bluuebunny/crossref_metadata_2025 huggingface dataset:
Recurrence of Hepatocellular Carcinoma in Noncirrhotic Liver After Hepatectomy
Authors: Chiche Laurence , Menahem B. , Bazille C. , Bouvier V. , Plard L. , Saguet V. , Alves A. , Salame E.
Published: June 2013

Background

Hepatocellular carcinoma in noncirrhotic liver (HCCNC) is rare. This tumor has a particular epidemiology and presentation, and it requires specific treatment, compared with HCC in cirrhotic liver. The aims of this study were to determine the survival and recurrence rates, prognostic factors, and optimum treatment of HCCNC and to propose a follow‐up protocol for patients who have undergone surgery for HCCNC.

Methods

This study included 131 patients who underwent surgical treatment for HCCNC from January 1992 to December 2010. Survival and recurrence rates were evaluated, and the prognostic factors and characteristics of recurrence were analyzed. Pathologic characteristics of the tumors and the nontumoral liver were examined.

Results

The mean survival time was 67.9 months. The 5‐ and 10‐year overall survival rates were 72.9 and 36.7 %, respectively. In all, 54 patients (41.2 %) developed recurrence at a median interval of 30.96 months. Of these recurrences, 31.5 % occurred during the first year, and 24.1 % occurred more than 5 years after surgery. Macro‐ or microvascular invasion and tumor size >5 cm were significantly associated with a poor survival rate. The predictive factors for recurrence were multiple tumors, tumor diameter >5 cm, and satellite nodules. Patients who underwent surgical treatment for recurrence had a significantly longer survival time than those who did not (p < 0.0292).

Conclusions

Recurrence is the most common cause of death after hepatectomy for HCC, and patients should undergo careful, long‐term follow‐up. Early detection and treatment of recurrence with curative intent should improve the prognosis of these patients.
Youth Initiated Mentoring: Investigating a New Approach to Working with Vulnerable Adolescents
Authors: Schwartz Sarah E. O. , Rhodes Jean E. , Spencer Renée , Grossman Jean B.
Published: June 2013

This study examines youth initiated mentoring (YIM), a new approach to mentoring in which youth nominate mentors from among the non‐parental adults within their existing social networks (e.g., teachers, family friends, extended family members). YIM is currently being implemented through the National Guard Youth ChalleNGe Program (NGYCP), an intensive residential intervention program for youth ages 16–18 who have dropped out or been expelled from high school. This study employed a mixed methods explanatory design, drawing on quantitative data from a national longitudinal evaluation of NGYCP (N = 1,173) and qualitative data from a subsample of participants (N = 30) in the evaluation. Results indicated that more enduring mentoring relationships were associated with increased retention of educational, vocational, and behavioral outcomes 3 years following entry into the study. Qualitative data suggested that, when relationships endured, mentors contributed to improvements in participants’ educational and occupational success, quality of relationships with parents, peers, and others, and self‐concept by providing social‐emotional support, instrumental support, and guidance. Results also revealed that relationships were more likely to endure when youth chose their mentors on their own (rather than receiving help from parents or program staff) and when mentors were of the same race as youth. Implications for research and practice are discussed.
Characterization of CoQ10 biosynthesis in fibroblasts of patients with primary and secondary CoQ10 deficiency
Authors: Buján Nuria , Arias Angela , Montero Raquel , García‐Villoria Judit , Lissens Willy , Seneca Sara , Espinós Carmen , Navas Plácido , De Meirleir Linda , Artuch Rafael , Briones Paz , Ribes Antonia
Published: June 2013

Primary coenzyme Q10 (CoQ10) deficiencies are associated with mutations in genes encoding enzymes important for its biosynthesis and patients are responsive to CoQ10 supplementation. Early treatment allows better prognosis of the disease and therefore, early diagnosis is desirable. The complex phenotype and genotype and the frequent secondary CoQ10 deficiencies make it difficult to achieve a definitive diagnosis by direct quantification of CoQ10. We developed a non‐radioactive methodology for the quantification of CoQ10 biosynthesis in fibroblasts that allows the identification of primary deficiencies. Fibroblasts were incubated 72 h with 28 μmol/L 2H3‐mevalonate or 1.65 mmol/L 13C6‐p‐hydroxybenzoate. The newly synthesized 2H3‐ and 13C6‐ labelled CoQ10 were analysed by high performance liquid chromatography‐tandem mass spectrometry. The mean and the reference range for 13C6‐CoQ10 and 2H3‐CoQ10 biosynthesis were 0.97 (0.83–1.1) and 0.13 (0.09–0.17) nmol/Unit of citrate synthase, respectively. We validated the methodology through the study of one patient with COQ2 mutations and six patients with CoQ10 deficiency secondary to other inborn errors of metabolism. Afterwards we investigated 16 patients’ fibroblasts and nine showed decreased CoQ10 biosynthesis. Therefore, the next step is to study the COQ genes in order to reach a definitive diagnosis in these nine patients. In the patients with normal rates the deficiency is probably secondary. In conclusion, we have developed a non‐invasive non‐radioactive method suitable for the detection of defects in CoQ10 biosynthesis, which offers a good tool for the stratification of patients with these treatable mitochondrial diseases.
Cross‐sectional observational study of 208 patients with non‐classical urea cycle disorders
Authors: Rüegger Corinne M. , Lindner Martin , Ballhausen Diana , Baumgartner Matthias R. , Beblo Skadi , Das Anibh , Gautschi Matthias , Glahn Esther M. , Grünert Sarah C. , Hennermann Julia , Hochuli Michel , Huemer Martina , Karall Daniela , Kölker Stefan , Lachmann Robin H. , Lotz‐Havla Amelie , Möslinger Dorothea , Nuoffer Jean‐Marc , Plecko Barbara , Rutsch Frank , Santer René , Spiekerkoetter Ute , Staufner Christian , Stricker Tamar , Wijburg Frits A. , Williams Monique , Burgard Peter , Häberle Johannes
Published: June 2013

Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non‐classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non‐classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ≥ 16 years old. The largest subgroup (121 patients) had X‐linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non‐classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial.
BERNOULLI'S LAW OF LARGE NUMBERS
Authors: Bolthausen Erwin , Wüthrich Mario V.
Published: June 2013

This year we celebrate the 300th anniversary of Jakob Bernoulli's path-breaking work Ars conjectandi, which appeared in 1713, eight years after his death. In Part IV of his masterpiece, Bernoulli proves the law of large numbers which is one of the fundamental theorems in probability theory, statistics and actuarial science. We review and comment on his original proof.
The Animal Kingdom
Authors: Cuvier Georges
Published: June 2013

Georges Cuvier (1769–1832), made a peer of France in 1819 in recognition of his work, was perhaps the most important European scientist of his day. His most famous work, Le Règne Animal, was published in French in 1817; Edward Griffith (1790–1858), a solicitor and amateur naturalist, embarked on in 1824, with a team of colleagues, an English version which resulted in this illustrated sixteen-volume edition with additional material, published between 1827 and 1835. Cuvier was the first biologist to compare the anatomy of fossil animals with living species, and he named the now familiar 'mastodon' and 'megatherium'. However, his studies convinced him that the evolutionary theories of Lamarck and St Hilaire were wrong, and his influence on the scientific world was such that the possibility of evolution was widely discounted by many scholars both before and after Darwin. Volume 3 is the third of four books on mammals.
The Animal Kingdom
Authors: Cuvier Georges
Published: June 2013

Georges Cuvier (1769–1832), made a peer of France in 1819 in recognition of his work, was perhaps the most important European scientist of his day. His most famous work, Le Règne Animal, was published in French in 1817; Edward Griffith (1790–1858), a solicitor and amateur naturalist, embarked on in 1824, with a team of colleagues, an English version which resulted in this illustrated sixteen-volume edition with additional material, published between 1827 and 1835. Cuvier was the first biologist to compare the anatomy of fossil animals with living species, and he named the now familiar 'mastodon' and 'megatherium'. However, his studies convinced him that the evolutionary theories of Lamarck and St Hilaire were wrong, and his influence on the scientific world was such that the possibility of evolution was widely discounted by many scholars both before and after Darwin. Volume 11 discusses the fossil remains of the animal kingdom.
The New Cambridge History of American Foreign Relations
Authors: Cohen Warren I.
Published: June 2013

Since their first publication, the four volumes of the Cambridge History of American Foreign Relations have served as the definitive source for the topic, from the colonial period to the Cold War. The fourth volume of the updated edition explores the conditions in the international system at the end of World War II, the American determination to provide leadership, and the security dilemma each superpower posed for the other. This revised and expanded edition incorporates recent scholarship and revelations, carrying the narrative through the years following the end of the Cold War into the administration of Barack Obama. The character of the American political system is explored, including the separation of political powers and the role of interest groups that prompted American leaders to exaggerate dangers abroad to enhance their domestic power. This new edition examines the conditions in the international system from the end of World War II to the present, focusing on the American determination to provide world leadership.
Recurrent flows: the clockwork behind turbulence
Authors: Cvitanović Predrag
Published: June 2013

The understanding of chaotic dynamics in high-dimensional systems that has emerged in the last decade offers a promising dynamical framework to study turbulence. Here turbulence is viewed as a walk through a forest of exact solutions in the infinite-dimensional state space of the governing equations. Recently, Chandler & Kerswell (J. Fluid Mech., vol. 722, 2013, pp. 554–595) carry out the most exhaustive study of this programme undertaken so far in fluid dynamics, a feat that requires every tool in the dynamicist’s toolbox: numerical searches for recurrent flows, computation of their stability, their symmetry classification, and estimating from these solutions statistical averages over the turbulent flow. In the long run this research promises to develop a quantitative, predictive description of moderate-Reynolds-number turbulence, and to use this description to control flows and explain their statistics.
Effects of inertia and stratification in incompressible ideal fluids: pressure imbalances by rigid confinement
Authors: Camassa R. , Chen S. , Falqui G. , Ortenzi G. , Pedroni M.
Published: June 2013

Consequences of density stratification are studied for an ideal (Euler) incompressible fluid, confined to move under gravity between rigid lids but otherwise free to move along horizontal directions. Initial conditions that generate horizontal pressure imbalances in a laterally unbounded domain are examined. The aim is to show analytically the existence of classes of initial data for which total horizontal momentum evolves in time, even though only vertical forces act on the fluid in this set-up. A simple class of such initial conditions, leading to momentum evolution, is identified by systematic asymptotic expansions of the governing inhomogeneous Euler equations in the small-density-variation limit. These results for Euler equations are compared and confirmed with long-wave asymptotic models, which can handle arbitrary density variations and provide closed-form mathematical expressions for limiting cases. In particular, the role of wave dispersion arising from the fluid inertia is captured by the long-wave models, even for short-time dynamics emanating from initial conditions outside the models’ asymptotic range of validity. These results are compared with direct numerical simulations for variable-density Euler fluids, which further validate the numerical algorithms and the analysis.
Horizontal convection dynamics: insights from transient adjustment
Authors: Griffiths Ross W. , Hughes Graham O. , Gayen Bishakhdatta
Published: June 2013

The dynamics of horizontal convection are revealed by examining transient adjustment toward thermal equilibrium. We restrict attention to high Rayleigh numbers (of $O(1{0}^{12} )$) and a Prandtl number ${\sim }5$ that characterize many practical applications, and consider responses to small changes in the thermal boundary conditions, using laboratory experiments, three-dimensional direct numerical simulations (DNS) and simple theoretical models. The experiments and the mechanical energy budget from the DNS demonstrate that unsteady forcing can produce flow dramatically more active than horizontal convection under steady forcing. The physical mechanisms at work are indicated by the time scales of approach to the new equilibrium, and we show that these can range over two orders of magnitude depending on the imposed change in boundary conditions. Changes that lead to a net destabilizing buoyancy flux give rapid adjustments: for applied heat flux conditions the whole of the circulation is controlled by conduction through the stable portion of the boundary layer, whereas for applied temperature difference the circulation is controlled by small-scale convection within the unstable part of the boundary layer. The experiments, DNS and models are in close agreement and show that the time scale under applied temperatures is as small as 0.01 vertical diffusion time scales, a factor of four smaller than for imposed flux. Both cases give adjustments too rapid for diffusion in the interior to play a significant role, at least through 99 % of the adjustment, and we conclude that diffusion through the full depth is not significant in setting the equilibrium state. Boundary changes leading to a net stabilizing buoyancy flux give a very different response, causing the convection to quickly form a shallow circulation cell, followed eventually by a return to full-depth overturning through a combination of penetrative convection and conduction. The time scale again varies by orders of magnitude, depending on the boundary conditions and the location of the imposed boundary perturbation.
Cross-generational feeding of Bt (Bacillus thuringiensis)-maize to zebrafish (Danio rerio) showed no adverse effects on the parental or offspring generations
Authors: Sanden Monica , Ornsrud Robin , Sissener Nini H. , Jorgensen Susanne , Gu Jinni , Bakke Anne Marie , Hemre Gro-Ingunn
Published: June 2013

In the present study, zebrafish (Danio rerio) were fed casein/gelatin-based diets containing either 19 % Bt (Bacillus thuringiensis)-maize or its parental non-Bt (nBt)-maize control for two generations (F0: sixty fish; F1: forty-two to seventy fish per treatment). The study focused on growth and reproductive performance, liver CuZn superoxide dismutase (SOD) enzyme activity, gene transcript levels targeting important cellular pathways in the liver and mid-intestine, histomorphological evaluation of the intestine, differential leucocyte counts, offspring larva swimming activity and global DNA methylation in offspring embryos. No significant effects were observed in the parental generation. The offspring were either fed the same diets as those fed to their parents (Bt–Bt or nBt–nBt) or switched from the Bt diet to the nBt diet (Bt–nBt). The Bt–Bt offspring exhibited a significantly higher body mass increase, specific growth rate and feed utilisation than fish fed the nBt–nBt diet and/or fish fed the Bt–nBt diet. Liver and mid-intestinal gene transcript levels of CuZn SOD were significantly higher in fish fed the nBt–nBt diet than in those fed the Bt–Bt diet. Liver gene transcript levels of caspase 6 were significantly lower for the nBt–nBt group than for the Bt–Bt group. Overall, enhanced growth performance was observed in fish fed the Bt diet for two generations than in those fed the nBt diet for one and two generations. Effects observed on gene biomarkers for oxidative stress and the cell cycle (apoptosis) may be related to the contamination of nBt-maize with fumonisin B1 and aflatoxin B1. In conclusion, it is suggested that Bt-maize is as safe and nutritious as its nBt control when fed to zebrafish for two generations.
Hepatoprotective effect of germanium-containingSpirulinain rats withd-galactosamine- and lipopolysaccharide-induced hepatitis
Authors: Yoshinari Orie , Shiojima Yoshiaki , Igarashi Kiharu
Published: June 2013

In the present study, the protective effects of dietarySpirulina(SP) and germanium-containingSpirulina(GeSP) were compared in rats with liver injury induced by an intraperitoneal injection ofd-galactosamine and lipopolysaccharide (GalN/LPS). Wistar rats were fed one of the following diets: the basal diet (GalN/LPS-CON group;n6), the basal diet supplemented with 5 % SP or GeSP (GalN/LPS-SP and GalN/LPS-GeSP group, respectively;n7 each). After administering these diets for 7 d, each rat was intraperitoneally injected with GalN/LPS. Increases in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were suppressed in the GalN/LPS-GeSP group (GalN/LPS-CONv. GalN/LPS-GeSP: ALT 1052 (sem187)v. 509 (sem88) IU/l and AST 2183 (sem368)v. 1170 (sem196) IU/l) following the injection of GalN/LPS. Plasma levels of interferon-γ (IFN-γ) and TNF-α in GeSP-fed rats were significantly lower when compared with those in the GalN/LPS-CON group (GalN/LPS-CONv. GalN/LPS-GeSP: IFN-γ 142·8 (sem17·5)v. 66·8 (sem9·7) pg/ml and TNF-α 72·3 (sem15·4)v. 31·2 (sem6·8) pg/ml). However, the decrease in these levels observed in the GalN/LPS-SP group was not as prominent as those observed in the GalN/LPS-GeSP group. Furthermore, the increase in liver catalase (CAT) and glutathione peroxidase (GPx) activities, as well as the level of oxidised glutathione (GSSG), was more suppressed in GeSP-fed rats (GalN/LPS-CONv. GalN/LPS-GeSP: CAT 457 (sem47)v. 262 (sem54) U/mg liver protein; GPx 1·30 (sem0·11)v. 0·53 (sem0·09) U/mg liver protein; GSSG 2·18 (sem0·33)v. 1·31 (sem0·24) mmol/kg liver) after the injection of GalN/LPS. These changes were more pronounced in the GalN/LPS-GeSP group than in the GalN/LPS-SP group. These results suggest that GeSP could afford a significant protective effect in the alleviation of GalN/LPS-induced hepatic damage. In addition, the results indicate that GeSP is more effective than SP.
The Politics of Fission: An Analysis of Faction Breakaways among Italian Parties (1946–2011)
Authors: Ceron Andrea
Published: June 2013

This article investigates intra-party politics and explores the determinants of factional breakaways, going beyond the unitary actor assumption. It presents a game-theoretic model that focuses on intra-party competition and bargaining dynamics to analyse the interplay between party leaders and minority factions. It tests several hypotheses based on the formal model using a new dataset that contains information about the strength and policy positions of factions inside Italian parties, from 1946 to 2011, measured through quantitative content analysis of motions presented during party congresses. The results show that office, policy and electoral motives influence factions’ decisions to break away. Other elements – such as intra-party democracy, the electoral system and party system competitiveness – also affect leaders’ attitudes toward compromising and alter the likelihood of a split.
3-tuples have at most 7 prime factors infinitely often
Authors: MAYNARD JAMES
Published: June 2013

Let L1, L2L3 be integer linear functions with no fixed prime divisor. We show there are infinitely many n for which the product L1(n)L2(n)L3(n) has at most 7 prime factors, improving a result of Porter from 1972. We do this by means of a weighted sieve based upon the Diamond-Halberstam-Richert multidimensional sieve.
Distribution and habitat use of the Austral Rail Rallus antarcticus and perspectives on its conservation
Authors: BARNETT JUAN MAZAR , IMBERTI SANTIAGO , ROESLER IGNACIO
Published: June 2013

We present the results of searches for the Austral Rail Rallus antarcticus in Argentine and Chilean Patagonia between January 1998 and February 2006 and from subsequent visits. We surveyed 58 localities and found the rail in 22, which collectively cover approximately 85 km2 of habitat. A maximum of 175 individuals were detected. This poorly known species was rediscovered in 1998; since then, it has been found in 18 additional localities, providing further data on distribution, habitat and seasonal movements. During the searches, we found that the species faces different threats, such as reduction of wetlands due to cattle grazing, burning and abnormal water management, but also the presence of American mink Neovison vison. However, due to the lack of prior information we conclude that the species should be maintained as Vulnerable.
Turning Theory into Practice: Fee Earner Training Using the BIALL Legal Research 5 Stage Model
Authors: Fishleigh Jackie
Published: June 2013

In the article Jackie Fishleigh, a regular contributor to LIM, looks at the vital and seemingly never-ending task of how to provide relevant and effective training in legal research to lawyers. The author shares her experiences in putting the new BIALL Legal Research 5 Stage Model through its paces with real audiences of live humans!
The Howgill Family: A Dynasty of Musicians from Georgian Whitehaven
Authors: Fleming Simon D. I.
Published: June 2013

It has been often observed that Georgian Britain was alive with musical activity, and that London was one of the most important musical hubs in Europe. Most of Britain's important provincial centres were well connected to the capital by road or sea, and this helped facilitate the spread of the latest musical ideas around the country. The west Cumberland town of Whitehaven is situated over three hundred miles from London by road and, at the time, was isolated from the rest mainland Britain by the surrounding fells of the Lake District. Nevertheless, by the end of the eighteenth century Whitehaven had grown into one of Britain's most important ports and had a musical life that rivalled that at any other major town in the country.

Musical life in Whitehaven was dominated by the Howgill family. William Howgill senior was appointed organist of St Nicholas’ Church in 1756 and set himself up there as music teacher and concert promoter. Here he raised a family and was succeeded in his musical duties by his son, William Howgill junior. This article examines the Howgill family's musical activities in depth and explores their London connections. This research is based on the detailed study of primary sources including newspapers, but there has also been an effort to examine all of William Howgill junior's compositions. This study reveals that, despite Whitehaven's remote location, Howgill junior was well aware of the latest musical developments in the capital.
Do arguments matter? Argumentation and negotiation success at the 1997 Amsterdam Intergovernmental Conference
Authors: Reinhard Janine , Biesenbender Jan , Holzinger Katharina
Published: June 2013

It is widely debated in studies of international negotiations why certain negotiators are more successful than others. Institutionalist and rationalist approaches claim that institutions and negotiators’ resources largely explain the outcome of negotiations, whereas constructivist approaches stress the importance of shared norms and values. The article asks to what extent the use of normative arguments explains negotiation success in EU treaty negotiations. We apply our approach to the negotiations leading to the Treaty of Amsterdam. We first define normative arguments as justifications for positions that refer to common norms and develop a concept of common values for EU constitutional negotiations. Second, we assess to what degree governments justify their positions by normative arguments using an automated analysis of position papers. Finally, we ask if such justifications increase success in negotiations. The results of our statistical models show that arguing affects negotiation success significantly and positively.
Standby citizens: diverse faces of political passivity
Authors: Amnå Erik , Ekman Joakim
Published: June 2013

The current debate on political participation is bound to a discussion about whether citizens are active or passive. This dichotomous notion is nurtured by an extensive normative debate concerning whether passivity is an asset or a threat to democracy; and it is especially manifest in studies of young people's political orientations. Drawing on this discussion, the present study goes beyond the dichotomy by keeping political interest conceptually separate from participation in order to improve our understanding of political passivity. Multivariate cluster analysis of empirical data on Swedish youth suggests that we need to consider three distinctive forms of ‘political passivity’. In the paper we present empirical evidence not only of the existence of a particular ‘standby citizen’, but also of two kinds of genuinely passive young people: unengaged and disillusioned citizens. Alongside active citizens, these people are in distinctly different categories with regard to their political behavior. This entails a new analytical framework that may be used to analyze an empirical phenomenon that has received surprisingly little attention in the literature on political participation and civic engagement.
Relationship between Stress Symptoms and Drug use among Secondary Students
Authors: Frade Iracema Francisco , De Micheli Denise , Monezi Andrade André Luiz , de Souza-Formigoni Maria Lucia Oliveira
Published: June 2013

The aim of this study was to evaluate the relationship between drug use and four kinds of stress symptoms in 954 Brazilian students from the 6thto the 11thgrades, in 4 public and 5 private schools in the city of Sao Paulo. Based on their answers to the Drug Use Screening Inventory (DUSI-R) and to the Stress Scale for Adolescents (SSA), we compared regular drug users with non/occasional drug users regarding the frequency of four kinds of stress symptoms (psychological, cognitive, physiological, interpersonal), and the period in which it happened. When compared to non/occasional drug users, regular drug users presented higher levels of psychological, cognitive and physiological symptoms of stress and these symtoms were in the most severe spectrum of severity (near to exhaustion and exhaustion). The association between drug use and stress was even stronger in the youngest age group (11 to 13 years old). Most of the regular drug users were 16 years old and over, from upper-middle class families, had poor family relationships and more academic problems. These results confirm the association between drug use and stress in adolescents and highlight the need for early screening and intervention in both drug use and stressful situations.
Monochorionic Dizygous Twins Presenting With Blood Chimerism and Discordant Sex
Authors: Smeets Dominique , van Vugt John M.G. , Gomes Ingrid , van den Heuvel Simone , van Heijst Arno , Reuss Annette , Claahsen-van der Grinten Hedi L.
Published: June 2013

Monochorionic dizygous twins are probably more frequent than considered previously as many cases remain unrecognized, especially when the children have the same sex. Here we present a pair of dizygous, sex-discordant monochorionic twins who were conceived after artificial insemination. Histological examination of the placenta and extensive genetic studies of the healthy boy and girl clearly proved that they indeed were monochorionic dizygous twins with a fully joined blood circulation. We conclude that when counseling parents expecting monochorionic twins of discordant sex, not only a disorder of sexual differentiation in one of the twins should be addressed but also the possibility of dizygosity with a completely normal (sexual) development of both children.
Diabetes und Sicherheit in Beruf, Sport und Verkehr
Authors: Weissenberger Benno
Published: June 2013

Die vorliegende Übersichtsarbeit möchte eine Hilfestellung bei der Beurteilung der Tauglichkeit von Patienten mit Diabetes mellitus anbieten. Da der Patient nicht nur Verkehrsteilnehmer ist, wird die Tauglichkeit auch beim Beruf und dem Sport diskutiert. Die zur Beurteilung notwendigen Informationen werden vorgestellt. Dabei hat die Hypoglykämie mit dem Problem der Wahrnehmungsstörung die absolut gesehen grösste Bedeutung. Ausgehend von der Hypoglykämie wird auch die Hyperglykämie, die Stabilität des Blutzuckerstoffwechsels und die für die Tauglichkeit relevanten Spätkomplikationen erwähnt. Die Beeinflussung der Tauglichkeitskriterien durch eine spezifische Schulung wird diskutiert. Es finden sich Hinweise über die notwendigen Inhalte eines medizinischen Attests zur Stellungnahme der Tauglichkeit und deren Kommunikation gegenüber dem Patienten und der Behörde.
Wachstumshormon bei Kindern und Jugendlichen: Erwartungen und Realität
Authors: Burckhardt Marie-Anne , Zumsteg Urs
Published: June 2013

Wachstumshormon wird seit etwas mehr als 50 Jahren therapeutisch eingesetzt. Noch bis vor einigen Jahren war die Wachstumshormontherapie reserviert für Kinder mit nachgewiesenem hypophysären Kleinwuchs. Heute können weitere Ursachen des Kleinwuchses – jedoch längst nicht alle – mit Wachstumshormon behandelt werden. Zu den etablierten Indikationen einer Wachstumshormontherapie gehören wie oben erwähnt der Wachstumshormonmangel, das Turner-Syndrom sowie das Prader-Willi-Syndrom, der intrauterine Kleinwuchs ohne Aufholwachstum sowie Kleinwuchs aufgrund von chronischer Niereninsuffizienz und gewisser hämatologischer und onkologischer Erkrankungen.Eine sorgfältige und akkurate Diagnostik ist essenziell. Eine Wachstumshormontherapie ist im Praxisalltag eher selten, so dass diese eine enge Zusammenarbeit mit einem pädiatrischen Endokrinologen erfordert.
Efficient translation initiation dictates codon usage at gene start
Authors: Bentele Kajetan , Saffert Paul , Rauscher Robert , Ignatova Zoya , Blüthgen Nils
Published: June 2013

The genetic code is degenerate; thus, protein evolution does not uniquely determine the coding sequence. One of the puzzles in evolutionary genetics is therefore to uncover evolutionary driving forces that result in specific codon choice. In many bacteria, the first 5–10 codons of protein‐coding genes are often codons that are less frequently used in the rest of the genome, an effect that has been argued to arise from selection for slowed early elongation to reduce ribosome traffic jams. However, genome analysis across many species has demonstrated that the region shows reduced mRNA folding consistent with pressure for efficient translation initiation. This raises the possibility that unusual codon usage is a side effect of selection for reduced mRNA structure. Here we discriminate between these two competing hypotheses, and show that in bacteria selection favours codons that reduce mRNA folding around the translation start, regardless of whether these codons are frequent or rare. Experiments confirm that primarily mRNA structure, and not codon usage, at the beginning of genes determines the translation rate.
Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals
Authors: Qiu Jing , Tan Yan-Wei , Hagenston Anna M. , Martel Marc-Andre , Kneisel Niclas , Skehel Paul A. , Wyllie David J. A. , Bading Hilmar , Hardingham Giles E.
Published: June 2013

The recent identification of the mitochondrial Ca2+ uniporter gene (Mcu/Ccdc109a) has enabled us to address its role, and that of mitochondrial Ca2+ uptake, in neuronal excitotoxicity. Here we show that exogenously expressed Mcu is mitochondrially localized and increases mitochondrial Ca2+ levels following NMDA receptor activation, leading to increased mitochondrial membrane depolarization and excitotoxic cell death. Knockdown of endogenous Mcu expression reduces NMDA-induced increases in mitochondrial Ca2+, resulting in lower levels of mitochondrial depolarization and resistance to excitotoxicity. Mcu is subject to dynamic regulation as part of an activity-dependent adaptive mechanism that limits mitochondrial Ca2+ overload when cytoplasmic Ca2+ levels are high. Specifically, synaptic activity transcriptionally represses Mcu, via a mechanism involving the nuclear Ca2+ and CaM kinase-mediated induction of Npas4, resulting in the inhibition of NMDA receptor-induced mitochondrial Ca2+ uptake and preventing excitotoxic death. This establishes Mcu and the pathways regulating its expression as important determinants of excitotoxicity, which may represent therapeutic targets for excitotoxic disorders.
pH- and Temperature-responsive Hydrogels in Drug Delivery
Authors: Puoci Francesco , Curcio Manuela
Published: June 2013

Stimuli-responsive drug-delivery systems may be therapeutically advantageous over the prolonged release systems, because they offer the possibility of adapting drug levels to the biorhythms and the pathological changes in the body, notably enhancing the efficiency and safety of the treatments. Hydrogels already occupy a prominent position in the drug-delivery field due to their versatile composition and obtaining procedures, high hydrophilicity and tunable mechanical properties. Thus they result in systems suitable for being administered through almost all delivery routes. Adequate selection of ionizable components leads to networks sensitive to the changes in pH that take place under physiological (e.g. in the gastrointestinal tract or inside cell organelles) or pathological (e.g. cancer, inflammation, infection) conditions. On the other hand, monomers that can establish intra-/inter-molecular interactions through hydrophobic or hydrogen bonds endow the hydrogels with temperature-responsive behavior. Combination of both pH- and temperature-sensitive components is also feasible and demonstrated useful to achieve a more selective and precise drug release pattern. The chapter offers an overview of the recent research on pH- and thermo-responsive hydrogels and their applications in controlled drug delivery. Besides micro-sized materials, much attention is paid to hydrogels with nano-sized structure, which have a great potential in stimuli-responsive cell targeting therapies.
Elastin-like Hydrogels and Self-assembled Nanostructures for Drug Delivery
Authors: Rodríguez-Cabello José Carlos , González de Torre Israel , Pinedo Guillermo
Published: June 2013

Elastin-Like Recombinamers (ELRs) are a family of protein-based polymers showing extraordinary properties, mimicking those shown by natural elastin. Their smart behavior, self-assembly and high biocompatibility make them suitable candidates for the most cutting-edge applications in biomedicine and nanotechnology. ELRs present high versatility and can be modulated and processed in various forms, including films, fiber networks, nanoparticles and hydrogels. In this chapter the main features of ELRs and the preparation and the performance of chemical and physical ELR hydrogels and nano-sized structures are described and analyzed from the point of view of current potential applications in the field of drug, protein and gene delivery.
Introduction: Regulatory Development Hurdles for Biomarker Commercialization: The Steps Required to Get a Product to Market
Authors: Thompson Melissa A.
Published: June 2013

Taking a product from discovery to commercialization is a complex process. It is a process that requires familiarization and expertise in the regulatory arena and general understanding of quality‐system requirements. This chapter addresses the steps required to get a product to market and the considerations from a regulatory and quality perspective.
Introduction: The Cardinal Role of Biobanks and Human Biospecimen Collections in Biomarker Validation: Issues Impeding Impact of Biomarker Research Outcomes
Authors: Puchois Pascal , Miranda Lisa B , van Gool Alain
Published: June 2013

Chapter 3 highlights the value of biobank collections for biomarker development and validation, specifically providing an overview of critical issues in the biobanking pathway that impact biomarker research results. The chapter commences with an overview of the biobank-biomarker collaborative landscape in an effort to elucidate, key planning considerations for enhancing biomarker validation and research. Universal challenges in biospecimen collection and utilization are discussed. Four key areas of dysfunction are outlined: unsustainable biobanking operational models, difficulties in locating and accessing quality biospecimens with appropriate associated data, inefficient research business practices (resulting in inability to engage in timely collaborations) and limited prevalence of suitable biospecimen collections. Recommendations are presented as to how these critical challenges may be ameliorated. Thoughts are then offered as to how biospecimen and biomedical research practices may be improved to optimize and accelerate incidence of relevant biomarker research outcomes.
Sample Preparation and Profiling: Biomarker Discovery in Body Fluids by Proteomics
Authors: Govorukhina N. , Bischoff R.
Published: June 2013

The analysis of body fluids is challenging due to complexity of the sample and the wide dynamic concentration range of proteins and peptides. Sample preparation is a critical step to improve the overall sensitivity of the analytical methodology as well as to arrive at reproducible results. Sample preparation may affect the outcome of a study due to the introduction of changes in protein or metabolite profiles that are not related to disease but rather to sample stability. In this chapter we exemplify a number of cases related to the profiling of serum, urine, epithelial lining fluid and cerebrospinal fluid where sample preparation plays a crucial role. We further describe analytical workflows that allow fractionating proteins and peptides prior to LC-MS/MS analysis and discuss their merits and potential pitfalls.
Materials Science and Engineering of the Low Temperature Sensitive Liposome (LTSL): Composition-Structure-Property Relationships That Underlie its Design and Performance
Authors: Needham David , Dewhirst Mark W.
Published: June 2013

This chapter presents the material science and materials engineering concepts that went into the design and testing of the Low Temperature-Sensitive Liposome (LTSL), including: the roles of each of the components that make up the composite membrane; how the molecular and nanostructures that they form might influence the already anomalous permeability at the phase transition of the bilayer; and how this thermally sensitive “Smart Drug Delivery System” leads to ultrafast release of a loaded doxorubicin drug, triggered and controlled in the micro-vasculature of tumors by applied mild hyperthermia. This formulation approach, as ThermoDox®, has been used in a completed 700-patient Phase III human clinical trial in liver cancer (HEAT study), is in a Phase II trial in chest wall recurrence of cancer (DIGNITY study) and has been used in a Phase I trial of patients with colorectal liver metastases (ABLATE study). With additional research and preclinical studies underway, and a range of other drugs, imaging agents and biological modifiers poised for encapsulation, the LTSL could provide a new paradigm for drug and agent delivery for the treatment of localized tumors: rapid triggered drug release in the tumor bloodstream and deep penetration of drug into the tumor tissue.
Smart Dendrimers
Authors: Kojima Chie
Published: June 2013

Dendrimers are synthetic macromolecules with well-defined structures, many terminal functional groups and an inner space that can hold small molecules. These properties make dendrimers potential drug carriers. Recently, stimuli-responsive drug-delivery systems (DDSs) have become attractive because of their reduced side effects and provision of maximal drug action. This chapter reviews the properties of various dendrimer nanoparticles, in particular their sensitivity to stimuli including temperature, light, pH, redox state and enzymatic activity. Strategies for the design of dendrimers for stimuli-responsive DDS are provided. Because the combination of diagnosis and drug delivery is very attractive for DDS, this chapter also discusses theragnostic dendrimers; i.e. the use of smart dendrimers for therapy and diagnosis. These smart dendrimers are useful for next generation DDS.
Discovery and Clinical Validation of HCV Inhibitors Targeting the NS5A Protein
Authors: Belema Makonen , Meanwell Nicholas A. , Bender John A. , Lopez Omar D. , Hewawasam Piyasena , Langley David R.
Published: June 2013

HCV non‐structural protein 5A (NS5A) is a multifunctional protein that plays a diverse set of roles in the replication cycle of the virus. Although a significant level of effort has been invested over the past decade at characterizing this protein, our understanding and appreciation of its full structure and function remain far from complete. Despite these drawbacks, however, great strides have been made towards discovering potent HCV NS5A inhibitors that have exhibited promising efficacy in early clinical trials, and these inhibitors have the potential to become an integral component of effective combination therapies that are expected to emerge in the near future. Highlights of the biochemical characterization of the HCV NS5A protein, aspects of the seminal drug discovery effort that culminated in the identification of daclatasvir with which clinical proof‐of‐concept was obtained for NS5A as a target and the follow‐up efforts that identified additional inhibitors, along with findings from mode‐of‐action studies, are discussed.
Phenotypic Screening to Discover Inhibitors of Dengue Virus
Authors: Wang Qing‐Yin , Zou Bin , Teague Simon J. , Shi Pei‐Yong
Published: June 2013

Dengue is the most prevalent mosquito‐borne viral disease, posing a public health threat to 2.5 billion people worldwide. No clinically approved vaccine or antiviral therapy is currently available. Toward the development of antivirals for the treatment of dengue virus, we have established and applied various cell‐based phenotypic assays to screen large compound libraries. Our screening effort has led to the identification of inhibitors of dengue virus with distinct modes of action. This chapter reviews (i) the overall approaches for anti‐dengue drug discovery, (ii) the current status of cellular phenotypic screening assays for dengue virus and (iii) characterization of three classes of small inhibitors identified from the phenotypic screening. It remains to be determined whether these inhibitors could be further developed into clinical candidates for the treatment of dengue virus infection. However, considering the success of cell‐based screening in the development of antivirals for human immunodeficiency virus and hepatitis C virus, we expect that phenotypic screening should ultimately yield clinical candidates for dengue virus in the near future.
HCV Replication Inhibitors That Interact with NS4B
Authors: Roberts Christopher D. , Peat Andrew J.
Published: June 2013

We describe the discovery, development and in vivo activity of small molecules that inhibits HCV replication via direct interaction with the viral NS4B protein. The inhibitors were identified through a phenotypic, cell based, high throughput screen using the HCV subgenomic replicon. Compounds were then optimized to extremely high potency and pharmacokinetics. Mechanistic data generated suggests a hypothesis wherein the compounds described function by binding to NS4B, preventing the formation of the characteristic HCV induced sub‐cellular membranous web required for viral replication. Finally, in vivo proof of mechanism was established by employing a chimeric “humanized” mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo.
Virus‐coded Ion Channels as Antiviral Targets
Authors: Griffin Stephen
Published: June 2013

Ion channels constitute effective drug targets for myriad human diseases. Thus, essential ion channels encoded by globally important viruses represent an important opportunity for intervention. However, efforts targeting ‘viroporins’ to date are limited, with a single clinical precedent of adamantanes targeting influenza M2 proton channels. M2 inhibitors both help and hinder perceptions of viroporins as drug targets, providing proof‐of‐principle on the one hand, but now being clinically inexpedient due to resistance. This is perhaps unsurprising as 20 years passed between their identification and defining their mode of action, making them the equivalent of early ‘hits’ by today’s standards. Historically, viroporin research has been hampered by combined inherent difficulties of membrane protein biology and virus culture, with a lack of structural information in many cases. Efforts to improve or identify new viroporin inhibitors have been similarly restricted, with most examples comprising a handful of prototypic molecules. However, growing research focus has allowed revisitation of viroporins as drug targets, developing screening technologies and rapidly expanding structural information. As such, viroporins retain significant potential as an untapped area in drug discovery, increasingly amenable to modern methods, and applicable to some of the most significant viral challenges to human health.