bluuebunny/crossref_metadata_2025 huggingface dataset:
Proportional hazards models based on biased samples and estimated selection probabilities
Authors: Pan Qing , Schaubel Douglas E.
Published: February 2009

In non‐randomized biomedical studies using the proportional hazards model, the data often constitute an unrepresentative sample of the underlying target population, which results in biased regression coefficients. The bias can be avoided by weighting included subjects by the inverse of their respective selection probabilities, as proposed by Horvitz & Thompson (1952) and extended to the proportional hazards setting for use in surveys by Binder (1992) and Lin (2000). In practice, the weights are often estimated and must be treated as such in order for the resulting inference to be accurate. The authors propose a two‐stage weighted proportional hazards model in which, at the first stage, weights are estimated through a logistic regression model fitted to a representative sample from the target population. At the second stage, a weighted Cox model is fitted to the biased sample. The authors propose estimators for the regression parameter and cumulative baseline hazard. They derive the asymptotic properties of the parameter estimators, accounting for the difference in the variance introduced by the randomness of the weights. They evaluate the accuracy of the asymptotic approximations in finite samples through simulation. They illustrate their approach in an analysis of renal transplant patients using data obtained from the Scientific Registry of Transplant Recipients
Testing homogeneity in a mixture of von mises distributions with a structural parameter
Authors: Chen Jiahua , Li Pengfei , Fu Yuejiao
Published: February 2009

The modified likelihood ratio statistic can be used to test the homogeneity in a variety of mixture models. Here, the authors propose the use of the modified and the iterative modified likelihood ratio for testing homogeneity against a two‐component von Mises mixture with a structural parameter. They derive the limiting distributions of the test statistics and propose methods to improve the accuracy of the asymptotic approximation in finite samples. Their simulations show that the tests maintain their nominal level and that they have adequate power. Data on movements of turtles are used as an illustration
Logistic discrimination using robust estimators: An influence function approach
Authors: Croux Christophe , Haesbroeck Gentiane , Joossens Kristel
Published: February 2009

Logistic regression is frequently used for classifying observations into two groups. Unfortunately there are often outlying observations in a data set and these might affect the estimated model and the associated classification error rate. In this paper, the authors study the effect of observations in the training sample on the error rate by deriving influence functions. They obtain a general expression for the influence function of the error rate, and they compute it for the maximum likelihood estimator as well as for several robust logistic discrimination procedures. Besides being of interest in their own right, the influence functions are also used to derive asymptotic classification efficiencies of different logistic discrimination rules. The authors also show how influential points can be detected by means of a diagnostic plot based on the values of the influence function
Ranked set sampling for ordered categorical variables
Authors: Chen Haiying , Stasny Elizabeth A. , Wolfe Douglas A.
Published: February 2009

The authors show how ranked set sampling, both balanced and unbalanced, can be extended to ordered categorical variables with the goal of estimating the probabilities of all categories. They use ordinal logistic regression to aid in the ranking of the ordinal variable of interest. They also propose an optimal allocation scheme and methods for implementing it under either perfect or imperfect rankings. Results from a simulation study using data from the third National Health and Nutrition Examination Survey indicate that the use of ordinal logistic regression in ranking leads to substantial gains in precision for estimation of cell probabilities.
Forecasting mortality rates via density ratio modeling
Authors: Kedem Benjamin , Lu Guanhua , Wei Rong , Williams Paul D.
Published: February 2009

The authors propose a semiparametric approach to modeling and forecasting age‐specific mortality in the United States. Their method is based on an extension of a class of semiparametric models to time series. It combines information from several time series and estimates the predictive distribution conditional on past data. The conditional expectation, which is the most commonly used predictor in practice, is the first moment of this distribution. The authors compare their method to that of Lee and Carter.
Testing for lack of dependence in the functional linear model
Authors: Kokoszka Piotr , Maslova Inga , Sojka Jan , Zhu Lie
Published: February 2009

The authors consider the linear model Yn = ψXn + ϵn relating a functional response with explanatory variables. They propose a simple test of the nullity of ψ based on the principal component decomposition. The limiting distribution of their test statistic is chi‐squared, but this distribution is also an excellent approximation in finite samples. The authors illustrate their method using data from terrestrial magnetic observatories.
Local influence in multilevel models
Authors: Shi Lei , Chen Gemai
Published: February 2009

The authors study the local influence of observations in multilevel regression models. To this end, they perturb simultaneously the variances, responses and design matrix. To measure the local change caused by these perturbations, they use generalized Cook statistics for the fixed and random parameter estimates. Closed form local influence measures also allow them to assess the joint influence of various observations. They suggest a simple computation method and illustrate their results using two examples.
Nonparametric test for checking lack of fit of the quantité regression model under random censoring
Authors: Wang Lan
Published: February 2009

The author proposes a nonparametric test for checking the lack of fit of the quantile function of survival time given the covariates; she assumes that survival time is subjected to random right censoring. Her test statistic is a kemel‐based smoothing estimator of a moment condition. The test statistic is asymptotically Gaussian under the null hypothesis. The author investigates its behavior under local alternative sequences. She assesses its finite‐sample power through simulations and illustrates its use with the Stanford heart transplant data.
Outcomes of contemporary Interventional Therapy of ST Elevation Infarction in Patients Older than 75 Years
Authors: Zimmermann Stefan , Ruthrof Susanne , Nowak Kathrin , Klinghammer Lutz , Ludwig Josef , Daniel Werner G. , Flachskampf Frank A.
Published: February 2009

Background

Data on contemporary real‐world outcomes of interventional revascularization in patients ≥ 75 y of age with ST elevation infarction (STEMI) are limited.

Methods

We analyzed all 504 consecutive patients who underwent angiography for acute STEMI between 1999 and 2005 at our center, and followed them up over one year. Outcomes in patients ≥ 75 y of age were compared with younger patients.

Results

Patients ≥ 75 y of age (n = 115) were majority females (55% versus 21%, p < 0.001), more cases of diabetes (42% versus 27%, p = 0.004), hypertension (78% versus 65%, p = 0.03) and a history of coronary events (25% versus 15%, p = 0.002). Younger patients were more often smokers (63% versus 30%, p < 0.001). After coronary angiography patients ≥ 75 y of age underwent less frequent intervention (PCI; 84% versus 93%, p = 0.01). However, if PCI was performed, technical success rates were similar to younger patients (84% versus 86%). The 30‐d mortality was 13% versus 6.4% (p = 0.03), but after successful PCI, the 30‐d mortality rate was not significantly higher in old patients (7.4% versus 3.9%, p = 0.23). Bleeding complications were very low in both age groups if the radial access route was chosen. Multivariate predictors of 30‐d mortality were cardiogenic shock/survived cardiac arrest, ejection fraction < 30%, conservative treatment or unsuccessful PCI (OR 3.01), renal insufficiency, diabetes, and age. One‐y mortality was higher in the elderly (24.3% versus 9.9%, p < 0.001). Among 30‐d‐survivors, only multivessel disease and age were multivariate predictors of 1‐y mortality.

Conclusion

Patients ≥ 75 y of age benefit from PCI in STEMI, and failed or unattempted PCI worsens prognosis in the old as well as in younger patients. Copyright © 2009 Wiley Periodicals, Inc.
Essential Thrombocythemia: A Case of Acute ST‐Segment Elevation Myocardial Infarction in a Young Female
Authors: Bildirici Ulas , Celikyurt Umut , Ural Ertan
Published: February 2009

Essential thrombocythemia (ET) is a clonal disorder of the myeloid stem cell that causes abnormal proliferation of the megakaryocytes. The main feature of the disease is arterial and venous thrombosis caused by platelet dysfunction. Coronary artery involvement leading to acute coronary syndromes is a rare complication of the ET. We report a coronary angioplasty and stenting in a 30‐year‐old female patient with acute ST‐segment elevation myocardial infarction (MI) as the first clinical sign of essential thrombocythemia. Facilitated percutaneous coronary intervention with GPIIb/IIIa and/or thrombolytic therapy may be considered as the first treatment modality for this patient group. Copyright © 2009 Wiley Periodicals, Inc.
Would Different Routine Precordial Electrode Positions Be More Useful? Answer: Not Likely
Authors: Willis Hurst J.
Published: February 2009

There are reasons to wonder if the current precordial electrode positions are the best ones to study the electrical forces of the heart. Theoretically, more horizontal electrode positions and several superior and inferior electrode positions that are perpendicular to the horizontally placed electrode positions should make a superior lead system.

A study was designed to determine if that was true.

The result of the study indicated that such a system did not solve all of the problems that were posed by the current system. Although the new system was easier to use, the findings did not justify a change from the presently used system of precordial electrode placement. Copyright © 2009 Wiley Periodicals, Inc.
Cardiovascular Studies and the Radiation Dose
Authors: Conti C. Richard
Published: February 2009

In a previous editorial, I commented on ionizing radiation associated with multislice computed tomographic angiography and x‐ray coronary angiography performed in the catheterization laboratory.1 I mentioned that just by living, all of us are exposed to a background radiation dose, probably in the neighborhood of 3.6 millisieverts per year. Copyright © 2009 Wiley Periodicals, Inc.
Extreme Value Analysis of Istanbul Air Pollution Data
Authors: Ercelebi Selamet G. , Toros Hüseyin
Published: February 2009

With respect to air quality standards, extreme events are usually of the most interest. Air quality standards require that the observed extreme concentration in a given time interval must not exceed a certain value. In this paper, it is shown that the measured maximum concentration in a time interval can be represented by one of three types of large asymptotic distribution of extreme value statistics. By using this statistical tool, it is possible to analyze the data and to predict the future extreme concentrations with a given probability. The theoretical background of extreme value statistics, procedure to estimate the parameters of the largest extreme value distributions and procedure to forecast future extreme events are briefly explained. The theory is applied to data obtained from two permanent stations in Istanbul. Hourly SO2 and NO2 concentrations are analyzed and future largest SO2 and NO2 concentrations for the following 12 months are forecasted. It has been found that Gumbel's Type I and Type II extreme value distributions represent these air quality data obtained from the two stations very well. The expected maximum SO2 concentration is found to be 593.7 mg/m3 and the NO2 concentration is found to be 393.4 mg/m3 for the Alibeykoy station. The air quality exceeds the limit of EN standards for hourly SO2 concentration twice a year or in a return period of 5.77 months, and 5 times a year or in a return period of 2.6 months for the hourly NO2 concentrations. Similarly, for the Umraniye station, the expected maximum concentration is 514.5 mg/m3 SO2 with a return period of 1.78 months and 437.6 mg/m3 NO2 with a return period of 5.6 months. The performed prediction suggests that preventive measures should be carried out in the future in order to meet stringent air quality standards.
Prognostic impact of blood transfusion in patients undergoing primary surgery and free‐flap reconstruction for oral squamous cell carcinoma
Authors: Fenner Matthias , Vairaktaris Eleftherios , Nkenke Emeka , Weisbach Volker , Neukam Friedrich W. , Radespiel‐Tröger Martin
Published: February 2009

BACKGROUND:

The objective of this study was to assess the impact of perioperative transfusion on the prognosis of patients who underwent complete (R0) resection of oral squamous cell carcinoma and reconstruction by microvascular flaps.

METHODS:

By following an inclusion and exclusion protocol, 223 patients were included in the study who underwent R0 resection of oral squamous cell carcinoma and reconstruction by microvascular flaps at a single center. Clinical and pathologic factors as well as transfusion data were retrieved from a prospective database and analyzed retrospectively. Survival data were assessed using the method of Kaplan and Meier. For multivariate analysis the accelerated failure time model (Weibull distribution) was chosen.

RESULTS:

The overall survival rate was 71% at 1 year, 67% at 3 years, and 55% at 5 years. In univariate analysis, age (P = .003), tumor size (P = .005), lymph node status (P = .008), tumor differentiation (P = .008), transfusion (P = .006), American Society of Anesthesiologists (ASA) class (P = .001), and mandibular reconstruction (P = .045) were associated significantly with overall survival. Multivariate analysis identified only age, histopathologic differentiation, and ASA class as independent risk factors (P < .001, P = .04, and P = .049, respectively). Age was identified as the strongest independent predictor for overall survival (hazards ratio for each 13‐year increase in age, 1.97; 95% confidence interval, 1.36‐2.85).

CONCLUSIONS:

Transfusion of >4 U of blood did not appear to influence overall survival in patients who underwent primary surgery for oral squamous cell carcinoma. Because age and ASA class evolved as the strongest predictors of shortened overall survival, associated comorbidities may require more attention, particularly in elderly or socially deprived patients. Cancer 2009. © 2009 American Cancer Society.
Extracellular and intracellular mechanisms that mediate the metastatic activity of exogenous osteopontin
Authors: Mandelin Jami , Lin Emme C. K. , Hu Dana D. , Knowles Susan K. , Do Kim‐Anh , Wang Xuemei , Sage E. Helene , Smith Jeffrey W. , Arap Wadih , Pasqualini Renata
Published: February 2009

BACKGROUND:

Osteopontin affects several steps of the metastatic cascade. Despite direct correlation with metastasis in experimental systems and in patient studies, the extracellular and intracellular basis for these observations remains unsolved. In this study, the authors used human melanoma and sarcoma cell lines to evaluate the effects of soluble osteopontin on metastasis.

METHODS:

Exogenous osteopontin or negative controls, including a site‐directed mutant osteopontin, were used in functional assays in vitro, ex vivo, and in vivo that were designed to test the extracellular and intracellular mechanisms involved in experimental metastasis.

RESULTS:

In the extracellular environment, the results confirmed that soluble osteopontin is required for its prometastatic effects; this phenomenon is specific, arginine‐glycine‐aspartic acid (RGD)‐dependent, and evident in experimental models of metastasis. In the intracellular environment, osteopontin initially induced rapid tyrosine 418 (Tyr‐418) dephosphorylation of the cellular homolog of the Rous sarcoma virus (c‐Src), with decreases in actin stress fibers and increased binding to the vascular endothelium. This heretofore undescribed Tyr dephosphorylation was followed by a tandem c‐Src phosphorylation after tumor cell attachment to the metastatic site.

CONCLUSIONS:

The results of this study revealed a complex molecular interaction as well as a dual role for osteopontin in metastasis that depends on whether tumor cells are in circulation or attached. Such context‐dependent functional insights may contribute to antimetastasis strategies. Cancer 2009. © 2009 American Cancer Society.
Preoperative breast magnetic resonance imaging in early breast cancer
Authors: Tendulkar Rahul D. , Chellman‐Jeffers Melanie , Rybicki Lisa A. , Rim Alice , Kotwal Ashwin , Macklis Roger , Obi Betty B.
Published: February 2009

BACKGROUND:

Accelerated partial breast irradiation (APBI) of patients with early breast cancer is being investigated on a multi‐institutional protocol National Surgical Adjuvant Breast and Bowel Project (NSABP) B‐39/RTOG 0413. Breast magnetic resonance imaging (MRI) is more sensitive than mammography (MG) and may aid in selection of patients appropriate for PBI.

METHODS:

Patients with newly diagnosed breast cancer or ductal carcinoma in situ (DCIS) routinely undergo contrast‐enhanced, bilateral breast MRI at the Cleveland Clinic. We retrospectively reviewed the medical records of all early‐stage breast cancer patients who had a breast MRI, MG, and surgical pathology data at our institution between June of 2005 and December of 2006. Any suspicious lesions identified on MRI were further evaluated by targeted ultrasound ± biopsy.

RESULTS:

A total of 260 patients met eligibility criteria for NSABP B‐39/RTOG 0413 by MG, physical exam, and surgical pathology. The median age was 57 years. DCIS was present in 63 patients, and invasive breast cancer was found in 197 patients. MRI identified suspicious lesions in 35 ipsilateral breasts (13%) and in 16 contralateral breasts (6%). Mammographically occult, synchronous ipsilateral foci were found by MRI in 11 patients (4.2%), and in the contralateral breast in 4 patients (1.5%). By univariate analysis, lobular histology (infiltrating lobular carcinoma [ILC]), pathologic T2, and American Joint Committee on Cancer stage II were significantly associated with additional ipsilateral disease. Of patients with ILC histology, 18% had ipsilateral secondary cancers or DCIS, compared with 3% in the remainder of histologic subtypes (P = .004). No patient older than 70 years had synchronous cancers or DCIS detected by MRI.

CONCLUSIONS:

Breast MRI identified synchronous mammographically occult foci in 5.8% of early breast cancer patients who would otherwise be candidates for APBI. Cancer 2009. © 2009 American Cancer Society.
Predictors of inactive lifestyle among adult survivors of childhood cancer
Authors: Ness Kirsten K , Leisenring Wendy M. , Huang Sujuan , Hudson Melissa M. , Gurney James G. , Whelan Kimberly , Hobbie Wendy L. , Armstrong Gregory T. , Robison Leslie L. , Oeffinger Kevin C.
Published: February 2009

BACKGROUND:

Participation in physical activity is important for childhood cancer survivors, because inactivity may compound cancer/treatment‐related late effects. However, some survivors may have difficulty participating in physical activity, and these individuals need to be identified so that risk‐based guidelines for physical activity, tailored to specific needs, can be developed and implemented. The objectives of the current study were to document physical activity patterns in the Childhood Cancer Survivor Study (CCSS) cohort, to compare the physical activity patterns with siblings in the CCSS and with a population‐based sample from the Behavioral Risk Factor Surveillance System, and to evaluate associations between diagnosis, treatment, and personal factors in terms of the risk for an inactive lifestyle.

METHODS:

Percentages of participation in recommended physical activity were compared among survivors, siblings, and population norms. Generalized linear models were used to evaluate the associations between cancer diagnosis and therapy, sociodemographics, and the risk for an inactive lifestyle.

RESULTS:

Participants included 9301 adult survivors of childhood cancer and 2886 siblings. Survivors were less likely than siblings (46% vs 52%) to meet physical activity guidelines and were more likely than siblings to report an inactive lifestyle (23% vs 14%). Medulloblastoma (35%) and osteosarcoma (27%) survivors reported the highest levels of inactive lifestyle. Treatments with cranial radiation or amputation were associated with an inactive lifestyle as were being a woman, black race, older age, lower educational attainment, underweight or obese status, smoking, and depression.

CONCLUSIONS:

Childhood cancer survivors were less active than a sibling comparison group or an age‐ and sex‐matched population sample. Survivors who are at risk for an inactive lifestyle should be considered high priority for developing and testing of intervention approaches. Cancer 2009. © 2009 American Cancer Society.
Clinical significance of the diagnosis of low‐grade squamous intraepithelial lesion, cannot exclude high‐grade squamous intraepithelial lesion
Authors: Alsharif Mariam , Kjeldahl Klint , Curran Colleen , Miller Shelby , Gulbahce H. Evin , Pambuccian Stefan E.
Published: February 2009

BACKGROUND:

The diagnosis of low‐grade squamous intraepithelial lesion (LSIL), cannot exclude high‐grade squamous intraepithelial lesion (LSIL‐H) was not included in the 2001 Bethesda System. It is used in some institutions to diagnose cases that fulfill criteria for both the diagnosis of LSIL and atypical squamous cells, cannot exclude high‐grade squamous intraepithelial lesion (ASC‐H). In this study, the authors reviewed their experience with cases reported as LSIL‐H during a 4‐year interval.

METHODS:

Clinical information and histologic follow‐up data were retrieved for Papanicolaou (Pap) tests (PTs) that were diagnosed as LSIL‐H, LSIL, ASC‐H and high‐grade squamous intraepithelial lesion (HSIL) from January 1, 2004 to December 31, 2007.

RESULTS:

Of 235,645 PTs (97% SurePath) that were processed during the study period, the laboratory diagnosed 0.52% as ASC‐H, 2% as LSIL, 0.30% as LSIL‐H, and 0.39% as HSIL. Biopsy follow‐up was available for 47%, 49%, 56.7% and 74% of these cases, respectively. Cervical intraepithelial neoplasia 2 (CIN‐2) and CIN‐3 or more severe lesions (CIN‐3+) were identified on follow‐up cervical biopsy more often in women who had diagnoses of LSIL‐H and ASC‐H (33.14% and 26.33%, respectively) than in women who had a diagnosis of LSIL (16.11%).

CONCLUSIONS:

The similarity of histologic follow‐up results between LSIL‐H and ASC‐H suggested that the management of women who have a diagnosis of LSIL‐H should be similar to the management of women who have a diagnosis of ASC‐H. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.
Schallschutz – Neue Entwicklungen im Ziegelbau1 – Optimierte Ausführungen im Detail
Authors: Meier Andreas , Kuhlemann Clemens
Published: February 2009

Schallschutz im Wohnungsbau ist immer wieder ein wichtiges Thema. Leider auch dann, wenn es zu Beschwerden kommt. Ist da der hellhörige Bewohner schuld oder doch das Bauwerk? Als Architekt, Bauträger oder Investor muss man in dieser Situation sicher sein, dass die gewählte Bauweise den geschuldeten Anforderungen des Schallschutzes standhält. Vor diesem Hintergrund werden im vorliegenden Beitrag die aktuellen Entwicklungen im Ziegelbau in Bezug auf den Schallschutz beleuchtet (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Berechnung des sommerlichen Wärmeschutzes
Authors: Schwieger Hartmut
Published: February 2009

Die heutige Architektur (auch im Wohnungsbau) mit großen Glasanteilen führt im Winter zu den erwünschten Wärmegewinnen, kann aber zu Problemen im Sommer führen. Die Planung eines wirksamen Hitzeschutzes (sommerlicher Wärmeschutz) ist daher wichtig, damit auch während sommerlicher Hitzeperioden sichergestellt ist, dass in Gebäuden behagliche Raumtemperaturen herrschen. Neben vorhandenen Sonnenschutzeinrichtungen wird das sommerliche Temperaturverhalten eines Gebäudes wesentlich von seiner Bauart beeinflusst. Dabei wirken sich schwere, Wärme speichernde Bauteile positiv aus (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Neue Leitlinien für den Wohnungsbau
Authors: Eichener Volker
Published: February 2009

Wenn es in der politischen und öffentlichen Diskussion zurzeit ein Thema gibt, dem sämtliche anderen Fragen untergeordnet werden, dann ist es der Klimawandel. Von Regierungen bestellte und bezahlte Klimaforscher malen die globale Apokalypse an die Wand: Die Erde soll sich in Zukunft erwärmen, und als Hauptursache für äußerst komplexe klimatische Prozesse ist der menschenverursachte CO2‐Ausstoß identifiziert (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Die für 2009 geplante Verschärfung der EnEV ist nicht wirtschaftlich verträglich
Authors: Eichener Volker
Published: February 2009

Um die äußerst ehrgeizigen CO2‐Minderungsziele erfüllen zu können, zu denen sich die Bundesregierung in verschiedenen internationalen Abkommen selbst verpflichtet hat, ist es unumgänglich, große Teil e des Bestands an Wohngebäuden energetisch zu sanieren. Die Bundesregierung setzt dabei in erster Linie auf Zwangsmaßnahmen, wenn die ohnehin hohen Anforderungen der Energieeinsparverordnung (EnEV) in mehreren Schritten – zunächst 2009, dann 2012, und weitere Schritte sind bereits geplant – weiter verschärft werden sollen (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Erst Weiß, dann Schwarz und vielleicht wieder Weiß – Die Gegensätze in der Wohnungsbaupolitik
Authors: Rast Ronald
Published: February 2009

Die Zeit nach der deutschen Wiedervereinigung war ohne Zweifel eine historisch einmalige Phase. Um auch aus Ostdeutschland wieder blühende Landschaften zu machen, stellte die Politik alle Rahmenbedingungen pro Bau, insbesondere pro Wohnungsbau, ein (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Experience‐dependent regulation of TrkB isoforms in rodent visual cortex
Authors: Bracken Bethany K. , Turrigiano Gina G.
Published: February 2009

Within primary visual cortex (V1), brain‐derived neurotrophic factor (BDNF) signaling through its high‐affinity receptor TrkB is important for normal development and experience‐dependent plasticity. TrkB is expressed in several alternatively spliced isoforms, including full‐length TrkB (TrkB.FL), and several truncated isoforms (TrkB.T1, TrkB.T2, and TrkB.T4) that lack the intracellular tyrosine kinase domain. These isoforms are important components of BDNF signaling, yet little is known about the developmental or experience‐dependent regulation of their expression. Using immunohistochemistry, we found TrkB.FL and TrkB.T1 expressed in interneurons and pyramidal neurons within V1, but not in cortical astrocytes. We used real‐time PCR to quantify the changes in mRNA expression of BDNF, the four TrkB isoforms, and the low‐affinity receptor P75NTR during normal development, and in response to visual deprivation at two different ages. BDNF expression increased between postnatal days 10 (P10) and P30, and was rapidly down‐regulated by 3 days of visual deprivation during both the pre‐critical period (P14‐P17) and the critical period (P18‐P21). Over the same developmental period, expression of each TrkB isoform was regulated independently; TrkB.T1 increased, TrkB.FL and TrkB.T2 decreased, and TrkB.T4 showed transient changes. Neither brief visual deprivation nor prolonged dark‐rearing induced changes in either TrkB.FL or TrkB.T1 expression. However, TrkB.T4 expression was reduced by brief visual deprivation, whereas TrkB.T4, TrkB.T2 and P75NTR were up‐regulated by prolonged dark‐rearing into the critical period. Our data indicate that TrkB isoform expression can be selectively regulated by visual experience, and may contribute to experience‐dependent cortical plasticity. © 2009 Wiley Periodicals, Inc. Develop Neurobiol 2009
Increased apoptosis during neonatal brain development underlies the adult behavioral deficits seen in mice lacking a functional paternally expressed gene 3 (Peg3)
Authors: Broad Kevin D. , Curley James P. , Keverne Eric B.
Published: February 2009

Inactivation of the maternally imprinted, paternally expressed gene 3 (Peg3) induces deficits in olfactory function, sexual and maternal behaviors, oxytocin neuron number, metabolic homeostasis and growth. Peg3 is expressed in a number of developing hypothalamic and basal forebrain structures and is a component of the P53 apoptosis pathway. Peg3 inactivation in neuronal cell culture lines inhibits P53 mediated apoptosis, which is important in the early postnatal development and sexual differentiation of the brain. In this study, we investigated the effect of inactivating the Peg3 gene on the incidence of caspase 3 positive cells (a marker of apoptosis) in 4‐ and 6‐day postpartum mouse brain. Inactivating the Peg3 gene resulted in an increase in the incidence of total forebrain caspase 3 positive cells at 4 and 6 days postpartum. Increases in specific neuroanatomical regions including the bed nucleus of the stria terminalis, nucleus accumbens, caudate putamen, medial pre‐optic area, arcuate nucleus, medial amygdala, anterior cortical and posteriodorsal amygdaloid nuclei, were also observed. In wild‐type mice, sex differences in the incidence of caspase 3 positive cells in the medial amygdala, bed nucleus of the stria terminalis, nucleus accumbens, arcuate nucleus and the M2 motor cortex, were also observed. This neural sex difference was ameliorated in the Peg‐3 mutant. These findings suggest that the neuronal and behavioral deficits seen in mice lacking a functional Peg3 gene are mediated by increases in the incidence of early neonatal apoptosis in neuroanatomical regions important for reproductive behavior, olfactory and pheromonal processing, thermoregulation and reward. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009
Formation of complex AChR aggregates in vitro requires α‐dystrobrevin
Authors: Pawlikowski Bradley T. , Maimone Margaret M.
Published: February 2009

Efficient function at the neuromuscular junction requires high‐density aggregates of acetylcholine receptors (AChRs) to be precisely aligned with the motor nerve terminal. A collaborative effort between the motor neuron and muscle intrinsic factors drives the formation and maintenance of these AChR aggregates. α‐Dystrobrevin (αDB), a cytoplasmic protein found at the postsynaptic membrane, has been implicated in the regulation of AChR aggregate density and patterning. To investigate the contribution of αDB to the muscle intrinsic program regulating AChR aggregate development, we analyzed the formation of complex, pretzel‐like AChR aggregates on primary muscle cell cultures derived from αDB knockout (αDB‐KO) mice in the absence of nerve or agrin. In myotubes lacking αDB, complex AChR aggregates failed to form, whereas aggregates formed readily in wildtype myotubes. Five major isoforms of αDB are expressed in skeletal muscle: αDB1, αDB1(−), αDB2, αDB2(−), and αDB3. Expression of αDB1 or αDB1(−) in αDB‐KO myotubes restored formation of complex AChR aggregates similar to those in wildtype myotubes. In contrast, individual expression of αDB2, αDB2(−), αDB3, or an αDB1 phosphorylation mutant resulted in the formation of few, if any, complex AChR aggregates. Collectively, these data suggest that αDB is a significant component of the muscle intrinsic program that mediates the formation of complex AChR aggregates and that αDB's tyrosine phosphorylation sites are of particular functional importance to this program. Although the muscle intrinsic program appears to influence synaptogenesis, the formation of complex mature AChR aggregates in αDB‐KO mice (with the motor neuron present) suggests the motor neuron, not the muscle intrinsic program, is the major stimulus driving the maturation of AChRs from plaque to pretzel in vivo. © 2009 Wiley Periodicals, Inc. Develop Neurobiol 2009
Myosin‐II negatively regulates minor process extension and the temporal development of neuronal polarity
Authors: Kollins K.M. , Hu J. , Bridgman P.C. , Huang Y.Q. , Gallo G.
Published: February 2009

The earliest stage in the development of neuronal polarity is characterized by extension of undifferentiated “minor processes” (MPs), which subsequently differentiate into the axon and dendrites. We investigated the role of the myosin II motor protein in MP extension using forebrain and hippocampal neuron cultures. Chronic treatment of neurons with the myosin II ATPase inhibitor blebbistatin increased MP length, which was also seen in myosin IIB knockouts. Through live‐cell imaging, we demonstrate that myosin II inhibition triggers rapid minor process extension to a maximum length range. Myosin II activity is determined by phosphorylation of its regulatory light chains (rMLC) and mediated by myosin light chain kinase (MLCK) or RhoA‐kinase (ROCK). Pharmacological inhibition of MLCK or ROCK increased MP length moderately, with combined inhibition of these kinases resulting in an additive increase in MP length similar to the effect of direct inhibition of myosin II. Selective inhibition of RhoA signaling upstream of ROCK, with cell‐permeable C3 transferase, increased both the length and number of MPs. To determine whether myosin II affected development of neuronal polarity, MP differentiation was examined in cultures treated with direct or indirect myosin II inhibitors. Significantly, inhibition of myosin II, MLCK, or ROCK accelerated the development of neuronal polarity. Increased myosin II activity, through constitutively active MLCK or RhoA, decreased both the length and number of MPs and, consequently, delayed or abolished the development of neuronal polarity. Together, these data indicate that myosin II negatively regulates MP extension, and the developmental time course for axonogenesis. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009
Age‐dependent differential expression of genes involved in steroid signalling pathway in the brain of protandrous black porgy, Acanthopagrus schlegeli
Authors: Tomy Sherly , Wu Guan‐Chung , Huang Horng‐Ru , Chang Ching‐Fong
Published: February 2009

The mechanisms underlying brain sex differentiation in animals are poorly understood. In the present study, using black porgy, Acanthopagrus schlegeli, as primary experimental model, we investigated the temporal expression patterns of receptors for androgen (ar) and estrogen (esr1 and esr2a) in the brain during posthatching ages and analyzed them against the timing of gonadal germ cell development. We hypothesized that endogenous estrogens naturally masculinize the brain of black porgy. The expression of sex steroid receptors was studied in relation to a wider suite of other related genes (nr5a2, nr0b1, star, and cyp19a1b) to provide some insight into the monomale sex differentiation pattern observed in this species. Our results revealed a highly significant increase in esr1 together with the increase in esr2a at 120 dph (days posthatching), suggesting a significant role for esr in sex differentiation in this species. Temporal expression patterns of nr5a2, nr0b1, star, sex steroid receptors, and cyp19a1b in the brain provided evidence for their physiological roles in the monomale sex differentiation in this species. The expression of nr5a2, star, ar, esr1, esr2a, and cyp19a1b increased at 120 dph, a period when brain sex differentiation probably occurs in this species. The study also suggests that neurosteroidogenesis in black porgy may be regulated by both nr5a2‐dependent and nr5a2‐independent mechanisms. The results demonstrated striking differences in the abundance of the gene transcripts in discrete brain region throughout ontogeny. In addition, the sex steroid hormone levels and aromatase activity in brain at different developmental states and the changes in the gene expression patterns in response to aromatase inhibitor treatment are also discussed. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009
MOG35–55 i.v suppresses experimental autoimmune encephalomyelitis partially through modulation of Th17 and JAK/STAT pathways
Authors: Jiang Zhilong , Li Hongmei , Fitzgerald Denise C. , Zhang Guang‐Xian , Rostami Abdolmohamad
Published: February 2009

Intravenous (i.v.) administration of encephalitogenic peptide can effectively prevent experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis; however, the underlying cellular and molecular mechanisms are not fully understood. In this study, we induced i.v. tolerance to EAE by administration of MOG35–55 peptide and determined the effect of this approach on intracellular signaling pathways of the IL‐23/IL‐17 system, which is essential for the pathogenesis of MS/EAE. In tolerized mice, phosphorylation of JAK/STAT‐1, ‐4, ERK1/2 and NF‐κBp65 were significantly reduced in splenocytes and the central nervous system. MOG i.v. treatment led to significantly lower production of IL‐17, and administration of exogenous IL‐17 slightly broke immune tolerance, which was associated with reduced activation of STAT4 and NF‐κB. Suppressed phosphorylation of these pathway molecules was primarily evident in CD11b+ and small numbers of CD4+, CD8+ and CD11c+ cells. More importantly, adoptive transfer of CD11b+ splenocytes of tolerized mice effectively delayed onset and reduced clinical severity of actively induced EAE. This study correlates MOG i.v. tolerance with modulation of Jak/STAT signaling pathways and investigates novel therapeutic avenues for the treatment of EAE/MS.
Tumor‐mediated down‐regulation of MHC class II in DC development is attributable to the epigenetic control of the CIITA type I promoter
Authors: Choi Young‐Eun , Yu Ha‐Nul , Yoon Cheol‐Hee , Bae Yong‐Soo
Published: February 2009

In patients with cancer, DC express significantly lower amounts of MHC class II compared with those of normal individuals. However, the underlying mechanisms for this have not yet been fully defined. In the present study, we found that IL‐10 plays a major role in the tumor‐conditioned medium (TCM)‐mediated decrease of MHC class II expression on BM‐derived DC. IL‐10 inhibited the expression of type I CIITA during DC differentiation. GM‐CSF‐mediated histone (H3 and H4) acetylation at the type I promoter (pI) locus of the CIITA gene was markedly increased during DC differentiation and this increase was blocked by IL‐10. We also found that STAT5 bound to the CIITA pI locus during DC differentiation, and the binding was markedly attenuated by TCM or IL‐10. Altogether, these findings suggest that (i) the down‐regulation of MHC class II in tumor microenvironments is most likely attributable to IL‐10 in the TCM and (ii) IL‐10‐mediated MHC class II down‐regulation results from the inhibition of type I CIITA expression. This inhibition is most likely due to blocking of the STAT5‐associated epigenetic modifications of the CIITA pI locus during the entire period of DC differentiation from BM cells, as opposed to a simple inhibition of MHC class II expression at the DC stage.
Regulation of macrophage activation and septic shock susceptibility via p21(WAF1/CIP1)
Authors: Trakala Marianna , Arias Cristina F. , García María I. , Moreno‐Ortiz M. Carmen , Tsilingiri Katerina , Fernández Pablo J. , Mellado Mario , Díaz‐Meco María T. , Moscat Jorge , Serrano Manuel , Martínez‐A Carlos , Balomenos Dimitrios
Published: February 2009

p21 is a cell‐cycle inhibitor that is also known to suppress autoimmunity. Here, we provide evidence of a novel role for p21 as an inhibitor of macrophage activation. LPS stimulation of p21‐deficient peritoneal macrophages induced increased activation compared with controls, with elevated production of proinflammatory mediators such as TNF‐α and IL‐1β. The enhanced activity of LPS‐stimulated p21‐deficient macrophages correlated with increased activity of the transcription factor NF‐κB. LPS stimulation of p21‐deficient macrophages led to increased IκBα kinase activity, and increased IκBα phosphorylation and degradation, resulting in elevated NF‐κB activity. The effect of p21 in macrophage activation was independent of its cell‐cycle inhibitory role. p21−/− mice showed greater sensitivity to LPS‐induced septic shock than did WT mice, indicating that p21 contributes to maintenance of a balanced response to inflammatory stimuli and suggesting biological significance for the role of p21 in macrophage activation. Our findings project a role for p21 in the control of NF‐κB‐associated inflammation, and suggest that therapeutic modulation of p21 expression could be beneficial in inflammation‐associated diseases.
CD152 (CTLA‐4) regulates effector functions of CD8+ T lymphocytes by repressing Eomesodermin
Authors: Hegel Johannes K. , Knieke Karin , Kolar Paula , Reiner Steven L. , Brunner‐Weinzierl Monika C.
Published: February 2009

CD8+ T lymphocytes are required for effective host defense against pathogens and also for mediating effector responses against uncontrolled proliferating self‐tissues. In this study, we determine that individual CD8+ T cells are tightly controlled in their effector functions by CD152 (CTLA‐4). We demonstrate that signals induced by CD152 reduce the frequency of IFN‐γ and granzyme B expressing CD8+ T cells independently of the transcription factors T‐bet or cKrox by selectively inhibiting accumulation of Eomesodermin mRNA and protein. Ectopic expression of Eomesodermin reversed the CD152‐mediated inhibition of effector molecule production. Additionally, enhanced cytotoxicity of individual CD8+ T cells differentiated in the absence of CD152 signaling was determined in vivo. These novel insights extend our understanding of how immune responses of CD8+ T cells are selectively modulated.
Correlates of protection efficacy induced by vaccinia virus‐specific CD8+ T‐cell epitopes in the murine intranasal challenge model
Authors: Moutaftsi Magdalini , Salek‐Ardakani Shahram , Croft Michael , Peters Bjoern , Sidney John , Grey Howard , Sette Alessandro
Published: February 2009

The recent identification of a large array of different vaccinia virus‐derived CD8+ T‐cell epitopes offers a unique opportunity to systematically analyze the correlation between protective efficacy and variables such as kinetics of expression and function of viral proteins, binding affinity to MHC molecules, immunogenicity, and viral antigen processing/presentation. In the current study, 49 different H‐2b restricted epitopes were tested for their ability to protect peptide‐immunized C57Bl/6 mice from lethal i.n. challenge with vaccinia virus. The epitopes varied greatly in their ability to confer protection, ranging from complete protection with minimal disease to no protection at all. The function or kinetics of the viral antigen expression did not correlate with protective efficacy. However, binding affinity partially predicted protection efficacy and ultimately epitope immunogenicity and recognition of infected cells offered the best correlation.
Thymic emigration: Sphingosine‐1‐phosphate receptor‐1‐dependent models and beyond
Authors: Drennan Michael B. , Elewaut Dirk , Hogquist Kristin A.
Published: February 2009

The thymus is a primary lymphoid organ supporting the development of self‐tolerant T cells. Key events in T‐cell development in the thymus include lineage commitment, selection events, and thymic emigration. This review discusses the proposed role of sphingosine‐1‐phosphate and its receptors in the emigration of both conventional and unconventional T‐cell subsets from the thymus, and the molecular machinery currently understood to regulate this process. Furthermore, we highlight a role for chemokines and actin‐associated proteins in T‐cell motility as recent data suggest that T‐cell emigration is regulated by more than just a sphingosine‐1‐phosphate receptor‐1‐dependent chemotactic axis.
Modular Synthesis of a New Type of Chiral Bis(carbene) Ligand from L‐Valinol and Iridium(I) and Rhodium(I) Complexes Thereof
Authors: Nagel Ulrich , Diez Claus
Published: February 2009

New, chiral bis(imidazol‐2‐ylidene) ligands, and their rhodium(I) and iridium(I) complexes, have been prepared by a simple six‐step synthesis starting from commercially available enantiomerically pure L‐valinol. The stepwise introduction of the imidazoles makes it possible to create chiral bis(NHC) complexes with different substituents at the terminal nitrogen atoms. Formation of IrI and RhI complexes by a one‐pot transmetallation reaction gives the endo and exo stereoisomers in different ratios, depending on the metal and the reaction conditions. Diastereomerically pure material was obtained by crystallisation.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Assessing the Potential of Zwitterionic NHC·CS2 Adducts for Probing the Stereoelectronic Parameters of N‐Heterocyclic Carbenes
Authors: Delaude Lionel , Demonceau Albert , Wouters Johan
Published: February 2009

Five imidazol(in)ium‐2‐dithiocarboxylates bearing cyclohexyl, mesityl, or 2,6‐diisopropylphenyl substituents on their nitrogen atoms were prepared from the corresponding N‐heterocyclic carbenes (NHCs) by reaction with carbon disulfide. They were characterized by IR, UV/Vis, and NMR spectroscopy, and by thermogravimetric analysis. Their molecular structures were determined by X‐ray diffraction. For the sake of comparison, tricyclohexylphosphonium dithiocarboxylate was also examined. The data acquired were scrutinized to evaluate their usefulness for assessing the steric and electronic properties of NHC ligands. Because of their outstanding ability to crystallize, the five NHC·CS2 betaines were found to be highly suitable for probing the steric influence of nitrogen atom substituents on imidazolylidene‐based ligand precursors via XRD analysis, while the corresponding NHC·CO2 adducts were deemed more appropriate for evaluating the σ‐donating properties of carbene ligands.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Syntheses, Structures and Reactivities of Rhodium 4,5‐Diazafluorene Derivatives
Authors: Jiang Huiling , Stepowska Elzbieta , Song Datong
Published: February 2009

Four rhodium 4,5‐diazafluorene derivatives, [RhL(PPh3)2] (1), [Rh(H)2(LH)(PPh3)2]Cl (2), [Rh(H)2L(PPh3)2] (3) and [Rh(H)2(LH)(PPh3)2]OTf (4), have been synthesized and fully characterized by NMR spectroscopy, elemental analysis and single‐crystal X‐ray diffraction. Compound 1 can be converted into 3 when treated with hydrogen gas. Compound 2 can be converted into 3 when treated with NaH, and the reverse reaction can be achieved by treating 3 with aqueous HCl. The air‐ and moisture‐stable compound 2 is an active catalyst for the hydrogenation of a variety of olefins, including non‐terminal ones; the chloride counterion in 2 appears to play a role in the catalytic system. Thus, compound 4, the triflate analogue of 2, is inactive towards olefin hydrogenation.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)