bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel Fc-engineered monoclonal antibody to CD37 with enhanced ADCC and high proapoptotic activity for treatment of B-cell malignancies
Authors: Heider Karl-Heinz , Kiefer Kerstin , Zenz Thorsten , Volden Matthias , Stilgenbauer Stephan , Ostermann Elinborg , Baum Anke , Lamche Herbert , Küpcü Zaruhi , Jacobi Alexander , Müller Steffen , Hirt Ulrich , Adolf Günther R. , Borges Eric
Published: July 2011

The tetraspanin CD37 is widely expressed in B-cell malignancies and represents an attractive target for immunotherapy with mAbs. We have chimerized a high-affinity mouse Ab to CD37 and engineered the CH2 domain for improved binding to human Fcγ receptors. The resulting mAb 37.1 showed high intrinsic proapoptotic activity on malignant B cells accompanied by homotypic aggregation. Furthermore, the Ab-mediated high Ab-dependent cell-mediated cytotoxicity (ADCC) on lymphoma and primary CLL cells. mAb 37.1 strongly depleted normal B cells as well as spiked B-lymphoma cells in blood samples from healthy donors as well as malignant B cells in blood from CLL patients. In all assays, mAb 37.1 was superior to rituximab in terms of potency and maximal cell lysis. A single dose of mAb CD37.1 administered to human CD37-transgenic mice resulted in a reversible, dose-dependent reduction of peripheral B cells. In a Ramos mouse model of human B-cell lymphoma, administration of mAb 37.1 strongly suppressed tumor growth. Finally, a surrogate Fc-engineered Ab to macaque CD37, with in vitro proapoptotic and ADCC activities very similar to those of mAb 37.1, induced dose-dependent, reversible B-cell depletion in cynomolgus monkeys. In conclusion, the remarkable preclinical pharmacodynamic and antitumor effects of mAb 37.1 warrant clinical development for B-cell malignancies.
Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin
Authors: Zhang Bin , Zheng Chunlei , Zhu Min , Tao Jiayi , Vasievich Matthew P. , Baines Andrea , Kim Jinoh , Schekman Randy , Kaufman Randal J. , Ginsburg David
Published: July 2011

The type 1-transmembrane protein LMAN1 (ERGIC-53) forms a complex with the soluble protein MCFD2 and cycles between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC). Mutations in either LMAN1 or MCFD2 cause the combined deficiency of factor V (FV) and factor VIII (FVIII; F5F8D), suggesting an ER-to-Golgi cargo receptor function for the LMAN1-MCFD2 complex. Here we report the analysis of LMAN1-deficient mice. Levels of plasma FV and FVIII, and platelet FV, are all reduced to ∼ 50% of wild-type in Lman1−/− mice, compared with the 5%-30% levels typically observed in human F5F8D patients. Despite previous reports identifying cathepsin C, cathepsin Z, and α1-antitrypsin as additional potential cargoes for LMAN1, no differences were observed between wild-type and Lman1−/− mice in the levels of cathepsin C and cathepsin Z in liver lysates or α1-antitrypsin levels in plasma. LMAN1 deficiency had no apparent effect on COPII-coated vesicle formation in an in vitro assay. However, the ER in Lman1−/− hepatocytes is slightly distended, with significant accumulation of α1-antitrypsin and GRP78. An unexpected, partially penetrant, perinatal lethality was observed for Lman1−/− mice, dependent on the specific inbred strain genetic background, suggesting a potential role for other, as yet unidentified LMAN1-dependent cargo proteins.
Angiogenesis gene expression in murine endothelial cells during post-pneumonectomy lung growth
Authors: Lin Miao , Chamoto Kenji , Gibney Barry C , Lee Grace S , Collings-Simpson Dinee , Houdek Jan , Konerding Moritz A , Tsuda Akira , Mentzer Steven J
Published: July 2011

Although blood vessel growth occurs readily in the systemic bronchial circulation, angiogenesis in the pulmonary circulation is rare. Compensatory lung growth after pneumonectomy is an experimental model with presumed alveolar capillary angiogenesis. To investigate the genes participating in murine neoalveolarization, we studied the expression of angiogenesis genes in lung endothelial cells. After left pneumonectomy, the remaining right lung was examined on days 3, 6, 14 and 21days after surgery and compared to both no surgery and sham thoracotomy controls. The lungs were enzymatically digested and CD31+ endothelial cells were isolated using flow cytometry cell sorting. The transcriptional profile of the CD31+ endothelial cells was assessed using quantitative real-time polymerase chain reaction (PCR) arrays. Focusing on 84 angiogenesis-associated genes, we identified 22 genes with greater than 4-fold regulation and significantly enhanced transcription (p <.05) within 21 days of pneumonectomy. Cluster analysis of the 22 genes indicated that changes in gene expression did not occur in a single phase, but in at least four waves of gene expression: a wave demonstrating decreased gene expression more than 3 days after pneumonectomy and 3 sequential waves of increased expression on days 6, 14, and 21 after pneumonectomy. These findings indicate that a network of gene interactions contributes to angiogenesis during compensatory lung growth.
Lafora disease E3-ubiquitin ligase malin is related to TRIM32 at both the phylogenetic and functional level
Authors: Romá-Mateo Carlos , Moreno Daniel , Vernia Santiago , Rubio Teresa , Bridges Travis M , Gentry Matthew S , Sanz Pascual
Published: July 2011

Background

Malin is an E3-ubiquitin ligase that is mutated in Lafora disease, a fatal form of progressive myoclonus epilepsy. In order to perform its function, malin forms a functional complex with laforin, a glucan phosphatase that facilitates targeting of malin to its corresponding substrates. While laforin phylogeny has been studied, there are no data on the evolutionary lineage of malin.

Results

After an extensive search for malin orthologs, we found that malin is present in all vertebrate species and a cephalochordate, in contrast with the broader species distribution previously reported for laforin. These data suggest that in addition to forming a functional complex, laforin and perhaps malin may also have independent functions. In addition, we found that malin shares significant identity with the E3-ubiquitin ligase TRIM32, which belongs to the tripartite-motif containing family of proteins. We present experimental evidence that both malin and TRIM32 share some substrates for ubiquitination, although they produce ubiquitin chains with different topologies. However, TRIM32-specific substrates were not reciprocally ubiquitinated by the laforin-malin complex.

Conclusions

We found that malin and laforin are not conserved in the same genomes. In addition, we found that malin shares significant identity with the E3-ubiquitin ligase TRIM32. The latter result suggests a common origin for malin and TRIM32 and provides insights into possible functional relationships between both proteins.
Population-genetic comparison of the Sorbian isolate population in Germany with the German KORA population using genome-wide SNP arrays
Authors: Gross Arnd , Tönjes Anke , Kovacs Peter , Veeramah Krishna R , Ahnert Peter , Roshyara Nab R , Gieger Christian , Rueckert Ina-Maria , Loeffler Markus , Stoneking Mark , Wichmann Heinz-Erich , Novembre John , Stumvoll Michael , Scholz Markus
Published: July 2011

Background

The Sorbs are an ethnic minority in Germany with putative genetic isolation, making the population interesting for disease mapping. A sample of N = 977 Sorbs is currently analysed in several genome-wide meta-analyses. Since genetic differences between populations are a major confounding factor in genetic meta-analyses, we compare the Sorbs with the German outbred population of the KORA F3 study (N = 1644) and other publically available European HapMap populations by population genetic means. We also aim to separate effects of over-sampling of families in the Sorbs sample from effects of genetic isolation and compare the power of genetic association studies between the samples.

Results

The degree of relatedness was significantly higher in the Sorbs. Principal components analysis revealed a west to east clustering of KORA individuals born in Germany, KORA individuals born in Poland or Czech Republic, Half-Sorbs (less than four Sorbian grandparents) and Full-Sorbs. The Sorbs cluster is nearest to the cluster of KORA individuals born in Poland. The number of rare SNPs is significantly higher in the Sorbs sample. FST between KORA and Sorbs is an order of magnitude higher than between different regions in Germany. Compared to the other populations, Sorbs show a higher proportion of individuals with runs of homozygosity between 2.5 Mb and 5 Mb. Linkage disequilibrium (LD) at longer range is also slightly increased but this has no effect on the power of association studies.

Oversampling of families in the Sorbs sample causes detectable bias regarding higher FST values and higher LD but the effect is an order of magnitude smaller than the observed differences between KORA and Sorbs. Relatedness in the Sorbs also influenced the power of uncorrected association analyses.

Conclusions

Sorbs show signs of genetic isolation which cannot be explained by over-sampling of relatives, but the effects are moderate in size. The Slavonic origin of the Sorbs is still genetically detectable.

Regarding LD structure, a clear advantage for genome-wide association studies cannot be deduced. The significant amount of cryptic relatedness in the Sorbs sample results in inflated variances of Beta-estimators which should be considered in genetic association analyses.
Cathepsin K deficiency in mice induces structural and metabolic changes in the central nervous system that are associated with learning and memory deficits
Authors: Dauth Stephanie , Sîrbulescu Ruxandra F , Jordans Silvia , Rehders Maren , Avena Linda , Oswald Julia , Lerchl Alexander , Saftig Paul , Brix Klaudia
Published: July 2011

Background

Cathepsin K is a cysteine peptidase known for its importance in osteoclast-mediated bone resorption. Inhibitors of cathepsin K are in clinical trials for treatment of osteoporosis. However, side effects of first generation inhibitors included altered levels of related cathepsins in peripheral organs and in the central nervous system (CNS). Cathepsin K has been recently detected in brain parenchyma and it has been linked to neurobehavioral disorders such as schizophrenia. Thus, the study of the functions that cathepsin K fulfils in the brain becomes highly relevant.

Results

Cathepsin K messenger RNA was detectable in all brain regions of wild type (WT) mice. At the protein level, cathepsin K was detected by immunofluorescence microscopy in vesicles of neuronal and non-neuronal cells throughout the mouse brain. The hippocampus of WT mice exhibited the highest levels of cathepsin K activity in fluorogenic assays, while the cortex, striatum, and cerebellum revealed significantly lower enzymatic activities. At the molecular level, the proteolytic network of cysteine cathepsins was disrupted in the brain of cathepsin K-deficient (Ctsk
-/-) animals. Specifically, cathepsin B and L protein and activity levels were altered, whereas cathepsin D remained largely unaffected. Cystatin C, an endogenous inhibitor of cysteine cathepsins, was elevated in the striatum and hippocampus, pointing to regional differences in the tissue response to Ctsk ablation. Decreased levels of astrocytic glial fibrillary acidic protein, fewer and less ramified profiles of astrocyte processes, differentially altered levels of oligodendrocytic cyclic nucleotide phosphodiesterase, as well as alterations in the patterning of neuronal cell layers were observed in the hippocampus of Ctsk
-/- mice. A number of molecular and cellular changes were detected in other brain regions, including the cortex, striatum/mesencephalon, and cerebellum. Moreover, an overall induction of the dopaminergic system was found in Ctsk
-/- animals which exhibited reduced anxiety levels as well as short- and long-term memory impairments in behavioral assessments.

Conclusion

We conclude that deletion of the Ctsk gene can lead to deregulation of related proteases, resulting in a wide range of molecular and cellular changes in the CNS with severe consequences for tissue homeostasis. We propose that cathepsin K activity has an important impact on the development and maintenance of the CNS in mice.
Rationale and design of the Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research Trial (MANTICORE 101 - Breast): a randomized, placebo-controlled trial to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer using cardiac MRI
Authors: Pituskin Edith , Haykowsky Mark , Mackey John R , Thompson Richard B , Ezekowitz Justin , Koshman Sheri , Oudit Gavin , Chow Kelvin , Pagano Joseph J , Paterson Ian
Published: July 2011

Background

MANTICORE 101 - Breast (Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research) is a randomized trial to determine if conventional heart failure pharmacotherapy (angiotensin converting enzyme inhibitor or beta-blocker) can prevent trastuzumab-mediated left ventricular remodeling, measured with cardiac MRI, among patients with HER2+ early breast cancer.

Methods/Design

One hundred and fifty-nine patients with histologically confirmed HER2+ breast cancer will be enrolled in a parallel 3-arm, randomized, placebo controlled, double-blind design. After baseline assessments, participants will be randomized in a 1:1:1 ratio to an angiotensin-converting enzyme inhibitor (perindopril), beta-blocker (bisoprolol), or placebo. Participants will receive drug or placebo for 1 year beginning 7 days before trastuzumab therapy. Dosages for all groups will be systematically up-titrated, as tolerated, at 1 week intervals for a total of 3 weeks. The primary objective of this randomized clinical trial is to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer, as measured by 12 month change in left ventricular end-diastolic volume using cardiac MRI. Secondary objectives include 1) determine the evolution of left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer, 2) understand the mechanism of trastuzumab mediated cardiac toxicity by assessing for the presence of myocardial injury and apoptosis on serum biomarkers and cardiac MRI, and 3) correlate cardiac biomarkers of myocyte injury and extra-cellular matrix remodeling with left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer.

Discussion

Cardiac toxicity as a result of cancer therapies is now recognized as a significant health problem of increasing prevalence. To our knowledge, MANTICORE will be the first randomized trial testing proven heart failure pharmacotherapy in the prevention of trastuzumab-mediated cardiotoxicity. We expect the findings of this trial to provide important evidence in the development of guidelines for preventive therapy.

Trial Registration

ClinicalTrials.gov: NCT01016886
Analysis of EGFR signaling pathway in nasopharyngeal carcinoma cells by quantitative phosphoproteomics
Authors: Ruan Lin , Li Xin-Hui , Wan Xun-Xun , Yi Hong , Li Cui , Li Mao-Yu , Zhang Peng-Fei , Zeng Gu-Qing , Qu Jia-Quan , He Qiu-Yan , Li Jian-Huang , Chen Yu , Chen Zhu-Chu , Xiao Zhi-Qiang
Published: July 2011

Background

The epidermal growth factor receptor (EGFR) is usually overexpressed in nasopharyngeal carcinoma (NPC) and is associated with pathogenesis of NPC. However, the downstream signaling proteins of EGFR in NPC have not yet been completely understood at the system level. The aim of this study was identify novel downstream proteins of EGFR signaling pathway in NPC cells.

Results

We analyzed EGFR-regulated phosphoproteome in NPC CNE2 cells using 2D-DIGE and mass spectrometry analysis after phosphoprotein enrichment. As a result, 33 nonredundant phosphoproteins including five known EGFR-regulated proteins and twenty-eight novel EGFR-regulated proteins in CNE2 were identified, three differential phosphoproteins were selectively validated, and two differential phosphoproteins (GSTP1 and GRB2) were showed interacted with phospho-EGFR. Bioinformatics analysis showed that 32 of 33 identified proteins contain phosphorylation modification sites, and 17 identified proteins are signaling proteins. GSTP1, one of the EGFR-regulated proteins, associated with chemoresistance was analyzed. The results showed that GSTP1 could contribute to paclitaxel resistance in EGF-stimulated CNE2 cells. Furthermore, an EGFR signaling network based on the identified EGFR-regulated phosphoproteins were constructed using Pathway Studio 5.0 software, which includes canonical and novel EGFR-regulated proteins and implicates the possible biological roles for those proteins.

Conclusion

The data not only can extend our knowledge of canonical EGFR signaling, but also will be useful to understand the molecular mechanisms of EGFR in NPC pathogenesis and search therapeutic targets for NPC.
Cytotoxic T lymphocyte responses against melanocytes and melanoma
Authors: Chang Gwendolen Y , Kohrt Holbrook E , Stuge Tor B , Schwartz Erich J , Weber Jeffrey S , Lee Peter P
Published: July 2011

Background

Vitiligo is a common toxicity associated with immunotherapy for melanoma. Cytotoxic T lymphocytes (CTLs) against melanoma commonly target melanoma-associated antigens (MAAs) which are also expressed by melanocytes. To uncouple vitiligo from melanoma destruction, it is important to understand if CTLs can respond against melanoma and melanocytes at different levels.

Methods

To understand the dichotomous role of MAA-specific CTL, we characterized the functional reactivities of established CTL clones directed to MAAs against melanoma and melanocyte cell lines.

Results

CTL clones generated from melanoma patients were capable of eliciting MHC-restricted, MAA-specific lysis against melanocyte cell lines as well as melanoma cells. Among the tested HLA-A*0201-restricted CTL clones, melanocytes evoked equal to slightly higher degranulation and cytolytic responses as compared to melanoma cells. Moreover, MAA-specific T cells from vaccinated patients responded directly ex vivo to melanoma and melanocytes. Melanoma cells express slightly higher levels of MART-1 and gp100 than melanocytes as measured by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry.

Conclusions

Our data suggest that CTLs respond to melanoma and melanocytes equally in vitro and directly ex vivo.
Safety and feasibility of third-party multipotent adult progenitor cells for immunomodulation therapy after liver transplantation--a phase I study (MISOT-I)
Authors: Popp Felix C , Fillenberg Barbara , Eggenhofer Elke , Renner Philipp , Dillmann Johannes , Benseler Volker , Schnitzbauer Andreas A , Hutchinson James , Deans Robert , Ladenheim Deborah , Graveen Cheryl A , Zeman Florian , Koller Michael , Hoogduijn Martin J , Geissler Edward K , Schlitt Hans J , Dahlke Marc H
Published: July 2011

Background

Liver transplantation is the definitive treatment for many end-stage liver diseases. However, the life-long immunosuppression needed to prevent graft rejection causes clinically significant side effects. Cellular immunomodulatory therapies may allow the dose of immunosuppressive drugs to be reduced. In the current protocol, we propose to complement immunosuppressive pharmacotherapy with third-party multipotent adult progenitor cells (MAPCs), a culture-selected population of adult adherent stem cells derived from bone marrow that has been shown to display potent immunomodulatory and regenerative properties. In animal models, MAPCs reduce the need for pharmacological immunosuppression after experimental solid organ transplantation and regenerate damaged organs.

Methods

Patients enrolled in this phase I, single-arm, single-center safety and feasibility study (n = 3-24) will receive 2 doses of third-party MAPCs after liver transplantation, on days 1 and 3, in addition to a calcineurin-inhibitor-free "bottom-up" immunosuppressive regimen with basiliximab, mycophenolic acid, and steroids. The study objective is to evaluate the safety and clinical feasibility of MAPC administration in this patient cohort. The primary endpoint of the study is safety, assessed by standardized dose-limiting toxicity events. One secondary endpoint is the time until first biopsy-proven acute rejection, in order to collect first evidence of efficacy. Dose escalation (150, 300, 450, and 600 million MAPCs) will be done according to a 3 + 3 classical escalation design (4 groups of 3-6 patients each).

Discussion

If MAPCs are safe for patients undergoing liver transplantation in this study, a phase II/III trial will be conducted to assess their clinical efficacy.
Garlic improves insulin sensitivity and associated metabolic syndromes in fructose fed rats
Authors: Padiya Raju , Khatua Tarak N , Bagul Pankaj K , Kuncha Madhusudana , Banerjee Sanjay K
Published: July 2011

Background

Type 2 diabetes mellitus, characterized by peripheral insulin resistance, is a major lifestyle disorder of the 21st Century. Raw garlic homogenate has been reported to reduce plasma glucose levels in animal models of type 1 diabetes mellitus. However, no specific studies have been conducted to evaluate the effect of raw garlic on insulin resistance or type 2 diabetes mellitus. This study was designed to investigate the effect of raw garlic on fructose induced insulin resistance, associated metabolic syndrome and oxidative stress in diabetic rats.

Methods

Male Sprague Dawley rats weighing 200-250 gm body weight were divided into 3 groups (n = 7 per group) and fed diet containing 65% cornstarch (Control group) and 65% fructose (Diabetic group) for 8 weeks. The third group (Dia+Garl group) was fed both 65% fructose and raw garlic homogenate (250 mg/kg/day) for 8 weeks. Whole garlic cloves were homogenized with water to make a fresh paste each day.

Results

At the end of 8 weeks, serum glucose, insulin, triglyceride and uric acid levels, as well as insulin resistance, as measured by glucose tolerance test, were significantly (p < 0.01) increased in fructose fed rats (Diabetic group) when compared to the cornstarch fed (Control) rats. Administration of raw garlic to fructose fed rats (Dia+Garl group) significantly (p < 0.05) reduced serum glucose, insulin, triglyceride and uric acid levels, as well as insulin resistance when compared with fructose fed rats. Garlic also normalised the increased serum levels of nitric oxide (NO) and decreased levels of hydrogen sulphide (H2S) after fructose feeding. Although body weight gain and serum glycated haemoglobin levels of fructose fed rats (Diabetic group) were not significantly different from control rats, significant (p < 0.05) reduction of these parameters was observed in fructose fed rats after garlic administration (Dia+Garl group). Significant (p < 0.05) increase in TBARS and decrease in GSH was observed in diabetic liver. Catalase was not significantly affected in any of the groups. Administration of raw garlic homogenate normalised both hepatic TBARS and GSH levels.

Conclusions

Our study demonstrates that raw garlic homogenate is effective in improving insulin sensitivity while attenuating metabolic syndrome and oxidative stress in fructose-fed rats.
Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: A pilot trial
Authors: Schmidt Melanie , Pfetzer Nadja , Schwab Micheal , Strauss Ingrid , Kämmerer Ulrike
Published: July 2011

Background

Tumor patients exhibit an increased peripheral demand of fatty acids and protein. Contrarily, tumors utilize glucose as their main source of energy supply. Thus, a diet supplying the cancer patient with sufficient fat and protein for his demands while restricting the carbohydrates (CHO) tumors thrive on, could be a helpful strategy in improving the patients' situation. A ketogenic diet (KD) fulfills these requirements. Therefore, we performed a pilot study to investigate the feasibility of a KD and its influence on the quality of life of patients with advanced metastatic tumors.

Methods

Sixteen patients with advanced metastatic tumors and no conventional therapeutic options participated in the study. The patients were instructed to follow a KD (less than 70 g CHO per day) with normal groceries and were provided with a supply of food additives to mix a protein/fat shake to simplify the 3-month intervention period. Quality of life [assessed by EORTC QLQ-C30 (version 2)], serum and general health parameters were determined at baseline, after every two weeks of follow-up, or after drop out. The effect of dietary change on metabolism was monitored daily by measuring urinary ketone bodies.

Results

One patient did not tolerate the diet and dropped out within 3 days. Among those who tolerated the diet, two patients died early, one stopped after 2 weeks due to personal reasons, one felt unable to stick to the diet after 4 weeks, one stopped after 6 and two stopped after 7 and 8 weeks due to progress of the disease, one had to discontinue after 6 weeks to resume chemotherapy and five completed the 3 month intervention period. These five and the one who resumed chemotherapy after 6 weeks report an improved emotional functioning and less insomnia, while several other parameters of quality of life remained stable or worsened, reflecting their very advanced disease. Except for temporary constipation and fatigue, we found no severe adverse side effects, especially no changes in cholesterol or blood lipids.

Conclusions

These pilot data suggest that a KD is suitable for even advanced cancer patients. It has no severe side effects and might improve aspects of quality of life and blood parameters in some patients with advanced metastatic tumors.
Mannose-binding lectin deficiency with eosinophilic meningoencephalitis due to Angiostrongylus cantonensis in children: a case series
Authors: Padilla-Docal Bárbara , Dorta-Contreras Alberto J , Bu-Coifiu-Fanego Raisa , Martínez-Alderete René H , de Paula-Almeida Olga Susana , Reiber Hansotto , Jensenius Jens Christian
Published: July 2011

Introduction

Eosinophilic meningitis, a potentially fatal disease caused by Angiostrongylus cantonensis, is considered an emerging infectious disease.

Case presentation

Three Caucasian boys (aged five-years-old, 10-years-old and six-years-old) with a diagnosis of eosinophilic meningoencephalitis caused by Angiostrongylus cantonensis were studied. Serum immunoglobulin A (IgA), IgM, IgG, and complements C3c and C4 levels were quantified by using an immunodiffusion technique. Immunoglobulin E in serum was quantified by nephelometry and mannose-binding lectin by time-resolved fluorometry. Mannose-binding lectin deficiency was observed in the three patients. The first patient showed a reduction in the levels of IgA and IgM and an increase in the values of IgE and C4. The second patient showed a reduction in mannose-binding lectin level with increased IgG, C4 and IgE levels, and the third patient showed a decrease in mannose-binding lectin level and increased levels of IgM and complement C3c as well as a low level of C4.

Conclusions

To the best of our knowledge, this is the first report of mannose-binding lectin deficiency associated with Angiostrongylus cantonensis meningoencephalitis in children, and it may contribute to the understanding of the participation of this component of the lectin pathway in the development of the disease.
Schistosoma-associated Salmonella resist antibiotics via specific fimbrial attachments to the flatworm
Authors: Barnhill Alison E , Novozhilova Ekaterina , Day Tim A , Carlson Steve A
Published: July 2011

Background

Schistosomes are parasitic helminths that infect humans through dermo-invasion while in contaminated water. Salmonella are also a common water-borne human pathogen that infects the gastrointestinal tract via the oral route. Both pathogens eventually enter the systemic circulation as part of their respective disease processes. Concurrent Schistosoma-Salmonella infections are common and are complicated by the bacteria adhering to adult schistosomes present in the mesenteric vasculature. This interaction provides a refuge in which the bacterium can putatively evade antibiotic therapy and anthelmintic monotherapy can lead to a massive release of occult Salmonella.

Results

Using a novel antibiotic protection assay, our results reveal that Schistosoma-associated Salmonella are refractory to eight different antibiotics commonly used to treat salmonellosis. The efficacy of these antibiotics was decreased by a factor of 4 to 16 due to this association. Salmonella binding to schistosomes occurs via a specific fimbrial protein (FimH) present on the surface on the bacterium. This same fimbrial protein confers the ability of Salmonella to bind to mammalian cells.

Conclusions

Salmonella can evade certain antibiotics by binding to Schistosoma. As a result, effective bactericidal concentrations of antibiotics are unfortunately above the achievable therapeutic levels of the drugs in co-infected individuals. Salmonella-Schistosoma binding is analogous to the adherence of Salmonella to cells lining the mammalian intestine. Perturbing this binding is the key to eliminating Salmonella that complicate schistosomiasis.
Fiber optic bronchoscopy in patients with acute hypoxemic respiratory failure requiring noninvasive ventilation - a feasibility study
Authors: Baumann Hans Jörg , Klose Hans , Simon Marcel , Ghadban Tarik , Braune Stephan A , Hennigs Jan K , Kluge Stefan
Published: July 2011

Introduction

Noninvasive ventilation (NIV) is a standard procedure in selected patients with acute respiratory failure. Previous studies have used noninvasive ventilation to ensure adequate gas exchange during fiberoptic bronchoscopy in spontaneously breathing hypoxemic patients, thus avoiding endotracheal intubation. However, it is unknown whether bronchoscopy can be performed safely in patients with acute hypoxemic respiratory failure already in need of NIV prior to the decision for bronchoscopy.

Methods

We prospectively investigated 40 consecutive, critically ill, adult patients with acute hypoxemic respiratory failure (14 women, 26 men, age 61 ± 15 years, partial pressure for oxygen/fraction of inspired oxygen (PaO2/FiO2) < 300 under noninvasive ventilation, Simplified Acute Physiology scores (SAPS II) 47 ± 9.9 points). All patients required noninvasive ventilation prior to the decision to perform bronchoscopy (median 10.5 h; range 2.2 to 114). Blood gases, heart rate, blood pressure and ventilation were monitored before, during and up to 120 minutes after bronchoscopy.

Results

Bronchoscopy could be completed in all patients without subsequent complications. Oxygen saturation fell to < 90% in two patients (5%), and the lowest value during the procedure was 84%. The mean PaO2/FiO2 ratio improved from 176 ± 54 at baseline to 240 ± 130 (P < 0.001) at the end of bronchoscopy and 210 ± 79 after 120 minutes. The transient mean partial pressure of carbon dioxide in the arterial blood (PaCO2) increase was 9.4 ± 8.1 mm Hg. Four patients (10%) required endotracheal intubation during the first eight hours after the procedure. Bronchoalveolar lavage yielded diagnostic information in 26 of 38 (68%) patients.

Conclusions

In critically ill patients with acute hypoxemic respiratory failure requiring noninvasive ventilation, bronchoscopy can be performed with an acceptable risk. Since these patients per se have a high likelihood of subsequent endotracheal intubation due to failure of NIV, bronchoscopy should only be performed by experienced clinicians.
When should a diagnosis of influenza be considered in adults requiring intensive care unit admission? Results of population-based active surveillance in Toronto
Authors: Kuster Stefan P , Katz Kevin C , Blair Joanne , Downey James , Drews Steven J , Finkelstein Sandy , Fowler Rob , Green Karen , Gubbay Jonathan , Hassan Kazi , Lapinsky Stephen E , Mazzulli Tony , McRitchie Donna , Pataki Janos , Plevneshi Agron , Powis Jeff , Rose David , Sarabia Alicia , Simone Carmine , Simor Andrew , McGeer Allison
Published: July 2011

Introduction

There is a paucity of data about the clinical characteristics that help identify patients at high risk of influenza infection upon ICU admission. We aimed to identify predictors of influenza infection in patients admitted to ICUs during the 2007/2008 and 2008/2009 influenza seasons and the second wave of the 2009 H1N1 influenza pandemic as well as to identify populations with increased likelihood of seasonal and pandemic 2009 influenza (pH1N1) infection.

Methods

Six Toronto acute care hospitals participated in active surveillance for laboratory-confirmed influenza requiring ICU admission during periods of influenza activity from 2007 to 2009. Nasopharyngeal swabs were obtained from patients who presented to our hospitals with acute respiratory or cardiac illness or febrile illness without a clear nonrespiratory aetiology. Predictors of influenza were assessed by multivariable logistic regression analysis and the likelihood of influenza in different populations was calculated.

Results

In 5,482 patients, 126 (2.3%) were found to have influenza. Admission temperature ≥38°C (odds ratio (OR) 4.7 for pH1N1, 2.3 for seasonal influenza) and admission diagnosis of pneumonia or respiratory infection (OR 7.3 for pH1N1, 4.2 for seasonal influenza) were independent predictors for influenza. During the peak weeks of influenza seasons, 17% of afebrile patients and 27% of febrile patients with pneumonia or respiratory infection had influenza. During the second wave of the 2009 pandemic, 26% of afebrile patients and 70% of febrile patients with pneumonia or respiratory infection had influenza.

Conclusions

The findings of our study may assist clinicians in decision making regarding optimal management of adult patients admitted to ICUs during future influenza seasons. Influenza testing, empiric antiviral therapy and empiric infection control precautions should be considered in those patients who are admitted during influenza season with a diagnosis of pneumonia or respiratory infection and are either febrile or admitted during weeks of peak influenza activity.
Universalism in One Country: La Protection Sociale over the Longue Durée
Authors: Adams Thomas M.
Published: July 2011

The republican model of social rights in France invokes the heritage of the Revolution. The meaning of this legacy is complex for several reasons. The articulation of rights during the Revolution took different forms in theory; practice fell short of aspirations. The political legacy of social rights drew strength from Enlightenment sources and from older antecedents such as the Erasmian humanism of Juan Luis Vives. Tracing the evolution of social rights in France since the Revolution, the historian encounters continuities both in the statement of principles and in the obstacles to their realization. At the same time, new players contend with challenges unforeseen by the leaders of the first French republic.

Le modèle républicain de la protection sociale en France s'inscrit dans l'héritage de la Révolution. Or, il faut préciser d'abord que le moment de sa conception n'est pas établi et qu'une recherche de paternité nécessiterait une approche historique de longue durée. Le fons et origo du droit social remonte au siècle des Lumières et dans une tradition plus lointaine que l'on peut qualifier d'érasmienne. Quand on trace les réalisations du droit social depuis l'époque révolutionnaire, on retrouve les qualités et les défauts de son ascendance. D'autre part, il faut reconnaître les apports multiples et les trébuchements d'une société et d'un état qui ne se sont pas révélés révolutionnaires sans réserve. Les réticences et les démarches nouvelles de la politique sociale contemporaine font état d'un monde imprévisible aux militants de 1789, 1793 et 1795. Pourtant, l'appel des droits universels a maintenant un retentissement mondial.
Notch signalling stabilises boundary formation at the midbrain-hindbrain organiser
Authors: Tossell Kyoko , Kiecker Clemens , Wizenmann Andrea , Lang Emily , Irving Carol
Published: July 2011

The midbrain-hindbrain interface gives rise to a boundary of particular importance in CNS development as it forms a local signalling centre, the proper functioning of which is essential for the formation of tectum and cerebellum. Positioning of the mid-hindbrain boundary (MHB) within the neuroepithelium is dependent on the interface of Otx2 and Gbx2 expression domains, yet in the absence of either or both of these genes, organiser genes are still expressed, suggesting that other, as yet unknown mechanisms are also involved in MHB establishment. Here, we present evidence for a role for Notch signalling in stabilising cell lineage restriction and regulating organiser gene expression at the MHB. Experimental interference with Notch signalling in the chick embryo disrupts MHB formation, including downregulation of the organiser signal Fgf8. Ectopic activation of Notch signalling in cells of the anterior hindbrain results in an exclusion of those cells from rhombomeres 1 and 2, and in a simultaneous clustering along the anterior and posterior boundaries of this area, suggesting that Notch signalling influences cell sorting. These cells ectopically express the boundary marker Fgf3. In agreement with a role for Notch signalling in cell sorting, anterior hindbrain cells with activated Notch signalling segregate from normal cells in an aggregation assay. Finally, misexpression of the Notch modulator Lfng or the Notch ligand Ser1 across the MHB leads to a shift in boundary position and loss of restriction of Fgf8 to the MHB. We propose that differential Notch signalling stabilises the MHB through regulating cell sorting and specifying boundary cell fate.
Interference in the autoDELFIA® hAFP immunoassay and effect on second-trimester Down's syndrome screening
Authors: Mannings Leanne , Trow Sandy , Newman Janet , Nix Barry , Evans Carol
Published: July 2011

Background

Falsely decreased serum alphafetoprotein (AFP) concentrations are reported in the autoDELFIA® hAFP immunoassay due to interference by complement. AFP is measured, using this assay, as part of second-trimester and integrated Down's syndrome screening tests. Decreased AFP concentrations increase the calculated risk of Down's syndrome; therefore falsely low AFP, due to assay interference, may artificially increase a patient's risk, and have the potential to cause false screen positive results. It was our aim to assess whether negative interference in the autoDELFIA® hAFP assay was a cause of very low AFP concentrations, and to examine the effect of falsely decreased concentrations on the calculated risk of Down's syndrome.

Methods

Three hundred and twenty-three sequential Down's screening serum samples with very low serum AFP concentration (<15 KU/L) using the autoDELFIA® hAFP immunoassay were selected and AFP re-measured using the E170 AFP immunoassay.

Results

Interference was detected in nine samples (from eight patients) on the basis of discordant AFP concentrations. The interference decreased following storage of samples at 4°C to deplete complement. Use of the falsely low AFP concentrations to calculate risk of Down's syndrome resulted in significantly increased calculated risk compared with complement depleted results.

Conclusions

Laboratories should be aware that falsely low AFP concentrations due to complement interference may be obtained using the autoDELFIA® hAFP immunoassay. We have shown that falsely low AFP concentrations increase the calculated risk of Down's syndrome. This is a potential cause of false Down's syndrome screen positive results.
Transcending Knowledge Differences in Cross-Functional Teams
Authors: Majchrzak Ann , More Philip H. B. , Faraj Samer
Published: July 2011

Knowledge differences impede the work of cross-functional teams by making knowledge integration difficult, especially when the teams are faced with novelty. One approach in the literature for overcoming these difficulties, which we refer to as the traverse approach, is for team members to identify, elaborate, and then explicitly confront the differences and dependencies across the knowledge boundaries. This approach emphasizes deep dialogue and requires significant resources and time. In an exploratory in-depth longitudinal study of three quite different cross-functional teams, we found that the teams were able to cogenerate a solution without needing to identify, elaborate, and confront differences and dependencies between the specialty areas. Our analysis of the extensive team data collected over time surfaced practices that minimized members' differences during the problem-solving process. We suggest that these practices helped the team to transcend knowledge differences rather than traverse them. Characteristic of these practices is that they avoided interpersonal conflict, fostered the rapid cocreation of intermediate scaffolds, encouraged continued creative engagement and flexibility to repeatedly modify solution ideas, and fostered personal responsibility for translating personal knowledge to collective knowledge. The contrast between these two approaches to knowledge integration—traverse versus transcend—suggests the need for more nuanced theorizing about the use of boundary objects, the nature of dialogue, and the role of organizational embeddedness in understanding how knowledge differences are integrated.
Bacterial STDs and Perceived Risk Among Sexual Minority Young Adults
Authors: Kaestle Christine E. , Waller Martha W.
Published: July 2011

CONTEXT: Most sexual health interventions focus on heterosexual sexual risk behavior. Health practitioners face a lack of information about the sexual health of sexual minority young adults (aged 18–26).

METHODS: Three indicators of sexual minority status (identity, behavior and romantic attractions) were assessed in 10,986 young adults who participated in Wave 3 of the National Longitudinal Study of Adolescent Health (2001–2002). Logistic regression analyses examined associations between these indicators and individuals’ perceived risk for STDs and actual infection with STDs. Data from the 1,154 respondents who had current or recent bacterial STDs were investigated further to determine whether they had underestimated their risk.

RESULTS: Outcomes varied by sexual minority status indicator and by sex. Bisexual females had significantly higher odds of STDs than heterosexual females (odds ratios, 1.4), and females attracted to both sexes had significantly higher odds of STDs than females attracted only to males (1.8). In contrast, none of the sexual minority status indicators predicted STDs for males. Among respondents who had an STD, females who reported only same‐sex sexual relationships were more likely to believe they were at very low risk for STDs than were females reporting only opposite‐sex sexual relationships (17.2); homosexual females had a higher likelihood of this outcome than heterosexual females (19.7).

CONCLUSIONS: Health practitioners need to assist sexual minority young adults, particularly females, in under‐standing their risk for STDs and in taking safer‐sex precautions.
Role of nipple sparing mastectomy in modern breast surgery
Authors: Mátrai Zoltán , Gulyás Gusztáv , Tóth László , Sávolt Ákos , Kunos Csaba , Pesthy Pál , Bartal Alexandra , Kásler Miklós
Published: July 2011

Recently an increasing number of reports of clinical experience have been published on nipple-sparing mastectomy. By the preservation of uninvolved skin and the nipple areola complex, this surgical technique greatly facilitates immediate reconstruction and optimal aesthetic outcome. However, the procedure raises serious oncologic concerns regarding the risk of an occult or a newly formed primary tumor due to parenchyma left behind in the nipple and the retroareola. Despite the ever increasing popularity of the method, there is still no evidence based confirmation to it. According to data from scientific literature on nipple-sparing mastectomy, there is no straightforward consequence to be drawn on oncologic safety; therefore the procedure is not generally considered to be alternative to standard mastectomy. In the indication of risk reduction, justification of the intervention seems to be well supported, and is expected to foster a greater rate of acceptance of surgical prophylaxis in patients with higher risk diseases. The procedure should be carried out possibly in the framework of clinical trials, in well selected patients with suitable preoperative and postoperative examinations, applying precise techniques and adequate patient education, according to international guidelines. Further long-term results are needed to form a substantive expert opinion. Authors give a detailed description of the surgical techniques, and provide a wide review of the literature, for the first time in Hungarian language. Orv. Hetil., 2011, 152, 1233–1249.
Association of the Scientific Societies of Hungarian Medical Doctors (MORTESZ) was founded 80 years ago
Authors: Kiss István , Sótonyi Péter
Published: July 2011

After the First World War the professional medical societies in Hungary, which have already organized themselves nationwide, started to operate independently from each other. In that time came the idea to create another association above the others to clamp them together while retaining their independent functioning. The Association of the Scientific Societies of Hungarian Medical Doctors (MORTESZ), established in 1931, became the nationwide forum for many medical associations. It also organized the first Hungarian Medical Grand-Week which became the annual meeting of the medical society. In the first year the cooperation only consisted of a common topic of two or three associations presented in the “Grand-Week”. From year 1935, reports were appointed annually that each professional association could comment on. The proceedings of the “Grand-Week” were published yearly as appendices of the Hungarian Medical Journal. After the Second World War the activities of the independent associations were shut down by the authorities. The scientific and professional associations could continue their work as sections inside of the Doctors and Health Workers’ Union. In 1966 the situation was solved thanks to the initiative of the Trade Union, the Department of Medicine and the Medical Section of the Hungarian Academy of Sciences which resulted in the foundation of the Association of the Hungarian Medical Societies (MOTESZ) which continues to clamp together the collective work of many scientific associations and carries out tasks of general interest since then, similarly to the now 80-years-old MORTESZ. Orv. Hetil., 2011, 152, 1250–1254.
Crystallization Behavior of Hf-rich Aluminates and Influence on Film Dielectric Properties
Authors: Climent M. , Crivelli B. , Righini G. , Alberici S. , Alessandri M. , Elbaz A. C. , Pavia G. , Wiemer C.
Published: July 2011

In this study, the investigation of crystallization behaviour of Hf-rich aluminate is presented. Different alloys were deposited by ALCVD™ with composition ranging between 16 and 47 Al2O3 mol%. Post-deposition annealings were carried out in single or sequential mode using purified N2 at atmospheric pressure. Process temperature and time were varied from 700°C to 900°C and from 1' to 30' respectively. Upon these conditions, film thermal evolution was observed without any relevant increasing of in interface layer and any change in material composition. Measurements on 20 Al2O3 mol% films evidenced that thermal treatments up to 800°C promoted initial shrinking in thickness and material densification. Above 900°C, all considered aluminates were found to crystallize in orthorhombic phase maintaining original alloy composition. The higher the alumina content, the lower the grain size, the higher the crystallites density. Stability of orthorhombic crystalline structure was demonstrated upon single prolonged annealing up to 30' and upon sequential processes. In correspondence with film crystallization, enhancement of dielectric constant was detected with an increasing trend upon hafnia content. For 20 Al2O3 mol% aluminate, change in k form 19 to 40-45 was observed together with limited degradation in conduction and breakdown characteristics.