due to the occurrence of local optima especially forthe196IEEE TRANSACTIONS ON MEDICAL IMAGING,VOL.16,NO.2,APRIL1997theand40mm,but we have not extensivelyinvestigated the robustness of the method with respect to theinitial positioning of the images,for instance by using multiplerandomised starting estimates.The choice of theﬂoating imagemay also inﬂuence the behavior of the registration criterion.In the experiment of Section VI-A,MR to CT matching wasfound to be more robust than CT to MR matching.However,it is not clear whether this was caused by sampling andinterpolation issues or by the fact that the MR image is morecomplex than the CT image and that the spatial correlation ofimage intensity values is higher in the CT image than in theMR image.We have not tuned the design of the search strategy towardspeciﬁc applications.For instance,the number of criterionevaluations required may be decreased by taking the limitedimage resolution into account when determining convergence.Moreover,the results of Section VI-B demonstrate that forhigh-resolution images subsampling of theﬂoating imagecan be applied without deteriorating optimization robustness.Important speed-ups can,thus,be realized by using a mul-tiresolution optimization strategy,starting with a coarselysampled image for efﬁciency and increasing the resolution asthe optimization proceeds for accuracy[20].Furthermore,thesmooth behavior of the MI criterion,especially when usingPV interpolation,may be exploited by using gradient-basedoptimization methods,as explicit formulas for the derivativesof the MI function with respect to the registration parameterscan be obtained[27].All the experiments discussed in this paper were for rigid-body registration of CT,MR,and PET images of the brainof the same patient.However,it is clear that the MI criterioncan equally well be applied to other applications,using moregeneral geometric transformations.We have used the samemethod successfully for patient-to-patient matching of MRbrain images for correlation of functional MR data and forthe registration of CT images of a hardware phantom to itsgeometrical description to assess the accuracy of spiral CTimaging[14].MI measures statistical dependence by comparing the com-plexity of the joint distribution with that of the marginals.Bothmarginal distributions are taken into account explicitly,whichis an important difference with the measures proposed by Hillet al.[13](third-order moment of the joint histogram)andCollignon et al.[6](entropy of the joint histogram),whichfocus on the joint histogram only.In Appendexes A and B wediscuss the relationship of these criteria and of the measureof Woods et al.[30](variance of intensity ratios)to the MIcriterion.MI is only one of a family of measures of statisticaldependence or information redundancy(see Appendix C).We have experimentedwith,the entropy correlation coefﬁcient[1].In some cases these measures performed better thanthe original MI criterion,but we could not establish a clearpreference for either of these.Furthermore,the use of MIfor multimodality image registration is not restricted to theoriginal image intensities only:other derived features such asedges or ridges can be used as well.Selection of appropriatefeatures is an area for further research.VIII.C ONCLUSIONThe MI registration criterion presented in this paper allowsfor subvoxel accurate,highly robust,and completely automaticregistration of multimodality medical images.Because themethod is largely data independent and requires no userinteraction or preprocessing,the method is well suited to beused in clinical practice.Further research is needed to better understand the inﬂuenceof implementation issues,such as sampling and interpolation,on the registration criterion.Furthermore,the performance ofthe registration method on clinical data can be improved bytuning the optimization method to speciﬁc applications,whilealternative search strategies,including multiresolution andgradient-based methods,have to be investigated.Finally,otherregistration criteria can be derived from the one presented here,using alternative information measures applied on differentfeatures.A PPENDIX AWe show the relationship between the multimodality reg-istration criterion devised by Hill et al.[12]and the jointentropy th-order moment of thescatter-plot[22]with the following properties.1)andand with。

蒙特利尔认知评估量表(MoCA)

蒙特利尔认知评估量表Montreal Cognitive Assessment (MoCA)使用与评分指导手册损害蒙特利尔认知评估（MoCA）是一个用来对轻度认知功能异常进行快速筛查的评定工具。

它评定了许多不同的认知领域，包括：注意与集中、执行功能、记忆、语言、视空间技能、抽象思维、计算和定向力。

完成MoCA检查大约需要10分钟。

本量表总分30分，英文原版的测试结果提示划界分≥26分。

1：交替连线测验指导语：“我们有时会用‘123……’或者汉语的‘甲乙丙……’来表示顺序。

请您按照从数字到汉字并逐渐升高的顺序画一条连线。

从这里开始[指向数字（1）]，从１连向甲，再连向２，并一直连下去，到这里结束[指向汉字（戊）]”。

评分：当患者完全按照“１-甲-２-乙-３-丙-４-丁-５-戊”的顺序进行连线且没有任何交叉线时给１分。

当患者出现任何错误而没有立刻自我纠正时，给０分。

2：视空间技能（立方体）指导语（检查者指着立方体）：“请您照着这幅图在下面的空白处再画一遍，并尽可能精确”。

评分：完全符合下列标准时，给１分：●图形为三维结构●所有的线都存在●无多余的线●相对的边基本平行，长度基本一致（长方体或棱柱体也算正确）上述标准中，只要违反其中任何一条，即为0分。

3：视空间技能（钟表）指导语：“请您在此处画一个钟表，填上所有的数字并指示出11点10分”。

评分：符合下列三个标准时，分别给１分：●轮廓（１分）：表面必须是个圆，允许有轻微的缺陷（如，圆没有闭合）●数字（１分）：所有的数字必须完整且无多余的数字；数字顺序必须正确且在所属的象限内；可以是罗马数字；数字可以放在圆圈之外。

●指针（１分）：必须有两个指针且一起指向正确的时间；时针必须明显短于分针；指针的中心交点必须在表内且接近于钟表的中心。

上述各项目的标准中，如果违反其中任何一条，则该项目不给分。

4：命名指导语：自左向右指着图片问患者：“请您告诉我这个动物的名字”。

急诊PCI的若干问题

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哺乳动物基因组功能注释项目

哺乳动物基因组功能注释项目The mammalian genome functional annotation project is a crucial endeavor in the field of genetics and genomics. It aims to decipher the functions and roles of genes withinthe genomes of various mammalian species. By understanding the functions of genes, scientists can gain insights into the underlying mechanisms of biological processes, diseases, and evolutionary relationships among species. This project requires a multidisciplinary approach, combining experimental techniques, computational analysis, and collaborative efforts from researchers worldwide.One perspective to consider is the importance of functional annotation in unraveling the mysteries of human biology. Humans share a significant portion of theirgenetic makeup with other mammals, making functional annotation of mammalian genomes highly relevant to understanding our own biology. By studying the genomes of other mammals, we can identify conserved genes andregulatory elements that play critical roles in humandevelopment, physiology, and disease. This knowledge can lead to the discovery of novel therapeutic targets and the development of personalized medicine approaches.Another perspective to explore is the impact of functional annotation on veterinary medicine and animal conservation. Many mammalian species are endangered or face various health challenges. Understanding the genetic basis of these conditions through functional annotation can aidin the development of diagnostic tools, treatments, and conservation strategies. By uncovering the unique genetic features of different mammalian species, researchers can also gain insights into their evolutionary history and relationships, contributing to our understanding of biodiversity and the conservation of endangered species.The functional annotation of mammalian genomes also has implications for agriculture and livestock breeding. By identifying genes responsible for desirable traits, such as disease resistance, milk production, or meat quality, researchers can develop targeted breeding programs to improve animal health and productivity. This can lead tomore sustainable and efficient agricultural practices, benefiting both farmers and consumers. Additionally, functional annotation can shed light on the genetic basisof diseases that affect livestock, enabling the development of preventive measures and treatments to improve animal welfare.From a technical perspective, the functional annotation of mammalian genomes involves multiple steps and techniques. It begins with the sequencing and assembly of the genome, followed by the identification and annotation of protein-coding genes, non-coding RNAs, and regulatory elements. Various experimental and computational methods are employed to assign functions to these elements, such as transcriptomics, proteomics, epigenomics, and comparative genomics. The integration of data from different sources is crucial for accurate functional annotation, requiring sophisticated bioinformatics tools and databases.Lastly, it is important to highlight the collaborative nature of the mammalian genome functional annotation project. Given the complexity and vastness of mammaliangenomes, no single research group or institution can accomplish this task alone. International collaborations and data sharing initiatives are essential for the success of this project. By pooling resources, expertise, and data, researchers can collectively tackle the challenges associated with functional annotation and accelerate scientific discoveries. Open access to annotated genomes and associated data also promotes transparency and facilitates further research and innovation in the field.In conclusion, the functional annotation of mammalian genomes is a vital project with far-reaching implications. It contributes to our understanding of human biology, aids in veterinary medicine and animal conservation, improves agricultural practices, and requires collaboration and advanced techniques. By unraveling the functions of genes, we gain insights into the intricate mechanisms of life and lay the foundation for future advancements in medicine, agriculture, and conservation.。

阿尔茨海默症英语介绍ppt模板

Dr. Alzheimer noticed changes in the brain tissue of a woman who had died of an unusual mental illness.
He found abnormal clumps. Scientists also have found other brain changes in people with AD.
Memories of Tomorrow
The Notebook
Thank you
Degradation of memory and cognition
➢ "the effects of Alzheimer's disease on the right parietal lobe of the brain are particularly severe, which directly affects the ability of the brain to visualize and develop the ability to draw pictures of the brain."said Dr. Bruce Miller, a neurologist.
Alzheimer’s Disease
阿尔茨海默症
Ronald Wilson Reagan 罗纳德·威尔逊·里根
第40任（第49-50届）美国总统 president “I know I'm on my way to the twilight. I know there's always a bright dawn ahead of the United states. Thank you, my friends. May God bless you forever.”

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emma 共聚物核磁氢谱 -回复

emma 共聚物核磁氢谱-回复Emma是一款广泛应用于医药、化工和材料科学领域的共聚物。

它的结构和性能决定了它在这些领域的重要性。

在研究和应用中，核磁氢谱是一种常用的分析工具，可以为我们提供关于Emma共聚物的丰富信息。

本文将详细介绍Emma共聚物和核磁氢谱的基本原理，以及如何进行该分析。

Emma共聚物是由具有不同化学结构的单体组合而成的高分子材料。

这种合成方式可以使Emma共聚物具有多种不同的性质和用途。

而核磁氢谱则是一种通过测量共聚物中氢（H）原子的核磁共振现象得到的谱图。

通过分析核磁氢谱，我们可以了解Emma共聚物中氢原子的位置、数量和环境，从而推断共聚物结构和性质。

那么，核磁氢谱是如何工作的呢？首先，我们需要了解核磁共振现象。

核磁共振是一种原子核在外加磁场作用下发生共振的现象。

在Emma共聚物中，氢原子是最常见的核磁共振原子，它们拥有一个自旋量子数为1/2的核自旋。

当Emma共聚物样品被置于强磁场中时，氢原子围绕磁场轴线旋转，产生一种称为拉莫尔进动的旋转运动。

接下来，我们需要应用一种称为射频脉冲的短暂高能辐射，用于扰动核磁共振系统。

射频脉冲的频率与氢原子跳跃能级之间的能量差相匹配，从而能够引起核磁共振。

核磁氢谱是通过记录射频脉冲后观察氢原子的信号产生的。

这些信号通过一种称为自由感应衰减（FID）的过程产生。

在FID过程中，当射频脉冲停止时，氢原子会重新排列自己的自旋，产生一个电流，该电流被称为自由感应信号。

这个信号可以在一个称为接收线圈的装置中检测到，并通过数学方法转换为所谓的谱图。

谱图是一个反映不同氢原子频率和强度的图像，可以提供关于共聚物结构和性质的重要信息。

在进行核磁氢谱分析之前，我们需要准备Emma共聚物的样品。

样品的制备通常包括将Emma共聚物溶解在一种能够与氢原子相互作用的溶剂中，通常是氘代溶剂。

氘代溶剂的使用是为了避免与样品中的氢原子产生相互作用，从而干扰核磁氢谱的分析。

一旦样品准备好，我们就可以将其放入核磁共振仪中进行分析。