四氢生物喋呤负荷试验在高苯丙氨酸血症鉴别诊断中的临床应用

目的探讨四氢生物喋呤（BH4）负荷试验在高苯丙氨酸血症（HPA）鉴别诊断中的应用价值。方法自2005年5月到2007年4月，51例HPA患儿采用口服BH4（20mg／kg）负荷试验。对其中血苯丙氨酸（Phe）浓度小于600μmol／L患儿采用口服Phe—BH4联合负荷试验，结合尿喋呤分析、血红细胞二氢喋呤还原酶（DHPR）活性测定。结果（1）在BH4负荷试验中，不同类型HPA患儿的血Phe浓度表现出各不相同的改变。51例HPA患儿中，共鉴别出5例BH4缺乏症，10例BH4反应性苯丙氨酸羟化酶（PAH）缺乏症，36例BH4无反应性苯丙氨酸羟化酶（PAH）缺乏症。（2）在17例中度苯丙酮尿症（PKU）患儿中，9例（52．9％）为BH4反应性PAH缺乏症。结论BH4负荷试验在HPA早期鉴别诊断中十分重要，部分中度PKU对BH4有反应，可使用BH4替代治疗。     

新喋呤与细胞介导免疫

新喋呤(Neopterin)是一种由鸟苷三磷酸(GTP)衍生的低分子化合物。GTP 经其环水解酶作用生成二氢新喋呤三磷酸,再经丙酮酰二氢喋呤综合酶和鸟喋呤还原酶作用生成四氢生物喋呤(BH_4),二氢新喋呤三磷酸是BH_4生物合成途径关键的中间产物,BH_4是苯丙氨酸、酪氨酸和色氨酸羟化酶的辅酶。当综合途径受阻时,此中间产物可不用酶的催化直接转变为新喋呤。如BH_4缺乏可发生血苯丙氨酸过高,因缺乏神经介质使精神严重迟钝。在临床上称为非典型苯丙酮尿,其血和尿中新喋呤浓度增高。     

新疆地区5例苯丙酮尿症的临床分析

苯丙酮尿症 (ｐｈｅｎｙｌｋｅｔｏｎｕｒｉａ ,ＰＫＵ)是引起儿童智能障碍的常见原因之一 ,表现为苯丙氨酸 (Ｐｈｅ)代谢异常 ,除少部分系四氢生物喋呤合成酶或二氢生物喋呤还原酶缺失外 ,绝大部分病例源于苯丙氨酸羟化酶 (ＰＡＨ)异常 ,使得过量的Ｐｈｅ及其中间代谢产物等在血和脑脊液中蓄积 ,抑制功能酶类的活性 ,导致继发性代谢紊乱等 ,严重者甚至危及生命。为大致了解新疆ＰＫＵ的患病情况 ,我们对近几年来在我院和新疆医科大学附属医院发现的ＰＫＵ患者进行了调查和随访 ,现将资料介绍如下。病例资料1 一般资料 :本文调查随访了 5例…     

苯丙酮尿症的研究进展

苯丙酮尿症(phenylketonuria,PKU)绝大部分是由于肝脏苯丙氨酸羟化酶(phenylalaninehydroxylase,PAH)缺乏,少部分(约1-5%)是由于四氢生物喋呤合成酶或二氢生物喋呤还原酶缺陷所致的一种遗传性氨基酸代谢障碍性疾病,呈常染色体隐性遗传。其特征是人体苯丙氨酸代谢异常,导致高苯丙氨酸血症。未经治疗的患者会出现脑组织损伤和不可逆的智力发育障碍,重症者可死亡。随着人们对疾病认识的不断增加和诊断技术日新月异的发展,该病的病因和发病机制已基本明确,目前已可对此病进行诊断、预防,并可通过及时治疗而使患儿能健康成长。 一、PKU的临床表现和分型 患儿出生时正常,至3-4个月时呈智能发育落后,头发逐     

经典型苯丙酮尿症合并21-三体综合征患儿一例临床研究

目的对一例经典型苯丙酮尿症合并21-三体综合征患儿的临床特征进行研究。方法采用BH4负荷试验结合尿喋呤谱和红细胞二氢喋啶还原酶(DHPR)活性测定的方法对高苯丙氨酸血症进行诊断分型;G显带技术分析外周血染色体核型。结果①患儿诊断为经典型苯丙酮尿症。②患儿外周血染色体核型为47,XX,+21,诊断为21-三体综合征。结论苯丙酮尿症可能合并有其他遗传代谢性疾病,临床诊断须全面。     

94例苯丙酮尿症的脑电图分析

本文分析９４例苯丙酮尿症患者的脑电图，结果异常率为６５％，异常表现以痫样放电为主８０％，少数为背景活动异常（２０％）。年龄越大，脑电图异常程度越重，提示早期治疗可防止或减轻脑损害。有抽搐和智力障碍表现或血苯丙氨酸浓度增高者，脑电图异常程度明显。经治疗后血苯丙氨酸浓度下降，脑电图亦明显改善。提示脑电图可以作为评价本病苯丙氨酸对脑的毒性作用的敏感指标。     

1066例高苯丙氨酸血症患者诊断及治疗随访

目的1066例高苯丙氨酸血症（HPA）患者治疗随访。方法自1984年10月到2009年12月,我院共诊治HPA患者1066例。采用高效液相色谱法进行尿喋呤分析,血红细胞二氢喋啶还原酶（DHPR）活性测定及四氢生物喋呤（BH4）负荷试验,进行四氢生物喋呤缺乏症（BH。D）的鉴别;对部分患者进行MRI、1HMRS检查;对不同类型的HPA进行治疗。结果（1）1066例中1016例为苯丙氨酸羟化酶缺乏症（PAHD）,其中51例为BH4反应性PAHD;50例为BH4Dc（2）28例筛查早治的BH4D患儿智商为（96±15）分,晚治疗的11例患儿治疗前为（46±15）分,治疗后为（69±11）分,前后有显著意义（P〈0．05）。DQ／IQ水平与治疗开始时间呈明显的负相关（r=-0．714,P〈0．01）。（3）33例BH4反应性PAHD患儿的智商为（92±18）分。（4）PAHD患者治疗中筛查组智商与非筛查组智商比较,筛查治疗理想组智商与筛查治疗不理想组智商比较,非筛查治疗理想组智商与非筛查治疗不理想组智商比较均有意义（P〈0．001）,47例非新筛并控制理想血Phe浓度PKU患儿智商从治疗前的（60．66±7．78）分,提高到治疗后的（76．62±7．55）分（P〈0．001）。（5）合并癫痫的患儿脑电图的异常率为94．3％,将血苯丙氨酸浓度控制在理想范围,可使脑电图异常有改善。（6）22例大于4个月的患儿血、脑Phe浓度与智商均呈负相关关系r血=-0．5045,r脑=-0．6471（P〈0．01）。结论对所有HPA患者都必须进行BH4D的鉴别诊断,尽早确诊和治疗效果越好。严格控制血苯丙氨酸浓度是减少智能落后的最好措施。     

上海部分地区新生儿苯丙酮尿症筛查14年临床总结

从１９８１年１０月至１９９５年１２月，我室对在上海部分医院出生的６０万新生儿进行了苯丙酮尿症（ＰＫＵ）的筛查，共查出３５个阳性病例，发病率为１／１７１７８（３５／６０１２１８）。３３例确诊为经典型ＰＫＵ，另２例确诊为四氢生物喋呤缺乏症（ＢＨ＿４ｄｅｆｉｃｉｅｎｃｙ）．所有ＰＫＵ患者（除１例外）均在生后３２±１６天开始接受低苯丙氨酸奶方的治疗，取得了显著的疗效．在对本组ＰＫＵ患儿的随访中发现，绝大部分患儿２岁以前的血苯丙氨酸（ｐｈｅｎｙｌａｌａｎｉｎｅ，Ｐｈｅ）浓度控制在较理想的范围内（４－１０ｍｇ／ｄｌ），智商正常；２岁以后其血苯丙氨酸浓度常常超过１０ｍｇ／ｄｌ，智商明显下降。作者对比作了分析并就完善ＰＫＵ筛查阳性病例的临床管理作了初步探讨。     

苯丙氨酸羟化酶缺乏症患儿治疗进展

苯丙氨酸羟化酶缺乏症是由于苯丙氨酸羟化酶基因突变所致的氨基酸代谢病。基因突变导致苯丙氨酸羟化酶活性降低,苯丙氨酸不能正常代谢,在体内蓄积,对大脑神经产生毒性作用,导致智力低下。通过新生儿疾病筛查可使患儿早期确诊。苯丙氨酸羟化酶缺乏症主要是通过低苯丙氨酸饮食治疗,使患者达到或接近正常的智力发育水平。对于四氢生物喋呤(tetrahydrobiopterin,BH_4)反应型的患者,可予以BH_4治疗;除此之外,糖巨肽和大分子中性氨基酸疗法可改善饮食状况。基因疗法和苯丙氨酸解氨酶仍处于临床研究阶段。     

16例新生儿苯丙酮尿症筛查确诊患儿治疗效果初步分析

目的 对新生儿苯丙酮尿症（PKU）筛查确诊患儿的治疗效果进行初步分析。方法 采用化学荧光分析法或细菌抑制法进行足跟血苯丙氨酸（phe）检测，对高苯丙氨酸症者进行尿碟呤谱分析、红细胞二氢碟啶还原酶（DHPR）活性检测，以及phe加BH。联合负荷试验；PKU患儿用饮食疗法，四氢生物碟呤缺乏症（BH4D）用药物治疗。结果 我省PKU发病率为1：18447，BH4D占55％；接受饮食治疗的PKU患儿7例，其智商〉90分5例，占71．4％，智商50—69分2例，占28．6％；接受药物治疗的BH4D患儿9例，其智商≥90分2例，占22．2％、智商70—84分3例，占33．3％、智商50—69分4例，占44．4％。结论 PKU患儿早期诊疗能达到避免严重弱智的目的。     

Renal dysplasia and asplenia in two sibs

A family is reported in which two sibs, one male and the other female, both died within 24 hours of birth with enlarged polycystic kidneys. Postmortem histology in the second child showed gross renal dysplasia. In both children the pancreas was enlarged, nodular and cystic but the liver appeared macroscopically normal. In the second child, histological examination confirmed pancreatic fibrosis with cystic dilation of ducts, but showed portal fibrosis with bile duct proliferation in the liver.
This combination of findings is very reminiscent of those in a girl and her brother reported by Ivemark et al. (1959). The children reported here also showed absence or hypoplasia of the spleen, cardiac anomalies and other features of the Ivemark syndrome (Ivemark 1955), a quite different, usually sporadic, congenital disorder. It is suggested that the children described here have a distinct lethal congenital disorder, probably inherited in an autosomal recessive manner.     

Schizophrenia in a North Swedish geographical isolate, 1900–1977. Epidemiology, genetics and biochemistry

Over 200 schizophrenic patients belonging to three major and interrelated pedigree complexes have been investigated over the past 30 years in a North Swedish geographically isolated population, presently numbering about 6,000. An intensive investigation of a number of biochemical correlates and genetic markers in a few selected families belonging to one of the major pedigrees has indicated new strategies for the current research program.
Schizophrenia, as defined operationally, is significantly associated with decreased activities of two enzymes (1) blood platelet monoamine oxidase, (2) plasma dopamine-β-hydroxylase, and (3) with the genetic marker Gc² (group specific antigen). Both enzymes are subject to genetic variation. A positive score for linkage between schizophrenia and low plasma DBH activity has been calculated, but, so far, available data are insufficient for discrimination between linkage and partial contribution of genetically controlled low plasma DBH to the pathogenesis of the disease. Alternatively, both mechanisms could be involved.
As a model for continued research, schizophrenia is explained as based on a double dominant-recessive genotype (Aabb), representing a vulnerability which in about 50 % of cases develops into clinical schizophrenia. It is suggested that the dominant mutation (A) operates on or affects MAO activity, and that the recessive genotype (bb) is instrumental in low variates of DBH activity and very likely such variates within the normal range of physiological variation. Moreover, it is suggested that the combined effects of MAO- and DBH-reduced efficiency on the metabolism of e.g. dopamine could be an essential pathogenic mechanism for the schizophrenic illness which is segregating in this population.     

The dominant diseases of modernized societies as omega-3 essential fatty acid deficiency syndrome: Substrate beriberi

About 1900, modern food selection and processing caused widespread $\text{epidemics}$ of the B vitamin deficiency diseases of beriberi and pellagra which, for genetic reasons, often expressed as different diseases ranging from bowel and heart disease to dermatoses and psychoses. But the B vitamins merely help convert essential fatty acids (EFA) into the prostaglandin (PG) tissue regulators and it now turns out that, through hydrogenation, milling and selection of w3-poor southern foods, we have also been systematically depleting, by as much as 90%, a newly discovered trace Nordic EFA (w3) of special importance to primates and sole precursor of the PG3(4) series, even as a concurrent fiber deficiency increases body demand for EFA. Since substrate EFA is processed by many B vitamin catalysts, an EFA deficiency will mimic a $\text{panh}$ypovitaminosis B, i.e., a mixture of $\text{substrate}$ beriberi and $\text{substrate}$ pellagra resembling vitamin beriberi and pellagra but exhibiting as even more diverse $\text{endemic}$ disease. This would consitute a second stage of the Modern Malnutrition and explain why some workers now hold the dominant diseases of modermized societies to be new, nutritionally based, pellagraform yet lipid-related and to range, once again, from heart disease to psychosis. It is an assumption that our dominant diseases are unrelated to each other or are merely revealed by our diagnostic acumen and therapeutic success; and that hydrogenating millions of tons of food oils annually, to destroy the rancidity producing w3-EFA, is safe for $\text{primates}$. Extensive beriberiform disease is reported here in 32 typical cases taken from medical practice which responds strikingly to linseed oil supplements (60% w3-EFA) in confirmation of identical results in Capuchins.     

What will studies of Fulani individuals naturally exposed to malaria teach us about protective immunity to malaria?

There are an estimated over 200 million yearly cases of malaria worldwide. Despite concerted international effort to combat the disease, it still causes approximately half a million deaths every year, the majority of which are young children with Plasmodium falciparum infection in sub-Saharan Africa. Successes are largely attributed to malaria prevention strategies, such as insecticide-treated mosquito nets and indoor spraying, as well as improved access to existing treatments. One important hurdle to new approaches for the treatment and prevention of malaria is our limited understanding of the biology of Plasmodium infection and its complex interaction with the immune system of its human host. Therefore, the elimination of malaria in Africa not only relies on existing tools to reduce malaria burden, but also requires fundamental research to develop innovative approaches. Here, we summarize our discoveries from investigations of ethnic groups of West Africa who have different susceptibility to malaria.     

'Very sore nights and days': the child's experience of illness in early modern England, c.1580-1720

Sick children were ubiquitous in early modern England, and yet they have received very little attention from historians. Taking the elusive perspective of the child, this article explores the physical, emotional, and spiritual experience of illness in England between approximately 1580 and 1720. What was it like being ill and suffering pain? How did the young respond emotionally to the anticipation of death? It is argued that children’s experiences were characterised by profound ambivalence: illness could be terrifying and distressing, but also a source of emotional and spiritual fulfilment and joy. This interpretation challenges the common assumption amongst medical historians that the experiences of early modern patients were utterly miserable. It also sheds light on children’s emotional feelings for their parents, a subject often overlooked in the historiography of childhood. The primary sources used in this article include diaries, autobiographies, letters, the biographies of pious children, printed possession cases, doctors’ casebooks, and theological treatises concerning the afterlife.     

Guidelines for the Validation and Use of Immunoassays for Determination of Introduced Proteins in Biotechnology Enhanced Crops and Derived Food Ingredients

Recent advancements in agricultural biotechnology have created a need for analytical techniques to determine introduced proteins in crops enhanced through modern biotechnology techniques. These proteins are expressed in plant tissues and may be present in food ingredients. Immunoassays are ideally suited for protein detection and may be used as both quantitative and threshold methods. Microplate ELISA and lateral flow devices are two of the most commonly used immunoassay formats for agricultural biotechnology applications. This paper provides general background information and a discussion of criteria for the validation and application of immunochemical methods to the analysis of proteins introduced into plants and food ingredients using biotechnology methods. It is the result of a collaborative effort of members of the Analytical Environmental Immunochemical Consortium. This collaborative effort represents the combined expertise of several organizations to reach consensus on establishing guidelines for the validation and use of immunoassays. Further, the paper offers developers and users a consistent approach to adopting the technology as well as aid in producing accurate and meaningful results.     

HLA in North Colombia Chimila Amerindians

HLA-A,-B,-C,-DRB1 and -DQB1 alleles have been studied in Chimila Amerindians from Sabana de San Angel (North Colombian Coast) by using high resolution molecular typing. A frequent extended haplotype was found:HLA-A*24:02-B*51:10-C*15:02-BRB1*04:07-DQB1*03:02 (28.7%) which has also been described in Amerinndian Mayos Mexican population (Mexico, California Gulf, Pacific Ocean). Other haplotypes had already been found in Amerindians from Mexico (Pacific and Atlantic Coast), Peru (highlands and Amazon Basin), Bolivia and North USA. A geographic pattern according to HLA allele or haplotype frequencies is lacking in Amerindians, as already known. Also, five new extended haplotypes were found in Chimila Amerindians. Their HLA-A*24:02 high frequencies characteristic is shared with aboriginal populations of Taiwan; also, HLA-C*01:02 high frequencies are found in New Zealand Maoris, New Caledonians and Kimberly Aborigines from Australia. Finally, this study may show a model of evolutionary factors acting and rising one HLA allele frequency (-A*24:02), but not in others that belong to the same or different HLA loci.     

Ultracryotomy: development and application (with examples from the yeast cytology) (author's transl)

The preparation steps usually necessary for obtaining ultrathin frozen sections of biological material (chemical prefixation, enclosing, cryoprotective treatment, freezing, sectioning, and post-staining the sections for transmission electron microscopy) are submitted to a critical analysis. The application of cryo-ultramicrotomy, in particularly for cytochemical purposes, is reviewed. Fundamental considerations of chemical prefixation and poststaining are supported by examples from yeast cytology. Furthermore, the efficiency of the cryo-ultramicrotomy (electron optical resolution of ultrastructural details) is demonstrated on yeast cells and protoplasts.     

The universal muscular chamber. A basic unit of the genitourinary, cardiovascular, gastro-intestinal, skeletal, cutaneous, respiratory and other systems, endocameral hypertension; and spasm, the key to their idiopathic diseases and arthropathies

Starting with the integument, we see many organs are contractile sacs or multiples thereof, which tubes or bags constitute the major part of the entire body. Recognition of this basic unit and its characteristics sheds new light, individually and collectively, on many disorders previously considered unrelated. Muscular tears and perforations develop in the walls of these chambers, being no way peculiar to those organs, wherein, hydrochloric acid occurs. So, it is not necessary to explain the absence of excessive acid from patients who exhibit holes in the gastric, uterine, aortic, duodenal, rectal, pulmonary, retina, and other walls. Muscle, not acid is the great common factor relating idiopathic disorders in the gastrointestinal tract to each other and to similar diseases in other systems. When the units are linked together, the lesions tend to appear as arthropathies, i.e. at the joints. Rephrasing common-place observations, frees us from conventional, conceptual cul-de-sacs. An observation is only as good as its interpretation, so all possibilities must be considered, otherwise, we will remain blinded by our misconceptions.