bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacologic Use of Niacin
Authors: Prousky Jonathan , Millman Christine G. , Kirkland James B.
Published: March 2011

Niacin is required for a host of critical redox and adenosine diphosphate-ribosylation reactions in metabolism. Niacin deficiency leads to the distinctive signs and symptoms of pellagra, but these can happen in an unpredictable progression and can be altered in patients with polymorphisms in any of the hundreds of niacin-dependent enzymes. The symptomatology of niacin deficiency is becoming a forgotten knowledge base, and niacin deficiency is likely underdiagnosed. Additionally, high levels of niacin and niacinamide have pharmacological effects distinct from their role as sources of vitamin B3, allowing a wide range of effects on processes such as blood flow and lipid metabolism, which can be used to treat or prevent a variety of disease processes.
Effect of Process and Material Parameters On Interlayer Peel Strength in Coextrusion Coating, Film Casting and Film Blowing
Authors: Morris Barry A.
Published: March 2011

Peel strength between layers in coextruded cast film and extrusion coating is found to increase with increasing process time, defined as the time between the die exit and when the polymer is quenched. The results suggest that adhesion is limited by the time and temperature available for bonding after new interfacial area is created during drawing. This contrasts with previous work in blown film where increases in peel strength with process time were attributed primarily to stress effects. The results from both processes, however, were found to collapse onto a single master curve by multiplying the peel strength by a function of the tie resin modulus and dividing the process time by the tie resin relaxation time.
Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase
Authors: Parry Erin M. , Alder Jonathan K. , Qi Xiaodong , Chen Julian J.-L. , Armanios Mary
Published: March 2011

Mutations in the essential telomerase components hTERT and hTR cause dyskeratosis congenita, a bone marrow failure syndrome characterized by mucocutaneous features. Some (∼ 3%) sporadic aplastic anemia (AA) and idiopathic pulmonary fibrosis cases also carry mutations in hTERT and hTR. Even though it can affect clinical outcome, because the mutation frequency is rare, genetic testing is not standard. We examined whether the cooccurrence of bone marrow failure and pulmonary fibrosis in the same individual or family enriches for the presence of a telomerase mutation. Ten consecutive individuals with a total of 36 family members who fulfilled these criteria carried a germline mutant telomerase gene (100%). The mean age of onset for individuals with AA was significantly younger than that for those with pulmonary fibrosis (14 vs 51; P < .0001). Families displayed autosomal dominant inheritance and there was an evolving pattern of genetic anticipation, with the older generation primarily affected by pulmonary fibrosis and successive generations by bone marrow failure. The cooccurrence of AA and pulmonary fibrosis in a single patient or family is highly predictive for the presence of a germline telomerase defect. This diagnosis affects the choice of bone marrow transplantation preparative regimen and can prevent morbidity.
Impact of inhaled corticosteroid use on outcome in COPD patients admitted with pneumonia
Authors: Singanayagam A. , Chalmers J.D. , Akram A.R. , Hill A.T.
Published: March 2011

The aim of this study was to investigate whether inhaled corticosteroid (ICS) use affects outcome in patients with chronic obstructive pulmonary disease (COPD) admitted with community-acquired pneumonia (CAP).

This was a prospective, observational study of patients with spirometry-confirmed COPD presenting with a primary diagnosis of CAP in Lothian, UK. Outcome measures were compared between ICS users and non-ICS users.

Of 490 patients included in the study, 76.7% were classified as ICS users. ICS users had higher Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage compared with non-ICS users (mean±sd3.2±0.8versus2.6±0.9; p<0.0001). There were no significant differences in pneumonia severity (mean±sdPneumonia Severity Index (PSI) 4.2±0.8versus4.3±0.8 (p = 0.3); mean±sdCURB-65 score 2.1±1.3versus2.3±1.3 (p = 0.07)) or markers of systemic inflammation (median C-reactive protein 148 (interquartile range 58–268) mg·L−1versus183 (IQR 85–302) mg·L−1; p = 0.08) between ICS users and non-ICS users. On multivariable analysis, after adjustment for COPD severity and PSI, ICS use was not independently associated with 30-day mortality (OR 1.71, 95% CI 0.75–3.90; p = 0.2), 6-month mortality (OR 1.62, 95% CI 0.82–3.16; p = 0.2), requirement for mechanical ventilation and/or inotropic support (OR 0.73, 95% CI 0.33–1.62; p = 0.4) or development of complicated pneumonia (OR 0.71, 95% CI 0.25–1.99; p = 0.5).

Prior ICS use had no impact on outcome in patients with COPD admitted with CAP.
Disaturated-phosphatidylcholine and Surfactant protein-B turnover in human acute lung injury and in control patients
Authors: Simonato Manuela , Baritussio Aldo , Ori Carlo , Vedovelli Luca , Rossi Sandra , Massara Lorenza Dalla , Rizzi Sabina , Carnielli Virgilio P , Cogo Paola E
Published: March 2011

Background

Patients with Adult Respiratory Distress Syndrome (ARDS) and Acute Lung Injury (ALI) have low concentrations of disaturated-phosphatidylcholine and surfactant protein-B in bronchoalveolar lavage fluid. No information is available on their turnover.

Objectives

To analyze disaturated-phosphatidylcholine and surfactant protein-B turnover in patients with ARDS/ALI and in human adults with normal lungs (controls).

Methods

2H2O as precursor of disaturated-phosphatidylcholine-palmitate and 113C-Leucine as precursor of surfactant protein-B were administered intravenously to 12 patients with ARDS/ALI and to 8 controls. Disaturated-phosphatidylcholine and surfactant protein-B were isolated from serial tracheal aspirates, and their fractional synthetic rate was derived from the 2H and 13C enrichment curves, obtained by gas chromatography mass spectrometry. Disaturated-phosphatidylcholine, surfactant protein-B, and protein concentrations in tracheal aspirates were also measured.

Results

1) Surfactant protein-B turned over at faster rate than disaturated-phosphatidylcholine both in ARDS/ALI patients and in controls. 2) In patients with ARDS/ALI the fractional synthesis rate of disaturated-phosphatidylcholine was 3.1 times higher than in controls (p < 0.01), while the fractional synthesis rate of surfactant protein-B was not different. 3) In ARDS/ALI patients the concentrations of disaturated-phosphatidylcholine and surfactant protein-B in tracheal aspirates were markedly and significantly reduced (17% and 40% of the control values respectively).

Conclusions

1) Disaturated-phosphatidylcholine and surfactant protein-B have a different turnover both in healthy and diseased lungs. 2) In ARDS/ALI the synthesis of these two surfactant components may be differently regulated.
Recovery of brachial plexus lesions resulting from heavy backpack use: A follow-up case series
Authors: Nylund Tuula , Mattila Ville M , Salmi Tapani , Pihlajamäki Harri K , Mäkelä Jyrki P
Published: March 2011

Background

Brachial plexus lesions as a consequence of carrying a heavy backpack have been reported, but the typical clinical course and long-term consequences are not clear. Here we evaluated the clinical course and pattern of recovery of backpack palsy (BPP) in a large series of patients.

Methods

Thirty-eight consecutive patients with idiopathic BPP were identified from our population of 193,450 Finnish conscripts by means of computerised register. A physiotherapist provided instructions for proper hand use and rehabilitative exercises at disease onset. The patients were followed up for 2 to 8 years from the diagnosis. We also searched for genetic markers of hereditary neuropathy with pressure palsies. Mann-Whitney U-test was used to analyze continuous data. The Fischer's exact test was used to assess two-way tables.

Results

Eighty percent of the patients recovered totally within 9 months after the onset of weakness. Prolonged symptoms occurred in 15% of the patients, but daily activities were not affected. The weight of the carried load at the symptom onset significantly affected the severity of the muscle strength loss in the physiotherapeutic testing at the follow-up. The initial electromyography did not predict recovery. Genetic testing did not reveal de novo hereditary neuropathy with pressure palsies.

Conclusions

The prognosis of BPP is favorable in the vast majority of cases. Electromyography is useful for diagnosis. To prevent brachial plexus lesions, backpack loads greater than 40 kg should be avoided.
An integrative approach to identifying cancer chemoresistance-associated pathways
Authors: Chao Shih-Yi , Chiang Jung-Hsien , Huang A-Mei , Chang Woan-Shan
Published: March 2011

Background

Resistance to chemotherapy severely limits the effectiveness of chemotherapy drugs in treating cancer. Still, the mechanisms and critical pathways that contribute to chemotherapy resistance are relatively unknown. This study elucidates the chemoresistance-associated pathways retrieved from the integrated biological interaction networks and identifies signature genes relevant for chemotherapy resistance.

Methods

An integrated network was constructed by collecting multiple metabolic interactions from public databases and the k-shortest path algorithm was implemented to identify chemoresistant related pathways. The identified pathways were then scored using differential expression values from microarray data in chemosensitive and chemoresistant ovarian and lung cancers. Finally, another pathway database, Reactome, was used to evaluate the significance of genes within each filtered pathway based on topological characteristics.

Results

By this method, we discovered pathways specific to chemoresistance. Many of these pathways were consistent with or supported by known involvement in chemotherapy. Experimental results also indicated that integration of pathway structure information with gene differential expression analysis can identify dissimilar modes of gene reactions between chemosensitivity and chemoresistance. Several identified pathways can increase the development of chemotherapeutic resistance and the predicted signature genes are involved in drug resistant during chemotherapy. In particular, we observed that some genes were key factors for joining two or more metabolic pathways and passing down signals, which may be potential key targets for treatment.

Conclusions

This study is expected to identify targets for chemoresistant issues and highlights the interconnectivity of chemoresistant mechanisms. The experimental results not only offer insights into the mode of biological action of drug resistance but also provide information on potential key targets (new biological hypothesis) for further drug-development efforts.
A 5-year longitudinal study of schistosomiasis transmission in Shian village, the Anning River Valley, Sichuan Province, the Peoples' Republic of China
Authors: Zhu Rong , Gray Darren J , Thrift Aaron P , Williams Gail M , Zhang Yi , Qiu Dong-Chuan , Zheng Feng , Li Yue-Sheng , Guo Jiagang , Zhu Hong-Qing , Wu Wei-Ping , Li Robert S , McManus Donald P
Published: March 2011

Background

Schistosoma japonicum is a major public health concern in the Peoples' Republic of China (PRC), with over one million people infected and another 50 million living in areas at risk of infection. Based on ecological, environmental, population genetic and molecular factors, schistosomiasis transmission in PRC can be categorised into four discrete ecosystems or transmission modes. It is predicted that the Three Gorges Dam (TGD) will impact upon the transmission of schistosomiasis in the PRC, with varying degree across the four transmission modes. We undertook longitudinal surveillance from 2002 to 2006 in sentinel villages both above and below the TGD across five provinces (Hunan, Jiangxi, Hubei, Anhui and Sichuan) to determine whether there was any impact of the TGD on schistosomiasis transmission during its construction. Here we present the results from a schistosomiasis-endemic village located above the dam in Sichuan Province.

Results

Baseline results showed a human S. japonicum prevalence of 42.0% (95% CI: 36.6-47.5). At follow-up, results showed that the incidence of S. japonicum infection in the selected human cohort in Shian decreased by three quarters from 46% in 2003 to 11.3% in 2006. A significant (P < 0.01) downward trend was also evident in the yearly adjusted (for water contact) odds ratios. Over the four years of follow-up, the incidence of S. japonicum infection in bovines declined from 11.8% in the first year to zero in the final year of follow-up.

Conclusions

The substantial decrease in human (75%) and bovine (100%) incidence observed in Shian village can probably be attributed to the annual human and bovine PZQ treatment of positives; as seen in drug (PZQ) intervention studies in other parts of PRC. If an increase in schistosome transmission had occurred as a result of the TGD, it would be of negligible size compared to the treatment induced decline seen here. It appears therefore that the construction of the TGD had virtually no impact on schistosomiasis transmission in Shian village over the period of study. Furthermore, contrary to previous reports from Sichuan downplaying the role of animals in human schistosome transmission, bovines may indeed play a role.
Detecting stratigraphic discontinuities using time-frequency seismic phase residues
Authors: Matos Marcílio Castro de , Davogustto Oswaldo , Zhang Kui , Marfurt Kurt J.
Published: March 2011

Spectral decomposition is a proven, powerful means of identifying strong amplitude anomalies at specific frequencies that are otherwise buried in the broadband response. Most publications focus on using spectral magnitude instead of phase components to identify lateral changes in stratigraphy, wavefield attenuation from the quality factor Q, and unconformities between geologic formations. Although seismic acquisition and processing preserve phase very well, little has been published about interpreting the phase components resulting from spectral decomposition. Morlet complex wavelet transform phase residues can improve seismic spectral decomposition interpretation by detecting the phase discontinuities in the joint time-frequency spectral phase component. Phase singularities can be associated with geologic features, and work with phase residues can improve interpretation of the Anadarko basin Red Fork channels of Oklahoma, U.S.A.
Growth Hormone Treatment in Short Children Born Prematurely—Data from KIGS
Authors: Boguszewski Margaret C. S. , Karlsson Hanna , Wollmann Hartmut A. , Wilton Patrick , Dahlgren Jovanna
Published: March 2011

Context:

Children born prematurely with growth failure might benefit from GH treatment.

Objectives:

The aim was to evaluate the first year growth response to GH treatment in short children born prematurely and to identify predictors of the growth response.

Design/Patients:

A total of 3215 prepubertal children born prematurely who were on GH treatment were selected from KIGS (The Pfizer International Growth Database), a large observational database. They were classified according to gestational age as preterm (PT; 33 to no more than 37 wk) and very preterm (VPT; <33 wk), and according to birth weight as appropriate for gestational age [AGA; between −2 and +2 sd score (SDS)] and small for gestational age (SGA; −2 SDS or below).

Results:

Four groups were identified: PT AGA (n = 1928), VPT AGA (n = 629), PT SGA (n = 519), and VPT SGA (n = 139). GH treatment was started at a median age of 7.5, 7.2, 6.7, and 6.0 yr, respectively. After the first year of GH treatment, all four groups presented a significant increase in weight gain and height velocity, with a median increase in height SDS higher than 0.6. Using multiple stepwise regression analysis, 27% of the variation in height velocity could be explained by the GH dose, GH peak during provocative test, weight and age at GH start, adjusted parental height, and birth weight SDS. The first year growth response of the children born PT and SGA could be estimated by the SGA model published previously.

Conclusion:

Short children born prematurely respond well to the first year of GH treatment. Long-term follow-up is needed.
Arterial-venous network formation during brain vascularization involves hemodynamic regulation of chemokine signaling
Authors: Bussmann Jeroen , Wolfe Scot A. , Siekmann Arndt F.
Published: March 2011

During angiogenic sprouting, newly forming blood vessels need to connect to the existing vasculature in order to establish a functional circulatory loop. Previous studies have implicated genetic pathways, such as VEGF and Notch signaling, in controlling angiogenesis. We show here that both pathways similarly act during vascularization of the zebrafish central nervous system. In addition, we find that chemokine signaling specifically controls arterial-venous network formation in the brain. Zebrafish mutants for the chemokine receptor cxcr4a or its ligand cxcl12b establish a decreased number of arterial-venous connections, leading to the formation of an unperfused and interconnected blood vessel network. We further find that expression of cxcr4a in newly forming brain capillaries is negatively regulated by blood flow. Accordingly, unperfused vessels continue to express cxcr4a, whereas connection of these vessels to the arterial circulation leads to rapid downregulation of cxcr4a expression and loss of angiogenic characteristics in endothelial cells, such as filopodia formation. Together, our findings indicate that hemodynamics, in addition to genetic pathways, influence vascular morphogenesis by regulating the expression of a proangiogenic factor that is necessary for the correct pathfinding of sprouting brain capillaries.
Role of epidermal primary cilia in the homeostasis of skin and hair follicles
Authors: Croyle Mandy J. , Lehman Jonathan M. , O'Connor Amber K. , Wong Sunny Y. , Malarkey Erik B. , Iribarne Daniela , Dowdle William E. , Schoeb Trenton R. , Verney Zoe M. , Athar Mohammad , Michaud Edward J. , Reiter Jeremy F. , Yoder Bradley K.
Published: March 2011

Skin and hair follicle morphogenesis and homeostasis require the integration of multiple signaling pathways, including Hedgehog (Hh) and Wingless (Wnt), and oriented cell divisions, all of which have been associated with primary cilia. Although studies have shown that disrupting dermal cilia causes follicular arrest and attenuated Hh signaling, little is known about the role of epidermal cilia. Here, epidermal cilia function was analyzed using conditional alleles of the ciliogenic genes Ift88 and Kif3a. At birth, epidermal cilia mutants appeared normal, but developed basaloid hyperplasia and ingrowths into the dermis of the ventrum with age. In addition, follicles in the tail were disorganized and had excess sebaceous gland lobules. Epidermal cilia mutants displayed fewer long-term label-retaining cells, suggesting altered stem cell homeostasis. Abnormal proliferation and differentiation were evident from lineage-tracing studies and showed an expansion of follicular cells into the interfollicular epidermis, as is seen during wound repair. These phenotypes were not associated with changes in canonical Wnt activity or oriented cell division. However, nuclear accumulation of the ΔNp63 transcription factor, which is involved in stratification, keratinocyte differentiation and wound repair, was increased, whereas the Hh pathway was repressed. Intriguingly, the phenotypes were not typical of those associated with loss of Hh signaling but exhibited similarities with those of mice in which ΔNp63 is overexpressed in the epidermis. Collectively, these data indicate that epidermal primary cilia may function in stress responses and epidermal homeostasis involving pathways other than those typically associated with primary cilia.
Extensive scar formation and regression during heart regeneration after cryoinjury in zebrafish
Authors: González-Rosa Juan Manuel , Martín Víctor , Peralta Marina , Torres Miguel , Mercader Nadia
Published: March 2011

The zebrafish heart has the capacity to regenerate after ventricular resection. Although this regeneration model has proved useful for the elucidation of certain regeneration mechanisms, it is based on the removal of heart tissue rather than its damage. Here, we characterize the cellular response and regenerative capacity of the zebrafish heart after cryoinjury, an alternative procedure that more closely models the pathophysiological process undergone by the human heart after myocardial infarction (MI). Localized damage was induced in 25% of the ventricle by cryocauterization (CC). During the first 24 hours post-injury, CC leads to cardiomyocyte death within the injured area and the near coronary vasculature. Cell death is followed by a rapid proliferative response in endocardium, epicardium and myocardium. During the first 3 weeks post-injury cell debris was cleared and the injured area replaced by a massive scar. The fibrotic tissue was subsequently degraded and replaced by cardiac tissue. Although animals survived CC, their hearts showed nonhomogeneous ventricular contraction and had a thickened ventricular wall, suggesting that regeneration is associated with processes resembling mammalian ventricular remodeling after acute MI. Our results provide the first evidence that, like mammalian hearts, teleost hearts undergo massive fibrosis after cardiac damage. Unlike mammals, however, the fish heart can progressively eliminate the scar and regenerate the lost myocardium, indicating that scar formation is compatible with myocardial regeneration and the existence of endogenous mechanisms of scar regression. This finding suggests that CC-induced damage in zebrafish could provide a valuable model for the study of the mechanisms of scar removal post-MI.
The pipsqueak-domain proteins Distal antenna and Distal antenna-related restrict Hunchback neuroblast expression and early-born neuronal identity
Authors: Kohwi Minoree , Hiebert Laurel S. , Doe Chris Q.
Published: March 2011

A fundamental question in brain development is how precursor cells generate a diverse group of neural progeny in an ordered manner. Drosophila neuroblasts sequentially express the transcription factors Hunchback (Hb), Krüppel (Kr), Pdm1/Pdm2 (Pdm) and Castor (Cas). Hb is necessary and sufficient to specify early-born temporal identity and, thus, Hb downregulation is essential for specification of later-born progeny. Here, we show that distal antenna (dan) and distal antenna-related (danr), encoding pipsqueak motif DNA-binding domain protein family members, are detected in all neuroblasts during the Hb-to-Cas expression window. Dan and Danr are required for timely downregulation of Hb in neuroblasts and for limiting the number of early-born neurons. Dan and Danr function independently of Seven-up (Svp), an orphan nuclear receptor known to repress Hb expression in neuroblasts, because Dan, Danr and Svp do not regulate each other and dan danr svp triple mutants have increased early-born neurons compared with either dan danr or svp mutants. Interestingly, misexpression of Hb can induce Dan and Svp expression in neuroblasts, suggesting that Hb might activate a negative feedback loop to limit its own expression. We conclude that Dan/Danr and Svp act in parallel pathways to limit Hb expression and allow neuroblasts to transition from making early-born neurons to late-born neurons at the proper time.
Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation
Authors: Kim Jin-Hong , Asthagiri Anand R.
Published: March 2011

Anchorage to a compliant extracellular matrix (ECM) and contact with neighboring cells impose important constraints on the proliferation of epithelial cells. How anchorage and contact dependence are inter-related and how cells weigh these adhesive cues alongside soluble growth factors to make a net cell cycle decision remain unclear. Here, we show that a moderate 4.5-fold stiffening of the matrix reduces the threshold amount of epidermal growth factor (EGF) needed to over-ride contact inhibition by over 100-fold. At EGF doses in the range of the dissociation constant (Kd) for ligand binding, epithelial cells on soft matrices are contact inhibited with DNA synthesis restricted to the periphery of cell clusters. By contrast, on stiff substrates, even EGF doses at sub-Kd levels over-ride contact inhibition, leading to proliferation throughout the cluster. Thus, matrix stiffening significantly sensitizes cells to EGF, enabling contact-independent spatially uniform proliferation. Contact inhibition on soft substrates requires E-cadherin, and the loss of contact inhibition upon matrix stiffening is accompanied by the disruption of cell–cell contacts, changes in the localization of the EGF receptor and ZO-1, and selective attenuation of ERK, but not Akt, signaling. We propose a quantitative framework for the epigenetic priming (via ECM stiffening) of a classical oncogenic pathway (EGF) with implications for the regulation of tissue growth during morphogenesis and cancer progression.
Functional interactions of Rec24, the fission yeast ortholog of mouse Mei4, with the meiotic recombination–initiation complex
Authors: Bonfils Sandrine , Rozalén Ana E. , Smith Gerald R. , Moreno Sergio , Martín-Castellanos Cristina
Published: March 2011

A physical connection between each pair of homologous chromosomes is crucial for reductional chromosome segregation during the first meiotic division and therefore for successful meiosis. Connection is provided by recombination (crossing over) initiated by programmed DNA double-strand breaks (DSBs). Although the topoisomerase-like protein Spo11 makes DSBs and is evolutionarily conserved, how Spo11 (Rec12 in fission yeast) is regulated to form DSBs at the proper time and place is poorly understood. Several additional (accessory) proteins for DSB formation have been inferred in different species from yeast to mice. Here, we show that Rec24 is a bona fide accessory protein in Schizosaccharomyces pombe. Rec24 is required genome-wide for crossing-over and is recruited to meiotic chromosomes during prophase in a Rec12-independent manner forming foci on linear elements (LinEs), structurally related to the synaptonemal complex of other eukaryotes. Stabilization of Rec24 on LinEs depends on another accessory protein, Rec7, with which Rec24 forms complexes in vivo. We propose that Rec24 marks LinE-associated recombination sites, that stabilization of its binding by Rec7 facilitates the loading or activation of Rec12, and that only stabilized complexes containing Rec24 and Rec7 promote DSB formation. Based on the recent report of Rec24 and Rec7 conservation, interaction between Rec24 and Rec7 might be widely conserved in DSB formation.
PERSPECTIVE—The Sociological Ambivalence of Bureaucracy: From Weber via Gouldner to Marx
Authors: Adler Paul S.
Published: March 2011

Reports of the demise of the bureaucratic form of organization are greatly exaggerated, and debates about bureaucracy's functions and effects therefore persist. For many years, a broad current of organizational scholarship has taken inspiration from Max Weber's image of bureaucracy as an “iron cage” and has seen bureaucracy as profoundly ambivalent—imposing alienation as the price of efficiency. Following a path originally sketched by Alvin Gouldner [Gouldner, A. W. 1954. Patterns of Industrial Bureaucracy. Free Press, Glencoe, IL], some recent research has challenged this view as overly pessimistic, arguing that bureaucracy need not always be coercive but can sometimes take a form that is experienced as enabling. The present article challenges both Weber's and Gouldner's accounts, arguing that although bureaucracy's enabling role may sometimes be salient to employees, even when it is, bureaucracy typically appears to them as ambivalent—simultaneously enabling and coercive. I offer an unconventional reading of Marx as a way to make sense of this ambivalence.
From Old Competence Destruction to New Competence Access: Evidence from the Comparison of Two Discontinuities in Anticancer Drug Discovery
Authors: Sosa M. Lourdes
Published: March 2011

Research in creative destruction has argued that competence-destroying discontinuities result in incumbents' underperformance in research and development (R&D) with respect to entrants, even if complementary assets aid incumbents in retaining market share. In this paper, I propose that attention to the extent of competence destruction is necessary but not sufficient. An analysis of differences in R&D performance through a discontinuity requires assessment not only of old competence destruction but also of new competence access; that is, it requires assessment of both old capability obsolescence and new capability acquisition. I find evidence for this proposition in data from the biotechnology disruption to the anticancer drug market. In particular, my research design is a within-market matched pair of discontinuities: from chemotherapy to small-molecule targeted drugs, and from chemotherapy to large-molecule targeted drugs. Although equally competence destroying, the two discontinuities differ in the access incumbents have to the new capabilities required: whereas all new capabilities are available in the former, one new capability is inaccessible to incumbents (and to many entrants) in the latter. The contrasting results of these two discontinuities support my proposition: in the competence-destroying discontinuity with full access to new capabilities, incumbents did not fall behind entrants; in the other discontinuity, incumbents fell behind only those entrants that owned the difficult-to-access new capability. I close with implications for research in creative destruction, in rational adaptation to environmental change, and in strategic renewal.
PERSPECTIVE—Explaining Influence Rents: The Case for an Institutions-Based View of Strategy
Authors: Ahuja Gautam , Yayavaram Sai
Published: March 2011

Research in strategy has identified and tried to explain four types of rents: monopolistic rents, efficiency rents, quasi rents, and Schumpeterian rents. Building on previous work on political and institutional strategies, we add a fifth type of rent: influence rents. Influence rents are the extra profits earned by a firm because the rules of the game (laws, regulations, and informal rules) are designed or changed to suit it. To aid the analysis of the relationship between institutional context and firm performance and to provide a structure to guide research, we develop a framework with five key components: (a) an identification of the five fundamental problems of a market economy, (b) a typology that describes the five different types of institutions that emerge to solve these problems, (c) the market-ordering mechanisms used by institutions to solve these problems, (d) the common causes of weak institutional performance, and (e) generic strategies used by firms to exploit these weaknesses of an institutional context to enhance firm performance. We highlight potential applications of the framework as well as an illustrative research agenda that can advance the development of theory to explain the emergence and persistence of influence rents.
The (N)Ever-Changing World: Stability and Change in Organizational Routines
Authors: Pentland Brian T. , Hærem Thorvald , Hillison Derek
Published: March 2011

This paper uses data on invoice processing in four organizations to distinguish empirically between two competing theories of organizational routines. One theory predicts that routines should generate patterns of action that are few in number and stable over time, and that atypical patterns of action are driven primarily by exceptional inputs. The competing theory predicts the opposite. By modeling the routines as networks of action and using a first-order Markov model to test for stationarity, we find support for the competing theory. The routines generated hundreds of unique patterns that changed significantly during a five-month period without any apparent external intervention. Changes did not appear to reflect improved performance or learning. Furthermore, we found that exogenous factors (such as large invoices from unusual vendors) are not associated with atypical patterns of action, but endogenous factors (such as the experience of the participants) are. We also found that increased automation can increase variation under some circumstances. These findings offer empirical support for endogenous change in organizational routines and underscore the importance of the sociomaterial context in understanding stability and change.
Cancer biomarkers for hepatocellular carcinomas: from traditional markers to recent topics
Authors: Masuda Tomomi , Miyoshi Eiji
Published: March 2011

Hepatocellular carcinomas (HCC) are the fifth most common tumor type and the third most common cause of cancer-related death worldwide. Some tumor markers for HCC, such as α-fetoprotein and des-γ-carboxyprothrombin, are used clinically. Recent advances in proteomics and glyco-proteomics might provide various types of novel tumor markers for HCC. While the clinical availability of these tumor markers is important, the molecular mechanisms underlying the production of tumor markers requires further clarification. Our group has investigated the glycobiology of tumor markers. In this review, we describe the impact of novel HCC markers and their possible implications for clinical use.
Perchlorate (Irenat®) may falsely lower measured ionised calcium
Authors: Gruber Michael , Nehring Carsten , Creutzenberg Marcus , Graf Bernhard , Hopf Susanne
Published: March 2011

Background:Discrepancies in ionised calcium concentrations between results from several point-of-care devices derived from intensive care unit (ICU) patients were postulated to be caused by perchlorate, a thyroid blocking agent. The deviations were serious concerning the diagnosis of hyper- or hypocalcaemia and administration of calcium infusions.

Methods:The problem was studied from three perspectives. First: quantification of ionised calcium in heparinised blood samples spiked with sodium perchlorate from healthy volunteers measured using five blood gas analysers (BGAs from IL, Radiometer, Roche and Siemens). Second: verification of clinical concentrations of perchlorate in blood samples after routine use for blood gas analysis from ICU patients. Third: retrospective analysis of data stored from patients during their stay in general ICU of the Departments of Anesthesio-logy and General Surgery by a patient data management system.

Results:Category 1: three of the point-of-care testing devices measure clinically relevant falsely low ionised calcium concentrations when exposed to concentrations perchlorate >0.1 mmol/L. Two were not able to identify hypercalcaemia of up to 4 mmol/L ionised calcium when specific perchlorate concentrations are exceeded. Category 2: measured clinical concentrations of perchlorate ranged between the lower limit of quantification [LOQ=0.03 mmol/L and 2.75 mmol/L (median=0.29 mmol/L; mean=0.585 mmol/L)]. A concentration above 0.1 mmol/L perchlorate was found in 74.3% of all samples that tested positive. Category 3: between February 2006 and July 2009, 42 patients per year (2.2%) received sodium perchlorate with a median length of treatment of 25 days.

Conclusions:Perchlorate causes clinically relevant lowering of measured ionised calcium in BGAs from two providers at concentrations obtained in samples from ICU patients (affecting about 1.1% of all ICU patients).
Focusing on the clinical impact of standardization of creatinine measurements: a report by the EFCC Working Group on Creatinine Standardization
Authors: Delanghe Joris R. , Cobbaert Christa , Harmoinen Aimo , Jansen Rob , Laitinen Päivi , Panteghini Mauro
Published: March 2011

The recent campaign for standardization of creatinine measurements has been promoted to allow the widespread use of formulas for estimating the glomerular filtration rate (GFR). However, studies on trueness verification and measurement interferences still show disappointing interassay variation of serum creatinine results. Creatinine recalibration has major clinical consequences. In particular, in pediatrics where reference ranges for serum and plasma creatinine are low, calculation of the GFR is problematic when based on alkaline picrate methods because of method non-specificity and the lack of appropriate GFR estimating formulas. Therefore, enzymatic creatinine assays are preferred. In the near future, cystatin C might offer an interesting alternative for GFR estimation. For the calculation of drug doses, the Modification of Diet in Renal Disease study formula generally offers reliable data. However, attention has to be paid to the elderly. Also, the calculation of the Model for End-Stage Liver Disease score, which is used to prioritize patients for liver transplantation, may significantly be influenced by recalibration of creatinine assays. Creatinine restandardization may also affect the current guidelines for referral of chronic kidney disease patients to nephrologists.
Messung von absoluten Kugelradiustopografien mit einem Kugelinterferometer
Authors: Bartl Guido , Krystek Michael , Nicolaus Arnold
Published: March 2011

Das Kugelinterferometer der PTB wurde ursprünglich dafür konzipiert, die Volumenbestimmung von sphärischen Maßverkörperungen über präzise Durchmessermessungen mit einer Unsicherheit von einem Nanometer oder weniger zu ermöglichen. Nun wurde ein Verfahren implementiert, mit dem der Verwendungszweck des Interferometers auf Bereiche erweitert werden kann, in denen nicht ein Kugelvolumen oder -durchmesser, sondern eine richtungsabhängige Radiusinformation gefragt ist. Ein Vergleich mit den Ergebnissen von unabhängigen Rundheitsmessungen zeigt eine Genauigkeit im Bereich weniger Nanometer.
Absolute Profilmessung optischer Oberflächen mit Mehrfachsensorsystemen
Authors: Wiegmann Axel , Schulz Michael , Elster Clemens
Published: March 2011

Es wird ein hochgenaues Verfahren und dessen Realisierung zur Messung von Profilschnitten von ausgedehnten (bis zu 1 m großen) optischen Oberflächen vorgestellt. Dabei wird ein kompaktes Interferometer (Aperturdurchmesser 3mm) über den Prüfling geführt und es werden mehrere sich überlappende Teilprofile aufgenommen. Eine zusätzliche Winkelmessung dient als Ebenheitsreferenz. Im Gegensatz zu herkömlichen “Stitching”-Verfahren ermöglicht das vorgestellte Messverfahren z. B. die Messung von Synchrotronspiegeln inklusive ihres parabolischen Anteils mit hoher lateraler Auflösung (Messpunktabstand 20 μm) und hohem Dynamikumfang (“peak-to-valley” Höhe bis 100 μm) bei gleichzeitigen Messunsicherheiten im Nanometer-Bereich. Beispielhaft werden die Ergebnisse einer Profilmessung mit zugehörigen Messunsicherheiten gezeigt.
Radargestützte Mehrobjekt-Verfolgung mit dem PHD-Filter
Authors: Kruse Marco , Puente León Fernando
Published: March 2011

Die Detektion und Verfolgung einer zeitlich variierenden Menge an Objekten ist für viele technische Anwendungen eine Grundvoraussetzung, wobei zukünftige Fahrerassistenzsysteme ein aktuelles Beispiel darstellen. Die Unsicherheiten der Sensorinformation lassen sich hierbei systematisch mit Hilfe der Bayes´schen Statistik handhaben. In diesem Beitrag werden zunächst der Ansatz für das PHD-Filter und anschließend einige ausgewählte Teilaspekte eines darauf basierenden Fusionsframeworks vorgestellt, sowie Fusionsergebnisse sowohl mit synthetischen als auch realen Messdaten präsentiert.
Robuste, adaptive Wireless-Sensor/Aktor-Kommunikation
Authors: Heynicke Ralf , Krüger Dirk , Scholl Gerd
Published: March 2011

Die Wellenausbreitung im industriellen Umfeld kann durch frequenzselektive und zeitvariante Funkkanäle mit hoher Signaldynamik beschrieben werden. Aus diesen können deterministische Muster extrahiert werden, welche bei der Auslegung von Funksystemen zur Steigerung der Robustheit und Leistungsfähigkeit oder zur Verringerung des Energieverbrauchs genutzt werden können.
Faser-Bragg-Gitter zur Detektion von transienten Lasten
Authors: Buck Thorbjörn C. , Müller Mathias S. , Koch Alexander W.
Published: March 2011

Zur Überwachung dynamischer Vorgänge an Luft- und Raumfahrtstrukturen wird ein neuartiges Messgerät zum Auslesen faseroptischer Sensoren entwickelt. Das System basiert auf einer integriert-optischen Komponente, die den Einsatz des Messgeräts unter starken Vibrationen und innerhalb eines großen Temperaturbereichs erlaubt. Das filterbasierte Messverfahren gestattet die Erfassung von dynamischen Vorgängen mit einer Bandbreite von 20kHz. In diesem Artikel präsentieren wir die Grundlagen filterbasierter Messverfahren für Faser-Bragg-Gitter Sensoren sowie den Aufbau und die Funktion des entwickelten Messsystems.
The effects of ACTH on steroid metabolomic profiles in human adrenal cells
Authors: Xing Yewei , Edwards Michael A , Ahlem Clarence , Kennedy Mike , Cohen Anthony , Gomez-Sanchez Celso E , Rainey William E
Published: March 2011

The adrenal glands are the primary source of mineralocorticoids, glucocorticoids, and the so-called adrenal androgens. Under physiological conditions, cortisol and adrenal androgen synthesis are controlled primarily by ACTH. Although it is well established that ACTH can stimulate steroidogenesis in the human adrenal gland, the effect of ACTH on overall production of different classes of steroid hormones has not been defined. In this study, we examined the effect of ACTH on the production of 23 steroid hormones in adult adrenal primary cultures and 20 steroids in the adrenal cell line, H295R. Liquid chromatography/tandem mass spectrometry analysis revealed that, in primary adrenal cell cultures, cortisol and corticosterone were the two most abundant steroid hormones produced with or without ACTH treatment (48 h). Cortisol production responded the most to ACTH treatment, with a 64-fold increase. Interestingly, the production of two androgens, androstenedione and 11β-hydroxyandrostenedione (11OHA), that were also produced in large amounts under basal conditions significantly increased after ACTH incubation. In H295R cells, 11-deoxycortisol and androstenedione were the major products under basal conditions. Treatment with forskolin increased the percentage of 11β-hydroxylated products, including cortisol and 11OHA. This study illustrates that adrenal cells respond to ACTH through the secretion of a variety of steroid hormones, thus supporting the role of adrenal cells as a source of both corticosteroids and androgens.
5′AMP-activated protein kinase activity is increased in adipose tissue of northern elephant seal pups during prolonged fasting-induced insulin resistance
Authors: Viscarra Jose A , Champagne Cory D , Crocker Daniel E , Ortiz Rudy M
Published: March 2011

Northern elephant seals endure a 2- to 3-month fast characterized by sustained hyperglycemia, hypoinsulinemia, and increased plasma cortisol and free fatty acids, conditions often seen in insulin-resistant humans. We had previously shown that adipose Glut4 expression and 5′AMP-activated protein kinase (AMPK) activity increase and plasma glucose decreases in fasting seals suggesting that AMPK activity contributes to glucose regulation during insulin-resistant conditions. To address the hypothesis that AMPK activity increases during fasting-induced insulin resistance, we performed glucose tolerance tests (GTT) on early (n=5) and late (n=8)-fasted seal pups and compared adipose tissue expression of insulin signaling proteins, peroxisome proliferator-activated receptor γ (PPARγ), and AMPK, in addition to plasma adiponectin, leptin, cortisol, insulin, and non-esterified fatty acid (NEFA) levels. Fasting was associated with decreased glucose clearance, plasma insulin and adiponectin, and intracellular insulin signaling, as well as increased plasma cortisol and NEFAs, supporting the suggestion that seals develop insulin resistance late in the fast. The expression of Glut4 and VAMP2 increased (52 and 63% respectively) with fasting but did not change significantly during the GTT. PPARγ and phosphorylated AMPK did not change in the early fasted seals, but increased significantly (73 and 50% respectively) in the late-fasted seals during the GTT. Increased AMPK activity along with the reduction in the activity of insulin-signaling proteins supports our hypothesis that AMPK activity is increased following the onset of insulin resistance. The association between increased AMPK activity and Glut4 expression suggests that AMPK plays a greater role in regulating glucose metabolism in mammals adapted to prolonged fasting than in non-fasting mammals.
The New Zealand obese mouse model of obesity insulin resistance and poor breeding performance: evaluation of ovarian structure and function
Authors: Radavelli-Bagatini Simone , Blair Amy R , Proietto Joseph , Spritzer Poli Mara , Andrikopoulos Sofianos
Published: March 2011

Infertility, associated with oligo/anovulation, increased ovarian volume, numerous follicular cysts, and metabolic disturbances such as obesity and insulin resistance (IR) are characteristics common to polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age. Here, we show that New Zealand obese (NZO) mice display similar metabolic characteristics such as obesity, leptin insensitivity, glucose intolerance, and IR. Importantly, NZO mice are poor breeders; however, the mechanism for this has not been investigated. The aim of this study was to assess the ovarian structure/morphology and sex hormone levels in female NZO and lean C57BL/6J control mice. Twenty-five NZO and twenty female control mice were studied at three different ages (young, adult, and aged). The animals were weighed, an insulin tolerance test was carried out, and blood was collected for measurement of hormone levels. The ovaries were removed for histological analysis. As expected, NZO mice presented higher body weights (P=0.001), increased basal plasma glucose (P=0.007), and insulin levels (P=0.001) as well as IR, compared with control mice. NZO mice showed an increased ovarian volume, reduced numbers of corpora lutea, and higher total follicle numbers (P=0.0001). The number of primordial follicles increased (P=0.02) at the young stage, as well as the amount of atretic follicles (P=0.03), in NZO compared with control mice. NZO mice also displayed reduced plasma LH and increased estradiol levels. In conclusion, NZO mice show a poor breeding performance due to decreased ovulation, increased number of primordial and atretic follicles, and ovarian size. Given that NZO mice are obese, hyperinsulinemic and insulin resistant, they are suitable for investigating pathophysiological mechanisms linking metabolic alterations with reproductive defects.
Bilateral Vertical Segmental Distraction in a Patient with Bilateral Cleft of Lip, Alveolus, and Palate
Authors: Pichelmayer Margit , Zemann Wolfgang
Published: March 2011

In cases of bilateral clefts of lip and palate there is often a vertical and transversal deficit of the cleft segments. Ideally these problems can be solved orthodontically. In severe cases there is a need of surgical support. Distraction osteogenesis allows the correction of transversal, horizontal, and vertical deficits. A case of a 13-year-old girl with a bilateral cleft of lip and palate is presented. The patient had a severe deficit of the distal cleft segments concerning the vertical and transversal dimension. Osteotomy of the segments was performed and a vertical distraction followed by a transpalatal distraction procedure was used to correct the discrepancies.