射频消融术后胆管损伤的病理学研究

目的观察射频消融(radiofrequency ablation,RFA)犬肝内大胆管旁的病理学改变。方法健康成年杂种犬20只,随机分4组。RFA射频针统一张开20mm,射频治疗时,能量由小到大序贯使用,开始能量为5W,以后每1min升高5W,最高可达95W的情况下,距肝内大胆管旁不同距离(1.0~2.9mm、3.0~4.9mm、5.0~7.9mm、8.0~10.0mm)行RFA,术后观察相关胆管的病理学改变。结果在肝内大胆管旁行RFA,当距离为1.0~2.9mm时,整个胆管壁全层均坏死或部分全层坏死;距离为3.0~4.9mm时,部分胆管壁全层坏死和胆管上皮细胞空泡样改变;当距离为5.0~10.0mm时,胆管上皮细胞胆管空泡样改变或正常。结论RFA位于肝内大胆管旁时,距离≥5.0mm时胆管上皮细胞改变损伤是轻微的、可逆的,而距离<5.0mm时胆管损伤是较严重的、不可逆的。     

射频消融术后胆管损伤的病理学研究

目的 观察射频消融（radiofrequency ablation，RFA）犬肝内大胆管旁的病理学改变。方法 健康成年杂种犬20只，随机分4组。RFA射频针统一张开20mm，射频治疗时，能量由小到大序贯使用，开始能量为5W，以后每1min升高5W，最高可达95W的情况下，距肝内大胆管旁不同距离（1．0～2．9mm、3．0～4．9mm、5．0～7．9mm、8．0～10．0mm）行RFA，术后观察相关胆管的病理学改变。结果 在肝内大胆管旁行RFA，当距离为1．0～2．9mm时，整个胆管壁全层均坏死或部分全层坏死；距离为3．0～4．9mm时，部分胆管壁全层坏死和胆管上皮细胞空泡样改变；当距离为5．0～10．0mm时，胆管上皮细胞胆管空泡样改变或正常。结论 RFA位于肝内大胆管旁时，距离≥5．0mm时胆管上皮细胞改变损伤是轻微的、可逆的，而距离〈5．0mm时胆管损伤是较严重的、不可逆的。     

肝门部血流对胆管腔内射频消融的影响

目的 观察活体时肝门部胆管腔内射频消融能否形成凝固区,探讨肝门部血流对凝固区大小的影响.方法 从6头健康家猪选取14个肝门部胆管靶点,分为非肝门阻断组和肝门阻断组,每组7个胆管靶点.将单极电极针13 mm裸露部分置入胆管腔内,输出功率5W,消融时间4min.病理检查胆管和邻近肝组织改变.结果 两组剖面均可见半椭圆形灰白色凝固区,凝固区周围有明显的暗红色环状带.光镜下凝固区胆管黏膜层和黏膜下层变性、坏死;肝组织变性;暗红色环状带为肝组织出血.非肝门阻断组和肝门阻断组凝固区平均长轴直径分别为(13.29±1.38)mm、(13.29±1.11)mm,差异无统计学意义(t=0.000,P>0.05);凝固区平均短轴直径分别为(3.14±1.07)mm、(4.57±0.98)mm,差异有统计学意义(t=2.611,P<0.05).结论 活体时肝门部胆管腔内射频消融可形成典型的射频消融区.肝门部血流影响凝固区短轴直径,不影响凝固区长轴直径.     

胆道内冷盐水灌注预防兔肝射频消融术中胆道急性热损伤的研究

目的探讨活体兔肝于射频消融(RFA)术中行胆道内冷盐水灌注冷却(ICSP)对胆道免受热损伤的保护作用。方法取健康雄性新西兰大白兔16只随机分为2组,每组8只。实验组于RFA术前开腹行胆总管置管,并于RFA术中经胆总管置管行ICSP;对照组于RFA术前开腹,但未行胆总管置管及ICSP。RFA术中射频针针尖定位于距肝门部主胆管约5 mm。RFA术后行超声造影(CEUS)测量消融灶大小,并于RFA术后6 h取兔肝脏大体标本对消融灶旁主胆管行组织病理学检查。分析比较两组间RFA消融灶大小及主胆管损伤程度的差异。结果实验组与对照组间RFA消融灶大小差异无统计学意义;对照组RFA术后主胆管损伤程度比实验组严重(P<0.05)。结论于RFA术中行ICSP对胆管可以起到较好的保护作用。     

肝门部胆管腔内射频消融相关并发症活体实验观察

目的：观察肝门部胆管腔内射频消融后与射频消融相关的并发症及消融区病理组织学转归。方法：将14条健康狗分为2组，每组7条。在全身麻醉下通过剖腹手术刊哿13mm长单极电极针裸露部分置入胆管腔内进行射频消融。第1组输出功率10W，消融时间4min；第2组输出功率5w，消融时间8min。每组于消融后3d各处死2条狗，9d各处死1条狗，14d各处死4条狗。观察与射频消融相关的并发症。光学显微。结果：1条狗发生门静脉、肝静脉和下腔静脉皿栓。1条狗发生胆管结石。所，没有发生射频消融所致胆汁漏。射频消融3d时，凝固区内胆管黏膜层和黏膜下层以及肝组织明显坏死。射频消鼬9d时，凝固区内胆管黏膜层和黏膜下层以及肝组织有炎细胞浸润和部分纤维化。射频消融14d时，凝固区内胆管壁和肝组织明显纤维化。结论：肝门部胆管腔内射频消融后与射频消融相关并发症极少发生。消融区内胆管黏膜层和黏膜下层以及肝组织坏死、炎症细胞浸润并逐渐纤维化。     

区域胆管、肝动脉、门静脉联合阻断治疗肝内胆管良性疾病的初步应用

目的探讨区域胆管和供应血管联合阻断在难治性肝内胆管疾病治疗中的价值。方法2007年3月～2010年5月对17例右肝内胆管结石、7例肝内型先天性胆管囊肿开展区域胆管和供应血管阻断治疗。对肝内胆管结石行肝内胆管切开取石、胆管注入封闭胶和区域胆管、肝动脉、门静脉阻断;对肝内型胆管囊肿经肝门分离病变胆管开口注入封闭胶后行区域动脉、门静脉、胆管阻断。所有患者术后3d、1周、2周复查肝功能,术后2周、1月、6月、1年行肝脏B超或CT随访。结果所有病例无肝衰、大出血、胆漏、严重感染等严重围手术期并发症;术后2周行肝脏B超或CT检查示病灶明显缩小或消失;术后1月和6月复查肝脏CT示病灶完全消失,病灶所在肝脏萎缩消失,残余肝脏代偿增生。结论通过病变区域胆管、肝动脉、门静脉联合阻断治疗某些难治性区域性良性肝内胆管疾病,可以达到较彻底的治疗效果,且能有效降低对患者的创伤,减少围手术期严重并发症的发生,明显提高该类患者的手术安全性。     

肝内胆管变异在肝移植胆道重建中的处理

目的 探讨肝移植胆道重建时肝内胆管变异的处理.方法 总结2005年1月～2006年9月肝移植工作中遇到的7例肝内胆管变异病例胆道重建的经验、教训.结果 7例供肝均是术后经T管胆道造影时发现有不同类型的肝内胆管变异.病例1由于术中遗漏了右前肝管,术后出现严重胆汁漏,开腹行外引流,二期胆肠吻合;病例2右肝管汇入胆囊管,T管上臂影响右肝管排空,介入技术处理;病例3、7术中及时发现肝管遗漏,及时纠正才避免胆汁漏的发生;病例4～6虽有胆管变异,但无相关并发症的发生.所有病例术后3个月顺利拔除T管.结论 熟悉肝内胆管解剖变异的类型,术中仔细分辨肝门组织结构,及时发现肝内胆管变异,正确处理可避免由于肝内胆管变异造成的技术相关性胆道并发症.     

肝胆管结石合并胆管癌的临床特点及防治

目的 探讨肝内胆管结石合并肝内胆管癌的临床特点及其防治.方法 对1990-2009年肝内胆管结石伴肝内胆管癌84例的临床资料进行回顾性研究.结果 肝内胆管结石合并肝内胆管癌的发生率占同期肝内胆管结石病例的4.6%(84/1840),术前明确诊断47例;肿瘤均发生于含结石的胆管处,以左肝多见;病程1～40年,平均18年.20例迟发性肝内胆管癌发生于取石后6-16年,平均9年.临床表现为久治不愈的肝脓肿、难以控制的肝内感染、肝内阻塞性进行性黄疸和影像学提示结石部位的肿瘤性改变.84例中晚期病例65例(65/84,77.4%).行根治性切除者仅35例,姑息性切除26例,射频消融4例,单纯活检19例.结论 (1)肝内胆管结石并发肝内胆管癌的概率较高.(2)对所有肝内占位性病变行术前、术中活检是避免误漏诊的重要方法.(3)早期诊断者行根治性切除可获得良好疗效.(4)对肝内结石伴胆管狭窄、肝段萎缩纤维化者行病灶肝段切除对继发胆管癌有预防作用.     

术中置胃胆管、胆总管一期缝合在胆总管探查术中的应用

目的建立胆总管探查术后胃胆管引流、胆总管一期缝合的动物模型(简称胃胆管引流术),探讨胃胆管引流术的可行性和临床价值.方法将30只犬随机分为3组:对照组(仅行腹腔探查,n=5),胆总管一期缝合组(简称一期缝合组,n=10),胃胆管引流、胆总管一期缝合组(简称胃胆管组,n=15).观察术后肝功能的变化、胆漏等并发症,评估胃胆管引流术的安全性.结果对照组术后无一血清总胆红素(TBil)升高.一期缝合组术后3只犬血清TBil显著升高,4只犬血清TBil轻度升高;胃胆管组术后无一血清TBil显著升高,后两者差异有统计学意义(P＜0.01).胃胆管组平均拔管时间(7.0±1.7)d,无一发生胆漏、腹腔感染及切口感染、裂开;一期缝合组术后5只犬胆漏,其中3只犬发生胆汁性腹膜炎,两者差异有统计学意义(P＜0.05).结论胃胆管引流术安全可行,胆道引流时间短、避免了胆总管一期缝合术后胆漏等并发症,具有其独特的临床应用价值.     

肝内胆管囊腺瘤17例诊治分析

目的 探讨肝内胆管囊腺瘤的诊断和治疗。 方法 回顾性分析2003年1月至2009年12月中国医科大学附属盛京医院收治的17例肝内胆管囊腺瘤病人的临床资料。 结果 主要临床表现为上腹部不适或疼痛。2例曾误诊为肝囊肿行开窗引流术。6例病人CA19-9升高,1例甲胎蛋白（AFP）轻度升高,癌胚抗原（CEA）水平均正常。7例术前影像学检查确诊。均行根治性肝切除手术。病理结果显示肝内胆管囊腺瘤14例,胆管囊腺瘤恶变3例。术后随访8~60个月无复发。 结论 肝内胆管囊腺瘤术前难以确诊,易恶变,根治性肝切除手术疗效满意。     

Vasopressor hormone response following mesenteric traction during major abdominal surgery

Background : We investigated the vasopressor hormone response following mesenteric traction (MT) with hypotension due to prostacyclin (PGI₂) release in patients undergoing abdominal surgery with a combined general and epidural anesthesia. Methods : In a prospective, randomized, placebo-controlled study we administered 400 mg ibuprofen (i.v.) in 42 patients scheduled for abdominal surgery. General anesthesia was combined with epidural anesthesia (T4-L1). Before as well as 5, 15, 30, 45, and 90 min after MT we recorded plasma osmolality, hemodynamics and measured 6-keto-PGFlα (stabile metabolite of PGI₂), TXB₂ (stabile metabolite of thromboxane A₂) active renin, and arginine vasopressin (AVP) plasma concentrations by radioimmunoassay. Catecholamine levels were assessed by high-pressure liquid chromatography (HPLC) with electrochemical detection. Results : Following MT, arterial hypotension occurred along with a substantial PGI₂ release. This was completely abolished by ibuprofen administration. Although plasma levels of 6-keto-PGF_1α (1133 (708) vs. 60 (3) ng/L, median (median absolute deviation), P=0.0001, placebo vs. ibuprofen) remained significantly elevated, blood pressure was restored within 30 min after MT in the placebo group. At the same point in time plasma concentrations of TXB² (164 (87) vs. 58 (1) ng/L, P=0.0001), epinephrine (46 (33) vs. 14 (6) ng/L, P=0.001), AVP (41 ± (18) vs. 12 (7) ng/L, P=0.0004), and active renin (27 (12) vs. 12 (4) ng/L, P = 0.001) were significantly higher in placebo-treated patients. Conclusion : Under combined general and epidural anesthesia arterial hypotension following MT due to endogenous PGI₂ release is associated with enhanced release of AVP, active renin, epinephrine and thromboxane A₂, presumably contributing to hemodynamic stability within 30 min after MT.     

A Teaspoon Pump for Pumping Blood with High Hydraulic Efficiency and Low Hemolysis Potential

Abstract: Virtually all blood pumps contain some kind of rubbing, sliding, closely moving machinery surfaces that are exposed to the blood being pumped. These valves, internal bearings, magnetic bearing position sensors, and shaft seals cause most of the problems with blood pumps. The original teaspoon pump design prevented the rubbing, sliding machinery surfaces from contacting the blood. However, the hydraulic efficiency was low because the blood was able to "slip around" the rotating impeller so that the blood itself never rotated fast enough to develop adequate pressure. An improved teaspoon blood pump has been designed and tested and has shown acceptable hydraulic performance and low hemolysis potential. The new pump uses a nonrotating "swinging" hose as the pump impeller. The fluid enters the pump through the center of the swinging hose; therefore, there can be no fluid slip between the revolving blood and the revolving impeller. The new pump uses an impeller that is comparable to a flexible garden hose. If the free end of the hose were swung around in a circle like half of a jump rope, the fluid inside the hose would rotate and develop pressure even though the hose impeller itself did not "rotate"; therefore, no rotating shaft seal or internal bearings are required.     

Microspheres Based Detoxification System: A New Method in Convective Blood Purification

Abstract: A variety of protein-bound or hydrophobic substances, accumulating as a result of pathologic conditions such as exogenous or endogenous intoxications, are removed poorly by conventional detoxification methods because of low accessibility (hemodialysis), insufficient adsorption capabilities (hemosorption), low efficiency (peritoneal dialysis), or economic limitations (high-volume plasmapheresis). Combining advantages of existing methods with microspheric technology, a module-based system was designed. Major operating parameters of the latter can be modified to allow for adjustment to individual clinical situations. An extracorporeal blood circuit including a plasmafilter is combined with a secondary high-velocity plasma circuit driven by a centrifugal pump. Different microspheric adsorbers can be combined in one circuit or applied in sequence. Thus, a prolonged treatment can be tailored using specially designed selective adsorber materials. Comparing this system with existing methods (high-flux hemodialysis, molecular adsorbent recycling system), results from our in vitro studies and animal experiments demonstrate the superior efficiency of substance removal.     

Tissue perfusion in relation to cardiac output during continuous positive-pressure ventilation and administration of propranolol or verapamil

Background : Our objective was to determine whether administration of propranolol or verapamil modifies the hemodynamic adaptation to continuous positive-pressure ventilation (CPPV), in particular the regional distribution of cardiac output (CO).
Methods : General hemodynamics and regional blood flows assessed by microsphere technique (15 (μm) were recorded in 16 anesthetized pigs during spontaneous breathing (SB) and CPPV with 8 cm H₂O end-expiratory pressure (CPPV8) before and after intravenous administration of propranolol (0.3 mg · kg⁻¹ followed by 0.15 mg · kg⁻¹ · h⁻¹, n=8) or verapamil (0.1 mg · kg⁻¹ followed by 0.3 mg · kg⁻¹ · h⁻¹, n=8).
Results : CPPV8 depressed CO by 25% without shifts in its relative distribution with the exception of a noteworthy increase in adrenal perfusion. Propranolol increased arterial blood pressure, and due to a fall in heart rate, CO dropped by 25%. The kidneys and, to a lesser extent, the splanchic region and central nervous system received increased fractions of the remaining CO at the expense of skeletal muscle flow. Similar patterns were seen during SB and CPPV8 such that the combination of propranolol and CPPV8 depressed CO by 50%. The circulatory effects of verapamil were less evident but myocardial perfusion tended to increase.
Conclusions : The combination of propranolol or verapamil with CPPV does not result in any specific hemodynamic interaction in anesthetized pigs, except that the combined effect of propranolol and CPPV may severely reduce CO.     

Bariatric Surgery in Some "Central and East-European (former Eastern bloc)"Countries - Current Status and Prediction for the Next Millennium

Background: Obesity is increasing globallly, including in the formerly "Eastern Bloc" countries. Methods: A survey was made of obesity and bariatric surgery. Results: In the 8 East and Central European countries studied, with total population 300 million, roughly 43% of the population was overweight (BMI 25-30), 23% obese (BMI > 30), with about 15 million people morbidly obese (BMI > 40). From 0-10 morbidly obese individuals/100,000/year undergo bariatric surgery. Conclusion: Most countries were found to provide inadequate treatment for obesity.The majority of the morbidly obese are not treated effectively. However, health-care awareness of obesity and bariatric surgeons are slowly increasing.     

Volatile anaesthetics reduce adhesion of blood platelets under low-flow conditions in the coronary system of isolated guinea pig hearts

Background : Inhibitory effects of volatile anaesthetics on platelet aggregation have been demonstrated in several studies. However, the influence of volatile anaesthetics on intracoronary platelet adhesion has not been elucidated so far.
Methods : Isolated hearts of guinea pigs were perfused with buffer in the absence or presence of volatile anaesthetics (0.5 and 1 MAC) at constant coronary flow rates of 5 ml/min for 25 min, then 1 ml/min for 30 min and again 5 ml/min for 10 min. Before, during and after low-flow perfusion, a bolus of human platelets was applied into the coronary system. To simulate thrombogenic conditions, 0.3 U/ml human thrombin was infused during low-flow perfusion and reperfusion. The number of platelets sequestered to the endothelium was calculated from the difference between coronary in- and output of platelets. The myocardial production of lactate and consumption of pyruvate and coronary perfusion pressure were also determined.
Results : At a flow rate of 5 ml/min only about 3% of the applied platelets did not emerge from the coronary system, in any group. In contrast, 13.1±1.2% (mean±SEM) of infused platelets became adherent in low-flow perfusion in the control group without anaesthetic. The adherence was reduced with each 1 MAC isoflurane (to 6.2±1.2%), sevoflurane (to 4.4±0.9%) or halothane (to 3.2±1.5%) (each P <0.05 vs. control). Volatile anaesthetic, 0.5 MAC, did not inhibit platelet adhesion to a statistically significant extent in any case. Perfusion pressure and metabolic parameters were not statistically different between the control and the hearts exposed to anaesthetics.
Conclusion : Volatile anaesthetics in a concentration of 1 MAC can reduce the adhesion of platelets in the coronary system under reduced flow conditions. This action does not arise from vasodilation or inhibition of ischaemic stress.     

Synergistic interaction between the effects of propofol and midazolam with fentanyl on phrenic nerve activity in rabbits

Background: It has been shown that the depressive effects of both propofol and midazolam on consciousness are synergistic with opioids, but the nature of their interactions on other physiological systems, e. g. respiration, has not been fully investigated. The present study examined the effect of propofol and midazolam alone and in combination with fentanyl on phrenic nerve activity (PNA) and whether such interactions are additive or synergistic. Methods: PNA was recorded in 27 anaesthetised and artificially ventilated rabbits. In three groups, propofol, fentanyl and midazolam were administered intravenously in incremental doses to construct dose-response curves for the depressant effects of each one on PNA. In another two groups, the effect of pretreatment with either fentanyl 1 μg · kg^?1 i. v. or midazolam 0.05 mg · kg^?1 i. v. on the effects of propofol and fentanyl respectively on PNA were studied. Results: Propofol and fentanyl caused a dose-dependent depression of PNA with complete abolition at the highest total doses of 16 mg · kg^?1 i. v. and 32 μg · kg^?1 i. v., respectively. In contrast, midazolam in incremental doses to a total of 0.8 mg · kg^?1 reduced mean PNA by 63%, but approximately 12% of PNA remained at a total dose as high as 6.4 mg · kg^?1. The mean ED₅₀s, calculated from dose-response curves, were 5.4 mg · kg^?1, 3.9 μg · kg^?1 and 0.4 mg · kg^?1 for propofol, fentanyl and midazolam, respectively. Initial doses of either fentanyl 1 μg · kg^?1 i. v. or midazolam 0.05 mg · kg^?1 i. v. acted synergistically with subsequent doses of either propofol or fentanyl to abolish PNA at total doses of 8 mg · kg^?1 and 8 μg · kg^?1, respectively. Conclusion: Fentanyl has a synergistic interaction with both propofol and midazolam on PNA and hence potentially on respiration.     

Influence of dopexamine hydrochloride on haemodynamics and regulators of circulation in patients undergoing major abdominal surgery

Background: Catecholaminergic support is often used to improve haemodynamics in patients undergoing major abdominal surgery. Dopexamine is a synthetic vasoactive catecholamine with beneficial microcirculatory properties. Methods: The influence of perioperative administration of dopexamine on cardiorespiratory data and important regulators of macro- and microcirculation were studied in 30 patients undergoing Whipple pancreaticduodenectomy. The patients received randomized and blinded either 2 μg · kg^?1 · min^?1 of dopexamine (n=15) or placebo (n=15, control group). The infusion was started after induction of anaesthesia and continued until the morning of the first postoperative day. Endothelin-1 (ET-1), vasopressin, atrial natriuretic peptide (ANP), and catecholamine plasma levels were measured from arterial blood samples. Measurements were carried out after induction of anaesthesia, 2 h after onset of surgery, at the end of surgery, 2 h after surgery, and on the morning of the first postoperative day. Results: Cardiac index (CI) increased significantly in the dopexamine group (from 2.61±0.41 to 4.57±0.78 1 · min^?1 · m^?2) and remained elevated until the morning of the first postoperative day. Oxygen delivery index (DO₂I) and oxygen consumption index (VO₂I) were also significantly increased in the dopexamine group (DO₂I: from 416±91 to 717±110 ml/m² · m²; VO₂I: from 98±25 to 157±22 ml/m² · m²), being significantly higher than in the control group. pHi remained stable only in the dopexamine patients, indicating adequate splanchnic perfusion. Vasopressive regulators of circulation increased significantly only in the untreated control patients (vasopressin: from 4.37±1.1 to 35.9±12.1 pg/ml; ET-1: from 2.88±0.91 to 6.91±1.20 pg/ml). Conclusion: Patients undergoing major abdominal surgery may profit from prophylactic perioperative administration of dopexamine hydrochloride in the form of improved haemodynamics and oxygenation as well as beneficial influence on important regulators of organ blood flow.     

Systemic analgesia adapted to the children's condition

A concept of balanced analgesia using nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol (acetaminophen), opioids, and corticosteroids can also be used in patients with pre-existing illnesses. NSAIDs are the most effective treatment for acute pain of moderate intensity in children; however, these drugs should be avoided in patients at increased risk for serious side effects, e.g. patients with renal impairment, bleeding tendency, or extreme prematurity. NSAIDs can be given with minimal risks to the younger child with mild to moderate asthma, and, in these patients, the use of steroids can be encouraged; in addition to their antiemetic and analgesic action, a beneficial effect on asthma symptoms can be expected. In the non-intubated child with cerebral trauma, exaggerated sedation caused by opioids and increased bleeding tendency caused by NSAIDs must be avoided. In neonates and small infants, the oral administration of sucrose or glucose is helpful to minimize pain reaction during short uncomfortable interventions.     

A comparison of the inhibitory effects of four volatile anaesthetics on the metabolism of chlorzoxazone, a substrate for CYP2E1, in rabbits

Background: Halothane inhibits in vitro and in vivo activity of cytochrome P-450 (CYP) 2E1. There are several fluorinated volatile anaesthetics besides halothane, and most of them are defluorinated by CYP2E1. It is unclear whether other fluorinated anaesthetics inhibit the in vivo activity of CYP2E1.
Methods: We compared the inhibitory effects of therapeutic concentrations of four inhalational anaesthetics, halothane, enflurane, isoflurane, and sevoflurane, on chlorzoxazone metabolism in rabbits receiving artificial ventilation.
Results: All four inhalational anaesthetics decreased arterial blood pressure and increased plasma chlorzoxazone concentration. However, no significant differences in the plasma chlorzoxazone concentration were found between the four anaesthetics. The estimated chlorzoxazone clearance increased after beginning inhalation with all four agents, but no significant difference in clearance was noted between agents.
Conclusions: At therapeutic concentrations, the in vivo inhibitory effect on chlorzoxazone metabolism was similar for all four inhalational anaesthetics examined, even though their chemical characteristics and extent of hepatic metabolism differ considerably.