New advances in the pathophysiologic and radiologic basis of the exstrophy spectrum

The exstrophy–epispadias complex is a rare spectrum of anomalies affecting the genitourinary system, anterior abdominal wall, and pelvis. Recent advances in the repair of classic bladder exstrophy (CBE) and cloacal exstrophy (CE) have resulted in significant changes in outcomes of surgical management (including higher continence rate, fewer surgical complications, and better cosmesis) and health-related quality of life in these patients. These noteworthy changes resulted from advances in the pathophysiological and genetic backgrounds of this disease and better radiologic assessment of the three-dimensional anatomy of the bony pelvis and its musculature. A PubMed search was performed with the keyword exstrophy. The resulting literature pertaining to genetics, stem cells, imaging, tissue engineering, epidemiology, and endocrinology was reviewed. The following represents an overview of the advances in basic science understanding and imaging of the exstrophy–epispadias spectrum and discusses their possible and future effects on the management of CBE and CE.     

烧伤病人HAD量表测评分析

目的 测定不同烧伤病人的焦虑抑郁程度，以便加强心理护理。方法 采用综合医院焦虑抑郁量表（HAD）对随机抽样的烧伤病人进行测试，并行分组对比，数据用t检验统计。结果 重度烧伤患焦虑抑郁发生率明显高于轻度烧伤；暴露部位（头、面、手部）高于非暴露部位。结论 重视烧伤病人的焦虑抑郁状况，加强心理护理极有必要。     

TRH与HAD单用及合用抗大鼠高原创伤失血性休克的作用

目的:在西藏拉萨进行现场实验,观察促甲状腺素释放激素(TRH)与5%NaCl/2.5%醋酸钠/6%右旋糖酐70(HAD)伍用对高原创伤失血性休克大鼠的治疗作用.方法:初进高原大鼠27只,分乳酸林格氏液对照组(8只),TRH治疗组(7只),HAD治疗组(6只)和TRH与HAD合用组(6只),大鼠右侧股骨粉碎性骨折加放血(维持动脉血压6.0 kPa 1 h)复制创伤失血休克模型,观察TRH(5 mg/kg),HAD(4 ml/kg)和两者合用对创伤失血性休克大鼠血流动力学指标和动物存活时间的影响,以等容量乳酸林格氏液作对照.结果:TRH、HAD单用或合用均能显著提升创伤休克大鼠血压,改善其左室内压(LVSP),左室内压最大变化速率(±dp/dtmax),实测心肌最大收缩速度(Vpm),心肌收缩向量环面积(Lo),明显延长休克动物的存活时间,合用效果稍优于TRH或HAD单用效果.结论:TRH、HAD均具有较好的抗高原创伤失血休克作用,两药可联合用于高原创伤休克的早期救治.     

个体化全方位护理干预对不稳定型心绞痛伴情绪障碍患者的影响

目的：探讨个体化全方位护理干预对不稳定型心绞痛伴情绪障碍患者的影响。方法将200例不稳定型心绞痛伴情绪障碍患者采用随机数字表法分为两组,均给予常规护理,研究组在此基础上给予个体化全方位护理干预。观察3周。采用综合医院焦虑抑郁量表评定患者的焦虑、抑郁程度,采用视觉疼痛模拟量表评定患者的心绞痛程度,比较两组心绞痛、心电图改善总有效率及住院时间。结果干预后两组综合医院焦虑抑郁量表及视觉疼痛模拟量表评分均显著低于干预前(P <0.01),研究组评分均显著低于对照组(P <0.01)。研究组心绞痛、心电图改善总有效率显著高于对照组(P <0.01),平均住院时间显著少于对照组(P <0.01)。结论个体化全方位护理干预可以明显改善不稳定型心绞痛患者的焦虑、抑郁情绪,减轻心绞痛发作程度,缩短住院时间。     

Expression of monocyte markers in HIV-1 infected individuals with or without HIV associated dementia and normal controls in Bangkok Thailand

HIV Associated Dementia (HAD) is a complication of HIV infection in developed countries and is still poorly defined in resource-limited settings. In this study we investigated the expression of the monocyte phenotype CD14CD16HLADR and the inflammatory profiles in monocytes supernatants by surface-enhanced laser desorption/ionization-time of flight (SELDI-TOF) mass spectrometry in a cohort of HAD and non-HAD Thai volunteers prior to the initiation of ARV. The CD14CD16HLADR phenotype was significantly increased in monocytes from HAD and non-HAD versus negative controls, but there was no difference in phenotype and in the secretion protein profiles between the two seropositive groups. In addition, monocytes supernatants from HAD and non-HAD did not induced apoptosis or cell death in brain aggregate culture. In conclusion it appears that HAD in Thai individuals has a different immunological profile then in North America cohorts.     

Correlation between hospital anxiety depression (HAD) scale and other measures of anxiety and depression in geriatric inpatients

Ninety-four patients on geriatric wards were examined as part of a study of prevalence of psychiatric disorders in elderly inpatients. A good correlation was found between depression measured on the HAD and on the Montgomery–Asberg scale. Lower, but still highly significant correlations were found between anxiety measured on the HAD and on the brief anxiety scale (BRAS), between anxiety on the self-rating anxiety scale (SRAS) and the BRAS, and between anxiety on the HAD and the SRAS.     

Consequences of domain insertion on sequence-structure divergence in a superfold

Although the universe of protein structures is vast, these innumerable structures can be categorized into a finite number of folds. New functions commonly evolve by elaboration of existing scaffolds, for example, via domain insertions. Thus, understanding structural diversity of a protein fold evolving via domain insertions is a fundamental challenge. The haloalkanoic dehalogenase superfamily serves as an excellent model system wherein a variable cap domain accessorizes the ubiquitous Rossmann-fold core domain. Here, we determine the impact of the cap-domain insertion on the sequence and structure divergence of the core domain. Through quantitative analysis on a unique dataset of 154 core-domain-only and cap-domain-only structures, basic principles of their evolution have been uncovered. The relationship between sequence and structure divergence of the core domain is shown to be monotonic and independent of the corresponding type of domain insert, reflecting the robustness of the Rossmann fold to mutation. However, core domains with the same cap type share greater similarity at the sequence and structure levels, suggesting interplay between the cap and core domains. Notably, results reveal that the variance in structure maps to α-helices flanking the central β-sheet and not to the domain–domain interface. Collectively, these results hint at intramolecular coevolution where the fold diverges differentially in the context of an accessory domain, a feature that might also apply to other multidomain superfamilies.The universe of protein structures is vast and diverse, yet these innumerable structures can be categorized into a finite number of folds (1). Ideally, the protein fold has a robust yet evolvable architecture to deliver chemistry, bind interaction partners, or provide scaffolding. A popular strategy for the acquisition of new function(s) is the topological alteration of the fold to provide a new evolutionary platform. More frequently, existing and stable scaffolds are elaborated to attain diversity that is due to accumulation of stochastic, independent, and near-neutral mutations in the protein sequence. In a large number of cases, the expansion of functional space has been achieved by the tandem fusion of two or three domains to form evolutionary modules known as supradomains (2). An analysis of catalytic domains fused to the nucleotide-binding Rossmann domain has revealed that the sequential order of their connections is conserved because each pairing arose from a single recombination event (3). Another common structural embellishment is that of domain insertion(s) into existing folds (4)—a strategy that is ubiquitous in all structural classes, i.e., all α, all β, α + β, and α/β (5). For example, members of the A, B, and Y DNA polymerase superfamilies, Rab geranylgeranyl transferase superfamily, and alcohol dehydrogenase superfamily have inserted different domains into the native fold to fine tune their cellular functions (6–8). The analysis of such noncontiguous domain organization has been facilitated by the availability of structures bearing insertions of domains that also occur as independent folds. It has been estimated that 9% of domain combinations observed in protein-structure databases are insertions (5). However, the way in which the sequence–structure relationship changes within a protein fold in the context of such domain insertions has yet to be fully understood. In this study, we assess how the insertion of an accessory domain affects the sequence–structure relationship of the Rossmann fold, a superfold used by at least 10 different protein superfamilies (9).Function-driven changes come with their own costs: most molecular modifications of proteins tend to be thermodynamically destabilizing (10). Although long hypothesized (11), it has been shown only recently that the stability of a fold promotes evolvability by allowing a high degree of structural plasticity (12). As a consequence, protein folds follow a power-law distribution where a few intrinsically stable folds, referred to as superfolds, have numerous members, and a multitude of folds have few members (9). Due to this interplay between stability and evolvability, it has been suggested that superfolds are compatible with a much larger set of sequences than other folds (13). This proposal raises the question of how protein sequence and structural diversity are related to one another. Pioneering work by Chothia and Lesk (14) illustrated that structural similarity is correlated with sequence similarity. Although the 3D structure retains the common fold during neutral drift, it undergoes subtle changes as sequence diverges, mainly due to packing modifications and backbone conformational changes. In a focused study, Halaby et al. (15) have shown that sequence diverges to a greater extent than structure in the Ig fold. More recently, Panchenko and coworkers noted a similar trend in a systematic study spanning 81 homologous protein families (16).We queried how large inserts into a protein fold shape the relationship between sequence and structure divergence, using as a model system, the Haloalkanoate Dehalogenase Superfamily (HADSF), where the inserts into a Rossmann catalytic domain impart substrate specificity. The HADSF is a highly successful family, and, with close to 80,000 members to date (17), it is one of the largest enzyme superfamilies. The HADSF is well-represented in all domains of life, and the majority of its members catalyze phosphate ester hydrolysis (18, 19). HADSF members have attained functional diversity via accessorization of the conserved core Rossmann-fold domain by the insertion of a cap domain. The Rossmann fold is a primordial nucleotide-binding fold that plays a significant role in maintenance and evolution of life (6). Structurally, it is organized as a three-layered sandwich made up of multiple α/β units. The fold is similar across superfamilies, apart from stochastic thermal fluctuations and structural divergence. Notably, the inserted cap domains in the HADSF have not yet been observed as independent folds in extant organisms (the term domain is defined here as an apparently stable arrangement of secondary structural units). The presence of the cap domains leads to a natural classification of the superfamily into different structural classes—C0 (no or minimal cap insert), C1 (α-helical cap insert after the first strand), C2 (α-helical and β-strand cap insert after the third strand, further subdivided into C2a and C2b depending on topology), and C1 + C2 (inserts in both positions), based on topology and location of the insert (20) (SI Appendix, Fig. S1). These characteristics make the HADSF an excellent model system for the study of the sequence–structure–function relationship in multidomain proteins.The unique cap–core architecture of the HADSF raises several intriguing biophysical and biochemical questions regarding molecular evolution. In a typical HADSF member, the substrate leaving group and the phosphoryl group are bound by the cap and core domains, respectively. However, binding and catalysis cannot be independent of one another (reflected in the definition of the specificity constant k_cat/K_m). How this functional codependence between the two domains manifests itself in the structure is an important question with implications for evolution and rational design of multidomain proteins. As cap and core domains form a single polypeptide chain, substrate binding and catalysis are inherently linked although the details of this linkage have yet to be defined. Another perplexing issue is the evolutionary mechanism of cap-domain evolution. Did it involve a rapid stage where the cap domain was grafted onto the core domain, followed by a slow stage where neutral mutations were accumulated? Or was there a gradual and continuous change where a small cap domain was inserted followed by subsequent duplication and elaboration? Herein, we attempt to answer such questions by analyzing a unique dataset of core-domain-only and cap-domain-only structures using quantitative informatics analyses. The relationship between sequence and structure divergence in the core fold is shown to be monotonic, as is generally the case, and notably, to be independent of the corresponding cap type. However, core domains with the same cap type bear a greater similarity at the sequence and structure level than do the core domains with different cap types, suggesting interplay between the cap and core domains. Surprisingly, we find that the variation between cap types maps to the flanking helices of the Rossmann fold rather than to the interface, suggesting that the core has changed more globally to accommodate the cap. Overall, our results suggest that the structure space of a superfamily has an underlying organizing principle despite its diversity.     

先天性巨结肠的病理—X线特征

目的 总结新生儿及婴儿期先天性巨结肠(HD)的X线表现，提高诊断准确率，并尝试与巨结肠类缘病(HAD)作出鉴别．方法 1岁以下先天性巨结肠病例的X线、手术及病理资料，其中详细分析最近100例病人的腹平片与钡灌肠表现．结果 214例病人钡灌肠诊断HD212例，手术结果全部病例均为HD；病理检查结果，HDl92例(89．2％)，先天性结肠神经从发育不良22例(10．3％)．100例HD的钡灌肠表现：均见不同程度痉挛狭窄段，其中45％见“S”征，77％的狭窄段僵直，63％见狭窄段不规则收缩，98％可见移行段；所有病例见不同程度扩张段，其中80％扩张段结肠袋减少或消失，47％扩张段收缩减弱．24小时后复查，94％病人见不同程度钡剂滞留．结论 钡灌肠是诊断先天性巨结肠的一个很好的手段，正确的方法与一些特殊的征象相结合，可以提高诊断的准确性，但与巨结肠类缘病的鉴别仍较困难．     

New promises for manipulation of kynurenine pathway in cancer and neurological diseases

Background: The kynurenine pathway (KP), the primary route of tryptophan degradation in mammalian cells, consists of a cascade of enzymatic reactions eventually leading to NAD⁺ formation. Many metabolites along the route have biological activities, especially in the nervous and immune systems. Objective/methods: This review focuses on three therapeutic areas, tumor immunoediting, schizophrenia, and Huntington's disease, apparently disconnected but linked by preliminary proof-of-concept of KP involvement. The potential embedded in drug discovery programs aimed at the identification of selective inhibitors with optimized pharmacodynamic and pharmacokinetic properties for human studies is discussed. Results/conclusions: Recent advances have shifted the attention on the kynurenine pathway from a scientific curiosity to a clinically relevant collection of targets. A relatively large number of ligands able to interfere with individual enzymes of the pathway have been made available, but none have so far proceeded into advanced clinical studies.