新生鼠吸入高氧视网膜血管发育与血管生成素2表达的变化

目的 研究新生鼠吸入高氧致视网膜病过程中血管生成素2(angiopoietin-2,ang-2)表达的变化规律,探讨其与新生鼠视网膜血管发育及新生血管形成之间的关系.方法 随机将80只新生Sprague-Dawiey大鼠(SD大鼠)分为高氧实验组和正常氧对照组,将其40只在生后24 h内置于(75±2)%氧环境中饲养7 d,然后返回室内空气饲养,以建立高氧模型;另40只在空气中饲养作为同龄对照组.两组各自在生后4 d(postnatal day 4 d4)、d 7、d 10、d 14和d 20等不同时间点处死,取左眼球用ADP酶(Adenosine diphosphate)组织化学染色法显示视网膜血管发育状况;取右眼通过常规HE染色以观察视网膜新生血管及计数突破内界膜且与其有联系的内皮细胞核数,定量反映视网膜血管增生情况,免疫组织化学方法标记视网膜ang-2的表达.结果 SD鼠视网膜血管出生后开始发育,d 20基本成熟;新生鼠吸高氧后从d 10开始出现新生血管,于d 14新生血管增生达到高峰;d 14实验鼠突破内界膜血管内皮细胞核数显著高于同龄对照组,分别为30.821与1.107个,P<0.001;d 7实验鼠ang-2表达明显低于同龄对照组及实验组d 10、d 14时间点,其平均光密度值分别为82.106 62±6.302 40与115.448 33±9.373 10、124.425 95±10.572 09、117.685 20±10.578 48,差异均有统计学意义,P<0.001,d 10实验鼠ang-2表达达高峰,高表达持续至d 14.结论 高氧可导致视网膜发育晚期出现大量新生血管,高氧并抑制ang-2的表达;新生血管形成与ang-2表达的变化相一致,提示吸入高氧的新生鼠的ang-2与视网膜新生血管发育关系密切.     

腺病毒介导色素上皮衍生因子基因转移治疗早产儿视网膜病变的实验研究

目的 探讨腺病毒介导的色素上皮衍生因子(ADV-PEDF)对视网膜病变(ROP)早产儿视网膜新生血管形成的抑制作用.方法 7日龄C57BL/6J正常新生鼠60只置氧体积分数为(750±5)mL/L的环境中连续生活5 d,再回到正常空气中建立氧诱导的ROP模型.随机分为实验组和对照组,每组各30只.实验组在鼠龄第12天玻璃体腔内注射1uL ADV-PEDF,对照组注射相同体积腺病毒空载体.在鼠龄第17天处死所有新生鼠.视网膜铺片,ADP酶染色,观察视网膜血管改变;组织切片观察并计数突破视网膜内界膜的血管内皮细胞细胞核数目;Western blotting检测视网膜PEDF的表达.结果 对照组视网膜铺片ADP酶染色可见自视盘发出的视网膜血管较细、迂曲,在视盘周围及中周部深层毛细血管广泛闭锁,有大片无灌注区形成,无灌注区边缘有致密的新生血管团形成.实验组视网膜血管分布规则、未见明显的无灌注区形成,突破内界膜的内皮细胞细胞核数目明显减少(P<0.01);二组组织切片均未见明显视网膜毒性及炎性反应;Western blotting检测到实验组视网膜PEDF的高表达.结论 ADV-PEDF可有效抑制ROP动物模型视网膜新生血管形成,为ROP的基因治疗奠定基础.     

波动氧诱导的新生大鼠视网膜病变模型

目的制备80%至10%的波动氧所致SD新生大鼠视网膜病变的模型。方法新生SD大鼠随机分成两组,模型组(n=12)置于氧箱中,80%至10%的波动氧24 h交替,持续7天后转入空气中饲养5天。对照组(n=12)置于空气中。应用腺苷二磷酸酶染色组织化学法进行视网膜铺片观察视网膜血管改变,眼球切片HE染色观察突破视网膜内界膜的内皮细胞核,免疫组织化学法检测视网膜血管内皮生长因子(VEGF)表达。对两组进行比较,判断波动氧诱导模型的可靠性。结果与对照组相比,模型组新生大鼠视网膜周边血管走形迂曲,神经节细胞排列紊乱,细胞数目减少。模型组视网膜内皮细胞核数目较对照组明显升高,差异有统计学意义[(31.2±6.2)比(1.5±1.0),P<0.01]。模型组VEGF在视网膜神经节层、内核层、外丛状层及色素细胞层均有强表达,对照组仅在神经节细胞层、内核层有较弱表达。结论吸入高幅波动氧可导致新生大鼠视网膜血管增生性病变,血管增生性视网膜组织中VEGF表达明显增强,证实80%至10%的波动氧诱导SD新生大鼠视网膜病变模型可靠。     

携带血管生成素1基因的骨髓间充质干细胞对早产儿视网膜病模型小鼠的干预研究

目的探讨携带血管生成素1(Ang-1)基因的骨髓间充质干细胞(BMSCs)对氧诱导视网膜病模型小鼠视网膜新生血管的作用。方法将出生7天的昆明小鼠随机分成空气对照组和高氧模型组(其中包括注射Ang-1+BMSCs组、单纯BMSCs组及高氧PBS组),每个亚组12只。除空气对照组之外,其余组均放入氧分压65%±5%的氧箱内饲养5天后取出。将携带Ang-1的BMSCs和不携带Ang-1的BMSCs各2 ml(内含细胞总数为1×105)在鼠龄第7、12、17日分别腹腔注入高氧模型组中的Ang-1+BMSCs组和单纯BMSCs组小鼠体内,空气对照组和高氧PBS组注入相同剂量的PBS缓冲液。于鼠龄17天时取小鼠眼球做标本固定,分别用免疫组织化学法检测Ang-1蛋白、qRT-PCR法检测Ang-1蛋白mRNA、计数突破视网膜内界膜的血管内皮细胞数及明胶墨汁灌注眼底视网膜血管,比较小鼠视网膜新生血管情况。结果高氧模型各组每只眼球均可见突出内界膜的新生血管内皮细胞。其中Ang-1+BMSCs组、单纯BMSCs组与高氧PBS组相比较,突破视网膜内界膜的血管内皮细胞核明显减少,差异有统计学意义(P<0.05);与高氧PBS组比较,Ang-1+BMSCs组及单纯BMSCs组血管走形较直,Ang-1蛋白表达量增加,免疫组织化学染色被黄染的胞浆较丰富;Ang-1+BMSCs组与单纯BMSCs组相比,前者血管走行较直,周边新生血管覆盖率降低,突破内界膜新生血管细胞数目减少,Ang-1蛋白的表达量增多。结论高氧能诱导新生鼠视网膜新生血管生成;Ang-1基因与BMSCs结合与单纯应用BMSCs相比,前者能更有效地改善视网膜新生血管的增生状况。     

不同吸氧浓度和时间在新生小鼠视网膜病发病中的作用

目的评价不同吸氧浓度（fraction of inhaled oxygen,FiO2）及吸氧时间在新生小鼠视网膜病中的致病作用。方法选择7日龄（P7）新生C57BL／6J小鼠204只,分为8组：组1～组3（每组均为24只）分别吸30％氧气5、7．9d,组4～组6（每组均为24只）分别吸50％氧气5、7、9d,组7（n=30）吸75％氧气5d,组8（n=30）对照组在空气中生长。采用视网膜铺片法经ADP酶染色,观察吸氧后视网膜血管形态的动态改变;视网膜切片经常规HE染色,计数平均每只小鼠每张切片上突破视网膜内界膜的新生血管内皮细胞核数目,以定量反映视网膜血管的增生情况。结果（1）视网膜铺片结果：①FiO2为30％：吸氧5d或7d后视网膜血管形态全部正常;吸氧9d后深层血管网轻度阻塞,出氧箱2d后迅速恢复正常,至P21发育成熟。②FiO2为50％：吸氧5d后视网膜血管较明显收缩,视网膜中央较大区域无血管灌注,出氧箱2d后出现较多新生血管,但出氧箱5d后血管形态基本恢复正常;随着吸氧时间的延长,视网膜血管异常程度逐渐减轻,恢复更快。③FiO2为75％：吸氧5d后视网膜血管明显收缩,视网膜中央大片区域无血管灌注,出氧箱2d后出现新生血管,P17～P21达到高峰;延长吸氧时间后母、幼鼠死亡率明显上升。（2）视网膜切片结果：仅组7（FiO275％×5d）新生血管内皮细胞核数目达（41．9±2．8）个,与其余各组（均〈1个）差异有显著统计学意义（P〈0．0001）,其余各组间差异均无统计学意义。结论吸氧浓度和持续时间可影响视网膜血管的发育,长时间高浓度吸氧导致不可逆的血管增生性改变,临床上应尽量避免。     

血管内皮生长因子mRNA在高氧诱导新生鼠视网膜异常新生血管化模型中的表达

目的：分析血管内皮生长因子（VEGF）在高氧诱导视网膜异常新生血管化大鼠模型中的表达变化，探讨VEGF在高氧诱导视网膜新生血管化进程中所起的作用。方法：150只SD新生大鼠随机分为氧诱导模型组和正常对照组，各75只。氧诱导模型组大鼠吸入浓度（80±2）% 7 d，随后在正常空气环境。视网膜铺片ADP酶染色了解视网膜血管形态改变；常规苏木精-伊红染色定量反映视网膜血管增生情况，判断建模成功。半定量逆转录 聚合酶链反应（RT-PCR)定量反映视网膜VEGF mRNA转录水平的变化。结果：氧诱导模型组7日龄时视网膜血管明显收缩、阻塞，出现大片无灌注区；14日龄见新生血管形成；苏木精-伊红染色见模型组14日龄大鼠视网膜出现较多新生血管内皮细胞核；RT-PCR结果显示，氧诱导模型组7 d时VEGF mRNA转录水平明显低于对照组，停氧后逐渐增强。VEGF mRNA的表达在新生血管发生前升高，随新生血管退行逐渐下降。结论：未成熟视网膜VEGF mRNA的转录水平与组织氧状态呈密切负性相关关系；停氧后视网膜的相对缺氧导致VEGF mRNA转录上调，促使视网膜血管病理性增生。VEGF的异常表达在ROP的新生血管化进程中起重要作用。［中国当代儿科杂志，2007，9（4）：371-374］     

不同吸氧方式对新生鼠视网膜血管发育的影响

目的：吸氧是早产儿视网膜病的高危因素之一,目前吸入氧浓度、吸氧方式等与早产儿视网膜病的关系仍有争议。该实验通过研究不同吸氧方式对新生鼠视网膜血管发育的影响,为早产儿临床合理用氧提供实验依据。方法：选择7日龄C57BL/6 J新生小鼠144只,随机分为6组,每组24只。实验组1:吸入氧浓度(F iO2)由30%逐渐升高至75%后突然中断吸氧;实验组2:F iO2由75%逐渐降低直至停氧;实验组3:吸75%高氧5天后骤然停氧;实验组4:吸75%高氧5天后逐渐降低F iO2直至停氧;实验组5:第1天吸75%高氧,第2天吸空气氧,交替进行,连续6 d;对照组:置于同实验条件下的空气中。实验组1,2,3,5和对照组分别于P12(生后第12天),P14,P17视网膜铺片(ADP酶染色法),实验组4于P14,P17,P22视网膜铺片,各组均在P17行视网膜切片(苏木素-伊红染色法)观察视网膜血管的增生和发育情况。结果：①视网膜铺片显示:对照组:P12见少量无灌注区,周边血管结构清晰,P14无灌注区消失,血管形态基本正常,P17血管形态全部正常。实验组1,3,5:P12视网膜中央部有大片无灌注区,血管收缩、闭塞,P14新生血管开始形成,P17大量新生血管形成。实验组4:P14视网膜中央部大片无灌注区,有少量新生血管形成,P17无灌注区缩小,血管走行基本正常,深层血管有阻塞,P22血管发育基本正常。实验组2:铺片显示视网膜血管形态与对照组相似。②视网膜切片显示:实验组1,2,3,4,5小鼠突破视网膜内界膜的新生血管内皮细胞核的数目分别为49.50±1.36,5.17±0.67,47.68±4.70,5.74±2.37,29.15±2.48个,对照组为1.22±0.20个。实验组1,3,5与对照组相比差异均有显著性(P<0.05),实验组2,4与对照组相比差异无显著性(P>0.05)。结论：不同吸氧方式对视网膜血管发育产生不同的影响,吸入氧浓度波动较大、吸入高浓度氧后突然停氧可严重影响新生鼠视网膜血管的发育,产生类似早产儿视网膜病的病变。因此临床上应尽早稳定早产儿的生命体征,减少氧疗,严密监测用氧情况,采取逐渐降低氧浓度的吸氧方式,并尽量避免氧浓度波动过大。     

血管生成素-1在高氧诱导新生鼠支气管肺发育不良的表达及与肺发育的关系

目的探讨血管生成素(Ang-1)在高氧诱导支气管肺发育不良(BDP)新生大鼠中的表达。方法 48只生后2~3日龄的新生大鼠随机分为高氧组和对照组,每组24只,分别置于高氧(氧浓度≥95%)和空气中持续喂养;于高氧暴露第1、3、7天,光镜下观察大鼠肺组织形态结构变化,并采用实时荧光定量PCR和Western blotting方法分别检测大鼠肺组织中Ang-1 mRNA和蛋白表达水平。结果随着高氧暴露时间延长,光镜下高氧组逐渐表现出肺组织发育不良、肺泡结构简单化、肺泡数目减少和肺微血管发育受阻等病理改变。高氧暴露第7天,高氧组的Ang-1 mRNA和蛋白相对表达为0.33±0.18和0.20±0.07,低于对照组的0.83±0.46和0.57±0.44,差异有统计学意义(P均0.05)。结论 Ang-1是肺血管发育过程中的重要调节因子,参与了BPD病理发生。     

高压氧治疗缺氧缺血性脑损伤新生大鼠的不良反应

目的 探讨高压氧治疗对HIBD新生大鼠视网膜血管和肺组织的不良反应.方法 将出生7日的SD新生大鼠162只随机分为6组:正常对照组(n=22),HIBD组(n=20),高体积分数氧组(高氧组,n=32),高压空气组(n=16),高压氧组(n=36),高氧加高压氧组(n=36).高压空气组和高压氧组于HIBD模型制作后2 h分别给予高压空气和高压氧(2个大气压)处理1 h,1次/d,连续7 d.高氧组于HIBD制作后给予900～950 mL/L氧,连续7 d.高氧加高压氧组于HIBD模型制作后进行高氧处理,同时予高压氧治疗,1次/d,连续7 d.21日龄处死动物,TUNEL法检测各组海马CAI区神经细胞凋亡;HE染色观察其眼球和肺组织病变;墨汁染色视网膜铺片观察其血管增生情况;免疫组织化学观察其血管内皮生长因子(VEGF)表达;ELISA法检测其脑组织8-异前列腺素F2α(8-iso-PGF2α)水平.结果 1.HIBD组、高压空气组、高氧组和高氧加高压氧组脑组织海马CA1区凋亡细胞数较正常对照组明显增多(Pa <0.01),高压氧组无明显增加.2.高氧组和高氧加高压氧组视网膜新生血管细胞核计数较正常对照组明显增多(Pa <0.01),高压氧组增加不明显.3.视网膜铺片显示高氧组和高氧加高压氧组视网膜血管明显增生,但HIBD组、高压空气组、高压氧组无明显血管增生现象.4.高氧组和高氧加高压氧组视网膜VEGF较正常对照组明显表达(Pa <0.01).5.肺组织HE染色观察到HIBD组、高压空气组和高压氧组结构均与正常对照组相似;高氧组和高氧加高压氧组肺泡样结构明显遭破坏,后者程度稍轻.6.脑组织8-iso-PGF2α水平在HIBD组、高压空气组和高压氧组均较正常对照组增加(Pa <0.01);高氧组和高氧加高压氧组均较高压氧组显著增高(Pa <0.01).结论 高压氧治疗对HIBD新生大鼠脑损伤有保护作用;高氧有刺激新生大鼠视网膜血管增生和肺组织损伤作用,而高压氧则无眼和肺的不良反应;高氧可加重HIBD后脑组织脂质过氧化物的产生,而高压氧无此作用.     

银杏叶提取物对氧诱导视网膜病新生鼠视网膜血管形态和密度的影响

目的探讨银杏叶提取物(金纳多)对氧诱导早产儿视网膜病变(ROP)新生鼠视网膜血管形态和密度的影响。方法将48只SD新生鼠随机分为对照组、模型组、治疗组各16只,模型组与治疗组建立波动氧诱导的新生鼠ROP模型,治疗组于造模第7天开始予以金纳多50mg/(kg·d)腹腔注射7天。各组分别于第14天和第19天随机抽取8只新生鼠,一侧眼球采用视网膜铺片ADP酶染色,观察视网膜血管形态改变,另一侧眼球行组织切片HE染色,观察并计数突破视网膜内界膜的血管内皮细胞核数目。结果视网膜铺片ADP酶染色显示,第14天和第19天时,模型组较对照组血管主干变细、形态异常,而治疗组血管形态和密度较模型组明显好转。HE染色显示模型组第14天和第19天视网膜各层细胞排列紊乱;第19天突破内界膜的细胞核数对照组、模型组、治疗组分别为(5.0±2.1)、(34.6±5.3)、(12.6±3.4),模型组高于对照组和治疗组,差异均有统计学意义(P<0.001)。结论高幅度氧浓度波动可成功构建ROP动物模型。金纳多在氧诱导视网膜病变新生鼠模型中对视网膜发挥保护作用。     

Resurgence of measles in Singapore: profile of hospital cases

OBJECTIVE: To ascertain the profile of cases of measles seen at a general hospital during a recent outbreak that occurred despite a measles vaccination program. METHODOLOGY: A retrospective study from January 1991 to March 1998. All patients with measles (ICD code 055. 9) seen at the emergency unit or as inpatients were included. RESULTS: There were 87 cases identified. The diagnosis was clinical in all and proven serologically in 71%. Eighty-five per cent of the cases occurred between January 1997 and March 1998. There was a bi-modal age distribution with peaks in the very young (相似文献   

Allergic factors associated with the development of asthma and the influence of cetirizine in a double-blind, randomised, placebo-controlled trial: First results of ETA®

There is a common progression known as the allergic march from atopic dermatitis to allergic asthma. Cetirizine has several antiallergic properties that suggest a potential effect on the development of airway inflammation and asthma in infants with atopic dermatitis. Methods. Over a two year period, 817 infants aged one to two years who suffered from atopic dermatitis and with a history of atopic disease in a parent or sibling were included in the ETAC^® (Early Treatment of the Atopic Child) trial, a multi-country, double-blind, randomised, placebo-controlled trial. The infants were treated for 18 months with either cetirizine (0.25mg/ kg b.i.d.) or placebo. The number of infants who developed asthma was compared between the two groups. Clinical and biological assessments including analysis of total and specific IgE antibodies were performed. Results. In the placebo group, the relative risk (RR) for developing asthma was elevated in patients with a raised level of total IgE (≥ 30 kU/I) or specific IgE (≥ 0.35 kUA/I) for grass pollen, house dust mite or cat dander (RR between 1.4 and 1.7). Compared to placebo, cetirizine significantly reduced the incidence of asthma for patients sensitised to grass pollen (RR = 0.5) or to house dust mite (RR = 0.6). However, in the population that included all infants with normal and elevated total or specific IgE (intention-to-treat - ITT), there was no difference between the numbers of infants developing asthma while receiving cetirizine or placebo. The adverse events profile was similar in the two treatment groups. Discussion. Raised total IgE level and raised specific IgE levels to grass pollen, house dust mite or cat dander were predictive of subsequent asthma. Cetirizine halved the number of patients developing asthma in the subgroups sensitised to grass pollen or house dust mite (i.e. 20% of the study population). In view of the proven safety of the drug, we propose this treatment as a primary pharmacological intervention strategy to prevent the development of asthma in specifically sensitised infants with atopic dermatitis.     

A profile of respiratory symptoms in urban and rural South Australian school children

This report describes the cross-sectional analyses of data from the first year of a longitudinal study using questionnaire and respiratory function data over a 5 year period from a sample of rural South Australian school children. The cumulative or lifetime prevalences of respiratory symptoms were estimated in 825 rural and 1261 urban school children aged between 5 and 15 years in order to determine if the prevalence rates differed between rural and urban school children. The study found the overall cumulative prevalence of asthma and/or wheezy breathing (AWB) to be 24.1% in the rural school children compared to 27.6% in the urban school children. Most children developed AWB symptoms before the age of 7 years, with 20% reporting moderately severe symptoms and 10% having more than one attack per fortnight. The cumulative prevalence of bronchitis, loose/rattly cough (BLRC) differed significantly between the rural school children (34.1%) and urban school children (47.9%). The BLRC symptoms preceded the development of AWB in many cases. Urban school children also reported a higher prevalence of atopic conditions.     

Hauttemperaturen verschiedener Körperoberflächenareale des Rumpfes bei Säuglingen

Summary In two groups of infants (3–53 weeks old) skin temperatures were controlled in different areas of the trunk—i.e.: regions of sternum, lungs, heart, liver, spleen, kidneys—at different room-temperatures (group I: 21–25°C; group II: 29–32°C). Rectal temperatures of some probands in both groups also had been controlled simultaneously. A definite change in the reaction to heat was proofed in different periods of the first year of life. In higher environmental temperatures the skin temperature was almost constant at every controll-point of the skin, even in older infants. In lower environmental temperatures the skin temperatures lowered continuously with age till 7. to 9. moth. From 10. to 12. month the lowering of skin temperature discontinued. The rectal temperatures were relatively constant in all infants. Only in infants from 7. to 12. month, whose skin temperatures were controlled in lower as well as in higher environmental temperatures, a tendency to higher rectal temperatures was proofed in warmer environmental temperatures.The significance of these results is discussed.

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Untersuchungen mit Unterstützung durch die Deutsche Forschungsgemeinschaft.     

Psychopathologie du syndrome d’Asperger et « aspérigisation » de la société contemporaine

The author has attempted here to point out, just for a start, the characteristics of Asperger syndrome from the point of view of psychopathology through a rereading of Hans Asperger's original paper (1944). This thesis merits reevaluation, if for no other reason than to fill the gaps in operational diagnostics based on the DSM. It is found by rereading that Asperger's view of the principal disturbances of autistic psychopathy include a “disturbance of natural evidence” or a “crisis of common sense”. This question of natural evidence that he evokes with regard to autistic psychopathy corresponds to W. Blankenburg's natural evidence, which constitutes a key concept for comprehending schizophrenia in the form poor-symptom (“symptomarme Schizophrenie”) that he observes in the speech of his patient Anne Rau. One can deduce from this that in terms of fundamental disturbances, Asperger syndrome and this “symptom-poor” schizophrenia overlap at the level of loss of natural evidence. It is moreover possible to classify Asperger syndrome among the disturbances of spacing in the sense meant by the evolutionary psychiatry of A. Stevens and J. Price. The author then develops our comprehension of Asperger syndrome from the point of view of the perspective proposed by the notion of resilience in people with Asperger syndrome and of the possibility for them, through these mechanisms of adaptation, to find in the organization of the personality of the “as if” type a position of relative equilibrium. They concur or overlap in the creation of crutches, of borrowed personalities secondarily legitimated by the reaction of the socius. This will end up in the production of inventions and œuvres (works). Clearly, one rarely encounters several cases that one could consider pertinently to be “successful” Asperger syndrome. Finally, the author notes that one can find a sort of isomorphism between Asperger syndrome and contemporary society when he proposes the term “asperigisation” to characterize our society, given that the equilibrium between emotion and logic is strongly disturbed in these patients, in whom logic undergoes hypertrophy while emotion is impoverished. From this perspective, the author hopes to suggest reasons for the increase in the number of cases of Asperger syndrome in the clinical setting and in society in general in our contemporary era.     

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孤独症谱系障碍(autistic-spectrum disorders,ASDs)近年来患病率逐年攀升至1%左右,其症状往往伴随终生,成为严重威胁儿童健康和发展的神经发育性疾患;注意缺陷多动障碍(attention deficit hyperactivity disorder,ADHD)是儿童期最常见的精神障碍,国内报道患病率为4.13%～5.83%,其症状可延续至青少年期,甚至到成年期[1]。这两类精神障碍在成年期的临床表现、共患病、治疗策略和预后与儿童期有哪些不同呢?本文通过回顾相     

Infiltrations of Epstein-Barr virus-carrying cells in granular lymphocyte-proliferative disorders corresponding to chronic active Epstein-Barr virus infection

A 21-year-old man with granular lymphocyte-proliferative disorders (GLPD) associated with chronic active Epstein-Barr virus (EBV) infection is described. Chromosomal analyses revealed several clonal abnormalities and two of them were mainly repetitious. High copy numbers of monoclonal EBV genome were also detected in the proliferative large granular lymphocytes (LGLs), indicating the monoclonal expansion of EBV-infected LGLs. The patient had an indolent course for several years, and there was no evidence of infiltrations of his bone marrow until the end stage. At autopsy, microscopic studies revealed marked infiltrations of LGL in the liver and spleen, and the infiltrating cells were NK-cell immunophenotype. The infiltrated LGLs showed latency I.     

LUTEINIZING HORMONE RECEPTOR MUTATIONS IN DISORDERS OF SEXUAL DEVELOPMENT AND CANCER

Human male sexual development is regulated by chorionic gonadotropin (CG) and luteinizing hormone (LH). Aberrant sexual development caused by both activating and inactivating mutations of the human luteinizing hormone receptor (LHR) have been described. All known activating mutations of the LHR are missense mutations caused by single base substitution. The most common activating mutation is the replacement of Asp-578 by Gly due to the substitution of A by G at nucleotide position 1733. All activating mutations are present in exon 11 which encodes the transmembrane domain of the receptor. Constitutive activity of the LHR causes LH releasing hormone-independent precocious puberty in boys and the autosomal dominant disorder familial male-limited precocious puberty (FMPP). Both germline and somatic activating mutations of the LHR have been found in patients with testicular tumors. Activating mutations have no effect on females. The molecular genetics of the inactivating mutations of the LHR are more variable and include single base substitution, partial gene deletion, and insertion. These mutations are not localized and are present in both the extracellular and transmembrane domain of the receptor. Inactivation of the LHR gives rise to the autosomal recessive disorder Leydig cell hypoplasia (LCH) and male hypogonadism or male pseudohermaphroditism. Severity of the clinical phenotype in LCH patients correlates with the amount of residual activity of the mutated receptor. Females are less affected by inactivating mutation of the LHR. Symptoms caused by homozygous inactivating mutation of the LHR include polycystic ovaries and primary amenorrhea.     

EXCITING NEW TREATMENT APPROACHES FOR PATHYPHYSIOLOGIC MECHANISMS OF SICKLE CELL DISEASE

During the past several decades, our understanding of the complex pathophysiology of vasoocclusion associated with sickle cell disease has improved greatly. Interaction of genes, hemoglobin molecules, red cell membrane and metabolic changes, cell-cell interactions and cell-plasma interactions, red cell adhesion to vascular endothelium, activation of coagulation, and vascular reactivity play a role in vaso occlusion. Penicillin prophylaxis of pneumococcal infections and appropriate use of blood transfusions and other supportive measures improved survival of sickle cell patients. Hydroxyurea made a major impact on sickle cell therapy when it was shown to decrease acute painful episodes, acute chest syndrome, and the need for blood transfusion in adults. Significant experience in the use of hydroxyurea has been accumulated in older children. The benefits and risks of hydroxyurea for younger children and long-term risks in all patients will be evaluated in future investigations. Other promising therapies include butyrate compounds, clotrimazole, magnesium supplementation, poloxamer 188, antiadhesion agents, anticoagulant approaches, and nitric oxide. Hemopoietic transplantation remains the only curative therapy. However, several transgenic mouse models are available for studies of gene therapy or other treatment approaches on biochemical, cellular, and pathologic effects of mutant genes.