BACKGROUND & AIMS: :Botulism during pregnancy is uncommon and raises concern due uncertainty about fetal impairment. This type of situation has not been reported to date. Treatment is basically symptomatic and based on nursing care. The prognosis is tightly correlated with the maternal status. Dietary hygiene is the basis of prevention. We describe a case of botulism occurring during the second quarter of pregnancy.

背景与目标： : 怀孕期间肉毒中毒并不常见，由于胎儿受损的不确定性，引起了人们的关注。迄今为止尚未报告这种情况。治疗基本以对症为主，以护理为主。预后与孕产妇状况密切相关。饮食卫生是预防的基础。我们描述了在怀孕第二季度发生的肉毒中毒病例。

BACKGROUND & AIMS: The Dlx homeobox gene family is expressed in a complex pattern within the embryonic craniofacial ectoderm and ectomesenchyme. A previous study established that Dlx-2 is essential for development of proximal regions of the murine first and second branchial arches. Here we describe the craniofacial phenotype of mice with mutations in Dlx-1 and Dlx-1 and -2. The skeletal and soft tissue analyses of mice with Dlx-1 and Dlx-1 and -2 mutations provide additional evidence that the Dlx genes regulate proximodistal patterning of the branchial arches. This analysis also elucidates distinct and overlapping roles for Dlx-1 and Dlx-2 in craniofacial development. Furthermore, mice lacking both Dlx-1 and -2 have unique abnormalities, including the absence of maxillary molars. Dlx-1 and -2 are expressed in the proximal and distal first and second arches, yet only the proximal regions are abnormal. The nested expression patterns of Dlx-1, -2, -3, -5, and -6 provide evidence for a model that predicts the region-specific requirements for each gene. Finally, the Dlx-2 and Dlx-1 and -2 mutants have ectopic skull components that resemble bones and cartilages found in phylogenetically more primitive vertebrates.

背景与目标： Dlx同源盒基因家族在胚胎颅面外胚层和外胚间质中以复杂的模式表达。先前的研究表明，Dlx-2对于鼠第一和第二鳃弓近端区域的发育至关重要。在这里，我们描述了具有Dlx-1和-2突变的小鼠的颅面表型。对具有Dlx-1和-2突变的小鼠的骨骼和软组织分析提供了额外的证据，表明Dlx基因调节鳃弓的近端模式。此分析还阐明了Dlx-1和Dlx-2在颅面发育中的独特和重叠作用。此外，缺少Dlx-1和-2的小鼠具有独特的异常，包括缺少上颌磨牙。Dlx-1和-2在近侧和远侧第一和第二拱形中表达，但只有近侧区域是异常的。Dlx-1、-2、-3、-5和-6的嵌套表达模式为预测每个基因的区域特异性需求的模型提供了证据。最后，Dlx-2和Dlx-1和-2突变体具有异位的头骨成分，类似于在系统发育上更原始的脊椎动物中发现的骨骼和软骨。

BACKGROUND & AIMS: In this study, we determined the outcome in cases of isolated nuchal lucency seen sonographically in the first trimester in fetuses without karyotypic abnormalities. We reviewed all cases of isolated localized fetal nuchal lucency (3 mm or greater) in 9 to 14 week fetuses over a 4 year period. Fetuses with additional sonographic abnormalities were excluded. The width of the nuchal lucency at initial sonogram as well as findings on subsequent scans were tabulated. Karyotypic, pathologic, and clinical follow-up data were obtained. Of 44 fetuses with an isolated, localized first trimester nuchal lucency, one was lost to follow-up and two were excluded owing to pregnancy termination without karyotype or pathologic analysis, thus resulting in 41 fetuses in our study group. Five fetuses (12%) had abnormal karyotypes. Twenty-seven of the remaining 36 fetuses had normal karyotypes, eight others showed no evidence of aneuploidy at birth, and one patient underwent spontaneous abortion prior to a karyotypic analysis. Among the 36 fetuses without evidence of aneuploidy, six had a poor outcometwo were spontaneous abortions, one was a therapeutic abortion of a fetus with hydrops and a pericardial effusion seen on fetopsy; one fetus died at birth of pulmonary hypoplasia associated with autosomal recessive polycystic kidney disease, and one fetus each had Noonan syndrome, and Joubert syndrome. In addition, three patients delivered their infants prematurely. Overall, 32 of 41 fetuses survived, and two (6%) were abnormal. Excluding premature infants, 27 were normally grown, term survivors. We conclude that other than having an increased risk for aneuploidy, fetuses with isolated nuchal lucency are also at risk for spontaneous miscarriage, premature delivery, and congenital anomalies unassociated with an abnormal karyotype.

背景与目标： 在这项研究中，我们确定了在没有核型异常的胎儿中，在早期妊娠的超声检查中发现的孤立的nuchal lucency病例的结果。我们回顾了在4年内9至14周胎儿中所有孤立的局部胎儿脐部透明度 (3毫米或更高) 的病例。排除了其他超声检查异常的胎儿。将初始超声检查时的nuchal透明宽度以及随后的扫描结果制成表格。获得了核型，病理和临床随访数据。在44个胎儿中，有孤立的，局部的早期妊娠的胎儿，其中1个失去了随访，2个由于没有核型或病理分析而终止妊娠而被排除在外，因此我们的研究组中有41个胎儿。五个胎儿 (12%) 的核型异常。其余36例胎儿中有27例具有正常的核型，其他8例在出生时没有显示出非整倍性的证据，一名患者在进行核型分析之前进行了自然流产。在没有非整倍性证据的36例胎儿中，有6例结果不佳，其中2例是自然流产，1例是胎儿水肿和心包积液的治疗性流产。一名胎儿死于与常染色体隐性遗传性多囊肾相关的肺发育不全，每名胎儿患有Noonan综合征，和朱伯特综合症。此外，三名患者早产。总体而言，41例胎儿中有32例存活，其中2例 (6% 例) 异常。除早产儿外，27例正常生长，足月幸存者。我们得出的结论是，除了增加非整倍性的风险外，具有孤立的nuchal透明的胎儿也有自发性流产，早产和与核型异常无关的先天性异常的风险。

BACKGROUND & AIMS: OBJECTIVES:Monochorionic (MC) twins are at increased risk of early fetal loss secondary to vascular complications such as twin-twin transfusion syndrome (TTTS). This study compared the early perinatal loss rates between MC and dichorionic (DC) twins in an era of invasive treatment for TTTS. METHODS:This was a retrospective study of all twin pregnancies of known chorionicity from a large regional cohort of nine hospitals over a 10-year period. Ultrasound data were matched to hospital delivery records and to a mandatory national register of pregnancy losses. Prospective risk of pregnancy loss from 14 to 24 weeks' gestation was calculated and the survival trend of MC and DC twins was analyzed using Kaplan-Meier survival analysis. RESULTS:The analysis included 3117 twin pregnancies (605 MC and 2512 DC). The total risk of early pregnancy loss (miscarriage and neonatal death) before 24 weeks was significantly higher in MC twins (60.3 per 1000 fetuses) than in DC twins (6.6 per 1000 fetuses), with a relative risk of 9.18 (95% CI, 6.0-13.9). Survival analysis showed a significant difference in overall and early mortality between MC and DC twins (log-rank test, P < 0.0001), while no difference was noted after 24 weeks' gestation (log-rank test, P = 0.08). CONCLUSIONS:Early pregnancy loss is significantly more common in MC than in DC twins, but no difference in the prospective risk of mortality between MC and DC twins is evident after 24 weeks' gestation. The observed early mortality rate has almost halved in comparison with previous studies in the published literature. Early detection and prompt treatment of complications in MC twins are likely to have contributed to this improvement in outcome.

背景与目标：

BACKGROUND & AIMS: :Fetal growth, birth weight specific mortality rates and effect of sick leave or hospitalization on the fetal growth were investigated in a material of 476 twin pregnancies managed at University Central Hospital of Turku in years 1970-81. Birth weights of twin babies at any gestational age were slightly but not significantly higher than in earlier materials. When compared to growth curve of singleton fetuses, the growth rate of both twins is equal to singletons up to 30th week of pregnancy, being thereafter slower than in singleton pregnancies. Although duration of sick leave and hospitalization increased considerably during the study period, no change in the duration of pregnancy nor in the weight of twin babies occurred. Instead perinatal mortality decreased from 101/per thousand to 36.2/per thousand. Birth weight specific mortality rates did not differ from those in singleton fetuses.

背景与目标： : 在图尔库大学中央医院1970-81年管理的476例双胎妊娠材料中，研究了胎儿生长，出生体重特定死亡率以及病假或住院对胎儿生长的影响。在任何胎龄的双胞胎婴儿的出生体重均略高于但不显着高于早期材料。与单胎胎儿的生长曲线相比，两个双胞胎的生长速度等于怀孕第30周的单胎，此后比单胎妊娠慢。尽管在研究期间病假和住院时间大大增加，但怀孕时间和双胞胎婴儿的体重没有变化。相反，围产期死亡率从101/每千下降到36.2/每千。出生体重特定死亡率与单胎胎儿没有差异。

BACKGROUND & AIMS: :Nut consumption is associated with a reduced risk of type 2 diabetes mellitus (T2DM). The aim of the present study was to assess the effects of adding peanuts (whole or peanut butter) on first (0-240 min)- and second (240-490 min)-meal glucose metabolism and selected gut satiety hormone responses, appetite ratings and food intake in obese women with high T2DM risk. A group of fifteen women participated in a randomised cross-over clinical trial in which 42·5 g of whole peanuts without skins (WP), peanut butter (PB) or no peanuts (control) were added to a 75 g available carbohydrate-matched breakfast meal. Postprandial concentrations (0-490 min) of glucose, insulin, NEFA, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), cholecystokinin (CCK), appetitive sensations and food intake were assessed after breakfast treatments and a standard lunch. Postprandial NEFA incremental AUC (IAUC) (0-240 min) and glucose IAUC (240-490 min) responses were lower for the PB breakfast compared with the control breakfast. Insulin concentrations were higher at 120 and 370 min after the PB consumption than after the control consumption. Desire-to-eat ratings were lower, while PYY, GLP-1 and CCK concentrations were higher after the PB intake compared with the control intake. WP led to similar but non-significant effects. The addition of PB to breakfast moderated postprandial glucose and NEFA concentrations, enhanced gut satiety hormone secretion and reduced the desire to eat. The greater bioaccessibility of the lipid component in PB is probably responsible for the observed incremental post-ingestive responses between the nut forms. Inclusion of PB, and probably WP, to breakfast may help to moderate glucose concentrations and appetite in obese women.

背景与目标： : 食用坚果与降低2型糖尿病 (T2DM) 的风险相关。本研究的目的是评估添加花生 (全或花生酱) 对第一 (0-240分钟) 和第二 (240-490分钟) 膳食葡萄糖代谢和选定的肠道饱腹激素反应的影响，高T2DM风险肥胖女性的食欲等级和食物摄入。一组15名妇女参加了一项随机交叉临床试验，其中将42·5克不含皮 (WP)，花生酱 (PB) 或无花生 (对照) 的全花生添加到75克可用的碳水化合物匹配早餐中。在早餐治疗和标准午餐后，评估餐后葡萄糖，胰岛素，NEFA，胰高血糖素样肽-1 (GLP-1)，肽YY (PYY)，胆囊收缩素 (CCK)，食欲感和食物摄入量的浓度 (0-490分钟)。与对照早餐相比，PB早餐的餐后NEFA增量AUC (IAUC) (0-240分钟) 和葡萄糖IAUC (240-490分钟) 响应较低。PB消耗后120和370分钟的胰岛素浓度高于对照消耗后的胰岛素浓度。与对照摄入量相比，摄入PB后的饮食欲望等级较低，而PYY，GLP-1和CCK浓度较高。WP导致了类似但不显著的影响。早餐中添加PB可降低餐后葡萄糖和NEFA的浓度，增强肠道饱腹激素的分泌并降低进食欲望。PB中脂质成分的更大的生物可及性可能是观察到的坚果形式之间摄入后的增量反应的原因。在早餐中加入PB (可能是WP) 可能有助于减轻肥胖女性的葡萄糖浓度和食欲。

BACKGROUND & AIMS: BACKGROUND:Second-generation antipsychotics are commonly associated with metabolic complications. These medications are being used more frequently for the treatment of mental health disorders in children, which has stimulated the need for creating formal guidelines on monitoring their safety and effectiveness. Previous guidelines have been developed for monitoring metabolic and neurological complications. To assist practitioners who perform these monitoring procedures, a complementary set of treatment recommendations have been created for situations in which abnormal measurements or results are encountered. OBJECTIVE:To create evidence-based recommendations to assist in managing metabolic complications in children being treated with second-generation antipsychotics. METHODS:A systematic review of the literature on metabolic complications of second-generation antipsychotic medications in children was conducted. Members of the consensus group evaluated the information gathered from the systematic review of the literature and used a nominal group process to reach a consensus on treatment recommendations. Wherever possible, references were made to existing guidelines on the evaluation and treatment of metabolic abnormalities in children. RESULTS:Evidence-based recommendations are presented to assist in managing metabolic complications including weight gain; increased waist circumference; elevation in prolactin, cholesterol, triglyceride and glucose levels; abnormal liver function tests and abnormal thyroid studies. CONCLUSION:The use of second-generation antipsychotics requires proper monitoring procedures. The present treatment guideline provides guidance to clinicians on the clinical management of metabolic complications if they occur.

背景与目标：

BACKGROUND & AIMS: :The molecular basis of nonlinear optical (NLO) chiral effects in the amide I region of type I collagen was investigated using sum-frequency generation vibrational spectroscopy; chiral and achiral tensor elements were separated using different input/output beam polarization conditions. Spectra were obtained from native rat tail tendon (RTT) collagen and from cholesteric liquid crystal-like (LC) type I collagen films. Although RTT and LC collagen both possess long-range order, LC collagen lacks the complex hierarchical organization of RTT collagen. Their spectra were compared to assess the role of such organization in NLO chirality. No significant differences were observed between RTT and LC with respect to chiral or achiral spectra. These findings suggest that amide I NLO chiral effects in type I collagen assemblies arise predominantly from the chiral organization of amide chromophores within individual collagen molecules, rather than from supramolecular structures. The study suggests that sum-frequency generation vibrational spectroscopy may be uniquely valuable in exploring fundamental aspects of chiral nonlinearity in complex macromolecular structures.

背景与目标： : 使用和频产生振动光谱研究了I型胶原的酰胺I区域中非线性光学 (NLO) 手性效应的分子基础; 使用不同的输入/输出光束偏振条件分离手性和非手性张量元素。光谱是从天然的大鼠尾腱 (RTT) 胶原蛋白和胆甾型液晶样 (LC) I型胶原蛋白膜获得的。尽管RTT和LC胶原蛋白都具有长程顺序，但LC胶原蛋白缺乏RTT胶原蛋白的复杂层次组织。比较了它们的光谱，以评估这种组织在NLO手性中的作用。在手性或无手性光谱方面，RTT和LC之间未观察到显着差异。这些发现表明，I型胶原蛋白组装体中的酰胺I NLO手性作用主要来自单个胶原蛋白分子中酰胺发色团的手性组织，而不是超分子结构。研究表明，和频产生振动光谱在探索复杂大分子结构中手性非线性的基本方面可能具有独特的价值。

BACKGROUND & AIMS: OBJECTIVES:To estimate the agreement between prenatal ultrasonography observations at 16 - 21 gestational weeks and fetal autopsy findings in pregnancies terminated because of fetal anomalies. STUDY DESIGN:This 4½ year retrospective study includes consecutive fetuses that were terminated because of fetal malformation and/or chromosomal anomaly diagnosed in the second trimester. Only fetuses that had undergone fetal anatomy scanning by an obstetrician trained in fetal ultrasound before the termination and with available fetal autopsy reports were included. The cases were identified through the malformation registry database of our ultrasound unit. The sensitivity and specificity of ultrasound were calculated per organ system. When estimating the agreement between ultrasound results and autopsy findings, the cases were allocated to one of four categories according to the degree of concordance between ultrasound and autopsy findings: full agreement, near match, partial agreement and unconfirmed ultrasound findings. RESULTS:71 of 95 pregnancy terminations due to fetal malformations met the inclusion criteria and constitute our study population. The sensitivity of ultrasonography with regard to malformations in the brain and spine was 100 % (27/27) and with regard to malformations in the internal organ system (including malformations in the urogenital and gastrointestinal systems and in the abdominal wall and diaphragm) was 91 % (30/33). The corresponding figures for malformations in the cardiovascular and skeletal organ systems were 63 % (17/27) and 71 % (25/35), respectively. The specificity was lowest for malformations in the central nervous system and internal organ system (33/38, 87 % and 39/44, 89 %, respectively). There was full agreement between the ultrasound and autopsy findings in 44 % (31/71) of all cases and a near match in 46 % (33/71) of cases. In almost 10 % (7/71) of the pregnancies, the ultrasound findings were only partially confirmed or not confirmed by autopsy. In one case the discrepancy between the ultrasound and autopsy findings suggests that the pregnant woman might have decided to terminate the pregnancy on the basis of incorrect interpretation of ultrasound findings. CONCLUSION:Even though the agreement between ultrasound and autopsy findings was acceptable from a clinical point of view, agreement with regard to the detailed description of malformations was far from perfect. The detection rates were suboptimal for the cardiovascular and skeletal organ systems. :ZIEL:: Bewertung, inwieweit bei Schwangerschaftsabbrüchen aufgrund fetaler Anomalien die Befunde der pränatalen Ultraschalluntersuchung in der 16.–21. SSW mit dem Autopsiebefund des Feten übereinstimmen. METHODEN:Diese 4½ jährige retrospektive Studie schließt fortlaufend Feten ein, bei denen im 2. Trimenon ein Schwangerschaftsabbruch (TOP) aufgrund fetaler Fehlbildungen und/oder aufgrund von diagnostizierten Chromosomenanomalien erfolgt ist. Es wurden nur Feten einbezogen, bei denen vor dem Abbruch eine anatomische Untersuchung durch einen in der Fetalsonografie geübten Geburtshelfer durchgeführt wurde und bei denen fetale Autopsiebefunde vorlagen. Die Fälle wurden durch die Datenbank unserer Sonografieabteilung zur „Registrierung von Fehlbildungen“ ermittelt. Die Sensitivität und Spezifität der Sonografie wurde für jedes Organsystem berechnet. Zur Abschätzung der Übereinstimmung von Ultraschall- und Autopsiebefunden wurden die Fälle einer der vier Kategorien zugewiesen, je nach Grad der Übereinstimmung der Befunde: Solche mit völliger, sich fast entsprechender und nur teilweiser Übereinstimmung sowie nicht bestätigte Ultraschallbefunde. ERGEBNISSE:Die Einschlusskriterien erfüllten 71 von 95 Schwangerschaftsabbrüchen aufgrund fetaler Anomalien und bildeten somit unsere Studienpopulation. Die Sensitivität der Sonografie in Bezug auf Malformationen des Gehirns und Wirbelsäule betrug 100 % (27/27) und in Bezug auf Anomalien der inneren Organe (einschließlich der Fehlbildungen des Urogenital- und Magen-Darm-Systems, der Bauchdecke und des Diaphragmas) 91 % (31/33). Die entsprechende Rate für Anomalien des Herz-Kreislauf-Systems betrug 63 % (17/27) und für die des Skelettsystems 71 % (25/35). Die niedrigste Spezifität wurde für Malformationen des zentralen Nervensystems (33/38, 87 %) und der inneren Organe (39/44, 89 %) ermittelt. Eine völlige Übereinstimmung von Ultraschall- und Autopsiebefunden wurde in 44 % (31/71) und eine sich fast entsprechende Übereinstimmung in 46 % (33/71) aller Fälle gefunden. Bei beinahe 10 % (7/71) der Schwangerschaften konnten die Ultraschallbefunde nur teilweise beziehungsweise gar nicht durch die Autopsie bestätigt werden. In einem Fall mit diskrepanten Ultraschall- und Autopsiebefunden kann angenommen werden, dass die Schwangere die Entscheidung für einen Abbruch vermutlich aufgrund der fehlerhaften Interpretation des Ultraschallbefundes fällte. SCHLUSSFOLGERUNG:Obwohl die Übereinstimmung von Ultraschall- und Autopsiebefunden vom klinischen Standpunkt betrachtet akzeptierbar schien, war sie bezüglich der genauen Beschreibung der Fehlbildungen bei weitem nicht perfekt. Die Trefferquoten beim Herz-Kreislauf- und Skelettsystem waren suboptimal.

背景与目标：

BACKGROUND & AIMS: :Second generation biofuel production has been appeared as a sustainable and alternative energy option. The ultimate aim is the development of an industrially feasible and economic conversion process of lignocellulosic biomass into biofuel molecules. Since, cellulose is the most abundant biopolymer and also represented as the photosynthetically fixed form of carbon, the efficient hydrolysis of cellulose is the most important step towards the development of a sustainable biofuel production process. The enzymatic hydrolysis of cellulose by suites of hydrolytic enzymes underlines the importance of cellulase enzyme system in whole hydrolysis process. However, the selection of the suitable cellulolytic enzymes with enhanced activities remains a challenge for the biorefinery industry to obtain efficient enzymatic hydrolysis of biomass. The present review focuses on deciphering the novel and effective cellulases from different environmental niches by unculturable metagenomic approaches. Furthermore, a comprehensive functional aspect of cellulases is also presented and evaluated by assessing the structural and catalytic properties as well as sequence identities and expression patterns. This review summarizes the recent development in metagenomics based approaches for identifying and exploring novel cellulases which open new avenues for their successful application in biorefineries.

背景与目标： : 第二代生物燃料生产已成为可持续和替代能源的选择。最终目的是开发一种工业上可行且经济地将木质纤维素生物质转化为生物燃料分子的过程。由于纤维素是最丰富的生物聚合物，也表示为光合固定形式的碳，因此纤维素的有效水解是发展可持续生物燃料生产过程的最重要步骤。通过一系列水解酶对纤维素进行酶促水解，突显了纤维素酶酶系统在整个水解过程中的重要性。然而，选择具有增强活性的合适的纤维素分解酶仍然是生物精炼工业获得生物质有效酶水解的挑战。本综述的重点是通过不可培养的宏基因组方法从不同的环境中破译新颖有效的纤维素酶。此外，还通过评估结构和催化特性以及序列同一性和表达模式来介绍和评估纤维素酶的综合功能方面。这篇综述总结了基于宏基因组学的方法在鉴定和探索新的纤维素酶方面的最新发展，为它们在生物精炼中的成功应用开辟了新的途径。

BACKGROUND & AIMS: :A 31-year-old woman complained of dyspnea and orthopnea at 38 weeks of gestation. A grade 3/6 pansystolic murmur was heard, and echocardiography revealed severe mitral regurgitation with a hyperechoic obstacle on the posterior mitral valve leaflet, consistent with a diagnosis of acute heart failure due to a ruptured chordae tendineae or an infectious endocarditis. An emergency cesarean section was performed under general anesthesia. A male infant was born weighing 2928 g with Apgar scores of 7 and 8 at 1 and 5 min, respectively. The patient was managed in the intensive care unit and underwent open-heart surgery for mitral valve repair on postpartum day 3. The two chordal tendineae appeared torn and frail, and a mitral annuloplasty was performed. No finding of infectious endocarditis was observed. Because it is a dramatic and life-threatening clinical situation, proper diagnosis and treatment in the intensive care unit assure a good outcome for both mother and fetus.

背景与目标： : 一名31岁的妇女在妊娠38周时抱怨呼吸困难和正呼吸。听到了3/6级的全收缩期杂音，超声心动图显示严重的二尖瓣反流，二尖瓣后叶上有高回声障碍，这与由于腱索破裂或感染性心内膜炎引起的急性心力衰竭的诊断一致。在全身麻醉下进行紧急剖宫产。出生时体重为2928  g的男婴，分别在1和5  min时Apgar评分为7和8。该患者在重症监护病房接受治疗，并于产后第3天接受心脏直视手术进行二尖瓣修复。两个腱索出现撕裂和脆弱，并进行了二尖瓣环成形术。未发现感染性心内膜炎。由于这是一个戏剧性的，危及生命的临床情况，因此在重症监护病房中进行适当的诊断和治疗可确保母亲和胎儿的良好结局。

BACKGROUND & AIMS: :The aim of this study was to investigate alterations in the leukocyte and differential leukocyte counts in different trimesters of pregnancy and the initial postpartum period. The study population consisted of 40,325 pregnant women. A full blood count and automated differential leukocyte count were performed and all the haemogram results in the different trimesters of pregnancy were recorded. Percentiles were calculated using statistical software. A total of 82,786 complete blood count evaluations were performed in 40,325 subjects from the 6th to 41st week of pregnancy and in the initial postpartum period. The leukocyte counts increased from the 1st to the 3rd trimester and peaked in the initial postpartum period. Our reference values for the total and differential leukocyte counts may assist clinicians in distinguishing between leukocytosis and pathological elevation of the white blood cell count during pregnancy and the initial postpartum period. Impact statement Pregnancy requires profound adaptation by multiple systems to accommodate the demands of the developing foetus. Similar to all other systems, many haematological changes occur during pregnancy. Studies of normal variation in leukocyte counts were insufficient to distinguish normal from abnormal leukocyte counts during pregnancy and in the initial postpartum period, due to small numbers of patients and a lack of differential leukocyte counts. Without reference leukocyte levels, infections may be more difficult to assess during pregnancy and in the postpartum period. In this study, we report the 3rd, 5th, 10th, 50th, 95th and 99th percentile values for the total and differential leukocyte counts according to trimester in normal pregnancy and the initial postpartum period. Our reference values for the total and differential leukocyte counts in each trimester and the initial postpartum period may assist clinicians in distinguishing between normal leukocytosis and pathological elevation of the white blood cell count during pregnancy and the initial postpartum period. Our results may prevent misdiagnosis of physiological elevated leukocytes as bacterial infection that leads to unnecessary medication use that may compromise the foetus.

背景与目标： : 这项研究的目的是调查妊娠不同三个月和产后初期白细胞和白细胞计数差异的变化。研究人群由40,325名孕妇组成。进行了全血细胞计数和自动差异白细胞计数，并记录了妊娠不同三个月的所有血象结果。使用统计软件计算百分位数。从怀孕的第6周至第41周和产后初期，对40,325名受试者进行了总共82,786次全血细胞计数评估。白细胞计数从第1个月到第3个月增加，并在产后初期达到峰值。我们的总白细胞计数和差异白细胞计数参考值可以帮助临床医生区分白细胞增多和妊娠和产后初期白细胞计数的病理升高。影响声明怀孕需要多个系统进行深刻的适应，以适应发育中的胎儿的需求。与所有其他系统相似，许多血液学变化发生在怀孕期间。由于患者人数少且缺乏差异的白细胞计数，对白细胞计数正常变化的研究不足以区分妊娠期间和产后初期的正常白细胞计数与异常白细胞计数。如果没有参考白细胞水平，则在怀孕期间和产后期间可能更难评估感染。在这项研究中，我们根据正常妊娠和产后初期的三个月报告了总白细胞计数和差异白细胞计数的第3、5、10、50、95和99个百分位数值。我们在每个孕期和产后初期的总白细胞计数和差异白细胞计数的参考值可以帮助临床医生区分正常的白细胞增多和妊娠和产后初期的白细胞计数的病理升高。我们的结果可以防止将生理性白细胞升高误诊为细菌感染，从而导致不必要的药物使用，从而可能损害胎儿。

BACKGROUND & AIMS: :Based on the previously reported clinical candidate, AMG 517 (compound 1), a series of related piperazinylpyrimidine analogues were synthesized and evaluated as antagonists of the vanilloid 1 receptor (VR1 or TRPV1). Optimization of in vitro potency and physicochemical and pharmacokinetic properties led to the discovery of (R)-N-(4-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (16p), a potent TRPV1 antagonist [rTRPV1(CAP) IC50 = 3.7 nM] with excellent aqueous solubility (>or=200 microg/mL in 0.01 N HCl) and a reduced half-life (rat t1/2 = 3.8 h, dog t1/2 = 2.7 h, monkey t1/2 = 3.2 h) as compared to AMG 517. In addition, compound 16p was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo (ED50 = 1.9 mg/kg, p.o. in the capsaicin-induced flinch model in rats) and was also effective at reducing thermal hyperalgesia induced by complete Freund's adjuvant in rats (MED = 1 mg/kg, p.o). Based on its improved overall profile, compound 16p (AMG 628) was selected as a second-generation candidate for further evaluation in human clinical trials as a potential new treatment for chronic pain.

背景与目标： : 基于先前报道的临床候选物AMG 517 (化合物1)，合成了一系列相关的哌嗪基嘧啶类似物，并评估其作为香草酸1受体 (VR1或TRPV1) 的拮抗剂。体外效价和理化及药代动力学性质的优化导致发现 (R)-N-(4-(6-(4-(1-(4-氟苯基) 乙基) piperazin-1-yl)pyrimidin-4-yloxy) 苯并 [d]thiazol-2-yl) 乙酰胺 (16p)，一种有效的TRPV1拮抗剂 [rTRPV1(CAP) IC50 = 3.7 nM]，具有优异的水溶性 (在0.01 N HCl中> 或 = 200微克/毫升) 和减少的半衰期 (大鼠t1/2 = 3.8 h，狗t1/2 = 2.7 h，与AMG 517相比，猴子t1/2 = 3.2 h。此外，化合物16p在体内可有效阻断TRPV1-mediated生理反应 (ED50 = 1.9 mg/kg，p.o.在辣椒素诱导的大鼠退缩模型中)，并且在减少完全弗氏佐剂诱导的大鼠热痛觉过敏方面也有效 (MED = 1 mg/kg，p.o)。基于其改善的总体特征，化合物16p (AMG 628) 被选为第二代候选物，用于在人类临床试验中进一步评估，作为潜在的慢性疼痛的新疗法。

BACKGROUND & AIMS: PURPOSE:Steroid sulfatase (STS) inhibitors that can decrease or prevent the biosynthesis of estrogenic steroids via the sulfatase route may play an important role in the treatment of breast cancer. We compare the in vivo efficacy of two potent STS inhibitors, STX64 and STX213, in a xenograft breast cancer model. EXPERIMENTAL DESIGN:MCF-7 cells stably expressing STS cDNA (MCF-7STS) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of estradiol sulfate (E2S) and bearing both MCF-7STS and wild-type MCF-7 (MCF-7WT) tumors were orally treated with STX64 and STX213. Treatment was given for 49 days followed by a recovery period of 35 days in which animals received only E2S. Mice were weighed, and tumor measurements were taken weekly. RESULTS:STX64 and STX213 exhibited potent STS inhibition in vivo. However, STX213 showed a greater duration of activity. In vehicle-treated nude mice receiving E2S, tumor volumes increased 5.5-fold for MCF-7WT and 3.8-fold for MCF-7STS after 49 days compared with day 0. MCF-7WT tumor growth was reduced by 56% by STX213 over the dosing period, and subsequent growth was retarded during the recovery period. All treatments fully inhibited growth of MCF-7STS tumors, and recovery of these tumors was significantly retarded (P<0.01). All compounds completely inhibited liver and tumor STS activity. Additionally, STS mRNA expression in the MCF-7STS tumors directly correlated with the corresponding STS enzyme activity. CONCLUSIONS:This study indicates that STS inhibitors attenuate hormone-dependent human breast cancer growth and therefore offer a potentially novel treatment for this condition.

背景与目标：

BACKGROUND & AIMS: :This study examined the effects of human pregnancy and advancing gestation on the intensity of respiratory discomfort (dyspnea) during cycle exercise. Fourteen pregnant women (PG) performed a progressive cycle ergometer exercise test involving 20 W/min increases in work rate to symptom limitation and/or a heart rate of 170-175 beats/min at 19.7+/-1.2 weeks (ENTRY), 28.2+/-0.3 weeks (TM2) and 36.3+/-0.3 weeks (TM3) gestation. Eight, age-matched, sedentary non-pregnant women (CG) were also studied for comparison purposes. Measurements included dyspnea intensity (Borg scale), minute ventilation (VE), breathing pattern and other cardiorespiratory parameters. At peak exercise, neither pregnancy nor advancing gestation had an effect on dyspnea, VE, breathing pattern, oxygen uptake or work rate (p>0.05). VE was significantly greater (by 11 L/min at 100 W) in the PG at TM3 versus CG (p<0.05) at all submaximal work rates. VE also increased progressively from ENTRY to TM2 and TM3 during submaximal exercise. Dyspnea was not significantly different at any submaximal work rate in the PG at TM3 versus CG or with advancing gestation in the PG. In addition, dyspnea at a standardized exercise VE of 40 L/min was not different at TM3 versus ENTRY or in the PG at TM3 versus CG. Neither pregnancy nor advancing gestation were associated with increased respiratory discomfort during strenuous non-weight bearing cycle ergometer exercise, despite substantial increases in VE and progressive mechanical adaptations of the respiratory system to accommodate the increasing size of the gravid uterus.

背景与目标： : 这项研究检查了人类怀孕和妊娠对周期运动期间呼吸不适 (呼吸困难) 强度的影响。14名孕妇 (PG) 进行了渐进式循环测力计运动测试，包括在19.7周 +/-1.2周 (进入) 时，工作速率增加20 W/min，以达到症状限制和/或心率170-175次/min，28.2 +/-0.3周 (TM2) 和36.3 +/-0.3周 (TM3)。为了比较目的，还研究了八名年龄匹配的久坐不动的非孕妇 (CG)。测量包括呼吸困难强度 (Borg量表)，分钟通气量 (VE)，呼吸模式和其他心肺参数。在运动高峰时，怀孕和妊娠均不会影响呼吸困难，VE，呼吸方式，摄氧量或工作效率 (p>0.05)。在所有次最大工作速率下，TM3的PG相对于CG (p<0.05) 的VE显着更高 (在100 W下为11 l/min)。在次最大运动期间，VE也从进入TM2和TM3逐渐增加。在TM3相对于CG的PG中，在任何亚最大工作速率下，或在PG中进行妊娠时，呼吸困难均无显着差异。此外，在标准化运动VE为40 l/min时的呼吸困难在TM3与ENTRY或PG在TM3与CG时没有差异。尽管VE的显着增加和呼吸系统的进行性机械适应以适应妊娠子宫的增加，但在剧烈的非负重循环测力计运动中，怀孕和妊娠都不会增加呼吸不适。