bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abnormal Matrix Remodeling in Adolescents and Young Adults with Kawasaki Disease Late after Onset
Authors: Lin Ming-Tai , Chen Shyh-Jye , Ho Yi-Lwun , Huang Kuo-Chin , Chen Chun-An , Chiu Shuenn-Nan , Sun Li-Chuan , Lee Wen-Jeng , Chen Hui-Chi , Wang Jou-Kou , Wu Mei-Hwan 
Published: September 2008

AbstractBackground: Patients with a history of Kawasaki disease (KD), have been found to have pericoronary and myocardial fibrosis. Serum biomarkers of fibrosis may be sensitive indices for detection of these late cardiac complications in KD patients.Methods: We studied a cohort of 60 adolescents and young adults comprising 10 KD patients with persistent coronary artery lesions (CAL) occurring at a mean (SD) time of 14.5 (4.4) years after disease onset, 25 KD patients with no CAL after disease onset, and 25 healthy age-matched volunteers. We compared laboratory data from the patients and volunteers, including lipid profile, liver function, amino-terminal propeptide of type III procollagen (PIIINP), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1), and MMP-9:TIMP-1 ratios. Severity of CAL was determined on the basis of computed tomography determinations of the frequency of aneurysms and the extent of coronary stenosis/occlusion, thrombosis, and calcification.Results: Increased PIIINP and decreased MMP-9 and TIMP-1 concentrations and decreased MMP-9:TIMP-1 ratios were found not only in KD patients with persistent CAL but also in KD patients without CAL, although to a lesser extent in the latter group. In KD patients, the concentrations of PIIINP were positively associated with the severity of coronary stenosis/occlusion (r = 0.72, P = 0.011) and with the extent of coronary thrombus (r = 0.64, P = 0.014). The concentrations of high-sensitivity C-reactive protein, however, did not differ across groups.Conclusions: Our results demonstrate alterations in extracellular matrix biomarkers in KD patients, suggesting enhanced collagen synthesis and ameliorated degradation in adolescents and young adults late after the onset of KD. We also observed an association between the concentrations of PIIINP and the extent of coronary stenosis/occlusion or thrombosis in KD patients, a finding that needs confirmation in further studies.
Hypothyroidism in patients with pseudohypoparathyroidism type Ia: clinical evidence of resistance to TSH and TRH
Authors: Balavoine Anne-Sophie , Ladsous Miriam , Velayoudom Fritz-Line , Vlaeminck Virginie , Cardot-Bauters Catherine , d'Herbomez Michèle , Wemeau Jean-Louis 
Published: September 2008

ObjectiveHypothyroidism is a manifestation of multi-hormonal resistance in pseudohypoparathyroidism type Ia (PHP Ia). The objective of the study was to determine the mechanisms of hypothyroidism in PHP Ia.DesignA prospective study.PatientsTen patients with PHP Ia.MeasurementsThe serum concentrations of TSH, free triiodothyronine (FT3), free thyroxine (FT4), and prolactin (PRL) were measured at baseline and after stimulation with TRH (200 μg i.v).ResultsThe median basal serum TSH concentration was 4.92 mU/l. Basal serum TSH concentration was slightly elevated in eight patients (4.22–7.0 mU/l; normal range, 0.4–3.6 mU/l), normal in one patient (2.5 mU/l), and high in one patient (13.1 mU/l). After the TRH test, TSH concentrations increased to 13.4–36.0 mU/l (normal range, 4.0–20.0 mU/l). The absolute values after the test were normal in three patients and high in seven patients. However, TSH responses relative to the baseline value (stimulated/basal TSH and expressed as a fold increase), which reflect the relative increases after TRH stimulation, were low in seven patients (2.3- to 4.3-fold TSH) and normal in three patients. Basal FT4 concentration was normal in seven patients and low in three patients (range, 8.4–20.0 pmol/l; mean, 14.1±4.3 pmol/l; normal range, 10.5–23.0 pmol/l). Basal FT3 concentration was normal in nine patients and low in one patient (range, 0.9–5.0 pmol/l; mean, 3.8±1.1 pmol/l; normal range, 3.3–6.1 pmol/l). FT4 and FT3 were not significantly increased after the TRH test. PRL concentration was normal at baseline and increased from 7 to 96 ng/ml after TRH.ConclusionOur results support the hypothesis that patients with PHP Ia have impaired sensitivity to both TSH and TRH.
Phenotypic and Functional Reversal Within the Early Human Hematopoietic Compartment
Authors: Knaän-Shanzer Shoshan , van der Velde-van Dijke Ietje , van de Watering Marloes J.M. , de Leeuw Philip J. , Valerio Dinko , van Bekkum Dirk W. , de Vries Antoine A.F. 
Published: September 2008

AbstractThe fate of phenotypically defined human hematopoietic stem cells (hHSCs) in culture and the link between their surface marker expression profile and function are still controversial. We studied these aspects of hHSC biology by relating the expression of the early lineage markers (ELM) CD33, CD38, and CD71 on the surface of human umbilical cord blood (UCB) CD34+ cells to their long-term nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse repopulation activity (LT-SRA). In uncultured UCB samples, LT-SRA was largely confined to the small CD34+ELM− cell fraction. CD34+ cells expressing ELM markers at their surface usually lacked LT-SRA. After culturing UCB CD34+ cells for 6 days in serum-free medium and on a feeder layer of Rat2 cells, the number of CD34+ELM− cells stayed roughly the same or showed a slight increase and the LT-SRA was preserved, suggesting a close association between LT-SRA and the CD34+ELM− phenotype. Indeed, transplantation of CD34+ELM− cells isolated from cultured UCB CD34+ cells resulted in long-term hematopoietic reconstitution of conditioned NOD/SCID mice, whereas CD34+ELM+ cells derived from the same cultures were devoid of LT-SRA. Remarkably, roughly 1% of the cells recovered from cultures initiated with isolated CD34+ELM+ cells had lost ELM surface expression. Concurrently, the cultured CD34+ELM+ cells acquired LT-SRA, suggesting that hematopoietic stem cells (HSCs) may arise by the dedifferentiation of early hematopoietic progenitor cells. The latter finding challenges the paradigm of unidirectional hematopoietic differentiation and opens new opportunities for HSC expansion prior to transplantation.Disclosure of potential conflicts of interest is found at the end of this article.
Brain Cancer Stem Cells Display Preferential Sensitivity to Akt Inhibition
Authors: Eyler Christine E. , Foo Wen-Chi , LaFiura Katherine M. , McLendon Roger E. , Hjelmeland Anita B. , Rich Jeremy N. 
Published: September 2008

Abstract
Malignant brain tumors are among the most lethal cancers, and conventional therapies are largely limited to palliation. Novel therapies targeted against specific molecular pathways may offer superior efficacy and less toxicity than conventional therapies, but initial clinical trials of molecular targeted agents in brain cancer therapy have been frequently disappointing. In brain tumors and other cancers, subpopulations of tumor cells have recently been characterized by their ability to self-renew and initiate tumors. Although these cancer stem cells, or tumor initiating cells, are often only present in small numbers in human tumors, mounting evidence suggests that cancer stem cells contribute to tumor maintenance and therapeutic resistance. Thus, the development of therapies that target cancer stem cell signal transduction and biology may improve brain tumor patient survival. We now demonstrate that populations enriched for cancer stem cells are preferentially sensitive to an inhibitor of Akt, a prominent cell survival and invasion signaling node. Treatment with an Akt inhibitor more potently reduced the numbers of viable brain cancer stem cells relative to matched nonstem cancer cells associated with a preferential induction of apoptosis and a suppression of neurosphere formation. Akt inhibition also reduced the motility and invasiveness of all tumor cells but had a greater impact on cancer stem cell behaviors. Furthermore, inhibition of Akt activity in cancer stem cells increased the survival of immunocompromised mice bearing human glioma xenografts in vivo. Together, these results suggest that Akt inhibitors may function as effective anticancer stem cell therapies.
Disclosure of potential conflicts of interest is found at the end of this article.
Isolation of Primordial Germ Cells from Differentiating Human Embryonic Stem Cells
Authors: Tilgner Katarzyna , Atkinson Stuart P. , Golebiewska Anna , Stojković Miodrag , Lako Majlinda , Armstrong Lyle 
Published: September 2008

Abstract
Of all the cell types that can be obtained from the differentiation of embryonic stem cells, primordial germ cells are arguably the most fascinating, as they represent the in vitro completion of the reproductive cycle of the organism from which the embryonic stem cell line was derived. It is also possible to obtain these cells from embryos at an appropriate stage of development, but this process yields only small numbers that are not applicable to investigations of their epigenetic architecture. A considerable body of data has been generated from the differentiation of mouse embryonic stem cells to this cell type, but despite the demonstration of their presence in human embryoid bodies, there has been little progress toward methods of producing human primordial germ cells in useful numbers. We present here a robust protocol to differentiate two human embryonic stem cell lines (H9 and hES-NCL1) that maximizes the numbers of primordial germ cells that may be obtained using a simple fluorescence-activated cell sorting strategy for their isolation. These primordial germ cells demonstrate high-level expression of the germ cell-specific VASA gene and show removal of parental imprints and chromatin modification changes that support their primordial germ cell identity.
Disclosure of potential conflicts of interest is found at the end of this article.
Bromodeoxyuridine Induces Senescence in Neural Stem and Progenitor Cells
Authors: Ross Heather H. , Levkoff Lindsay H. , Marshall Gregory P. , Caldeira Maria , Steindler Dennis A. , Reynolds Brent A. , Laywell Eric D. 
Published: September 2008

Abstract
Bromodeoxyuridine (BrdU) is a halogenated pyrimidine that incorporates into newly synthesized DNA during the S phase. BrdU is used ubiquitously in cell birthdating studies and as a means of measuring the proliferative index of various cell populations. In the absence of secondary stressors, BrdU is thought to incorporate relatively benignly into replicating DNA chains. However, we report here that a single, low-dose pulse of BrdU exerts a profound and sustained antiproliferative effect in cultured murine stem and progenitor cells. This is accompanied by altered terminal differentiation, cell morphology, and protein expression consistent with the induction of senescence. There is no evidence of a significant increase in spontaneous cell death; however, cells are rendered resistant to chemically induced apoptosis. Finally, we show that a brief in vivo BrdU regimen reduces the proliferative potential of subsequently isolated subependymal zone neurosphere-forming cells. We conclude, therefore, that BrdU treatment induces a senescence pathway that causes a progressive decline in the replication of rapidly dividing stem/progenitor cells, suggesting a novel and uncharacterized effect of BrdU. This finding is significant in that BrdU-incorporating neural stem/progenitor cells and their progeny should not be expected to behave normally with respect to proliferative potential and downstream functional parameters. This effect highlights the need for caution when results based on long-term BrdU tracking over multiple rounds of replication are interpreted. Conversely, the reliable induction of senescence in stem/progenitor cells in vitro and in vivo may yield a novel platform for molecular studies designed to address multiple aspects of aging and neurogenesis.
Disclosure of potential conflicts of interest is found at the end of this article.
Regulation of Prenatal Human Retinal Neurosphere Growth and Cell Fate Potential by Retinal Pigment Epithelium and Mash1
Authors: Gamm David M. , Wright Lynda S. , Capowski Elizabeth E. , Shearer Rebecca L. , Meyer Jason S. , Kim Hyun-Jung , Schneider Bernard L. , Melvan John Nicholas , Svendsen Clive N. 
Published: September 2008

Abstract
During development of the central nervous system, stem and progenitor cell proliferation and differentiation are controlled by complex inter- and intracellular interactions that orchestrate the precise spatiotemporal production of particular cell types. Within the embryonic retina, progenitor cells are located adjacent to the retinal pigment epithelium (RPE), which differentiates prior to the neurosensory retina and has the capacity to secrete a multitude of growth factors. We found that secreted proteinaceous factors in human prenatal RPE conditioned medium (RPE CM) prolonged and enhanced the growth of human prenatal retinal neurospheres. The growth-promoting activity of RPE CM was mitogen-dependent and associated with an acute increase in transcription factor phosphorylation. Expanded populations of RPE CM-treated retinal neurospheres expressed numerous neurodevelopmental and eye specification genes and markers characteristic of neural and retinal progenitor cells, but gradually lost the potential to generate neurons upon differentiation. Misexpression of Mash1 restored the neurogenic potential of long-term cultures, yielding neurons with phenotypic characteristics of multiple inner retinal cell types. Thus, a novel combination of extrinsic and intrinsic factors was required to promote both progenitor cell proliferation and neuronal multipotency in human retinal neurosphere cultures. These results support a pro-proliferative and antiapoptotic role for RPE in human retinal development, reveal potential limitations of human retinal progenitor culture systems, and suggest a means for overcoming cell fate restriction in vitro.
Disclosure of potential conflicts of interest is found at the end of this article.
Quantitative Mass Spectrometry Identifies Drug Targets in Cancer Stem Cell-Containing Side Population
Authors: Steiniger Sebastian C.J. , Coppinger Judith A. , Krüger Jörg A. , Yates John , Janda Kim D. 
Published: September 2008

Abstract
A multifaceted approach is presented as a general strategy to identify new drug targets in a breast cancer stem cell-containing side population. The approach we have utilized combines side population cell sorting and stable isotope labeling by amino acids in cell culture with mass spectrometry to compare and identify proteins with differential expression profiles between side population cells, know to be enriched in cancer stem cells, and nonside population cells, which are depleted in cancer stem cells, for two breast cancer cell lines, MCF7 and MDA-MB231. Almost 900 proteins were quantified, and several important proteins in cell cycle control and differentiation were found to be upregulated in the cancer stem cell-containing side population. Most interestingly, a splice isoform of pyruvate kinase M2 as well as peroxiredoxin 6 were found to be downregulated. The differential levels of three of these proteins, thymosin β4 (TB4), proliferation-associated protein 2G4, and SIAH-interacting protein, were validated using Western blot. Furthermore, functional validation provided clear evidence that elevated TB4 expression contributes to drug resistance in the stem cell population. Small interfering RNA silencing of TB4 led to a loss of chemoresistance in two separate breast cancer populations. These proteins likely contribute to resistance in the cancer stem cell-containing side population, and their altered expression in a tumor causes clinical resistance to chemotherapy. The ability to perform quantitative mass spectrometry has enabled the identification of a series of proteins that could serve as future therapeutic targets.
Disclosure of potential conflicts of interest is found at the end of this article.
The Stem Cell-Associated Antigen CD133 (Prominin-1) Is a Molecular Therapeutic Target for Metastatic Melanoma
Authors: Rappa Germana , Fodstad Oystein , Lorico Aurelio 
Published: September 2008

Abstract
CD133 (Prominin-1) is considered the most important cancer stem cell (CSC)-associated marker identified so far, with increased expression in the CSC fraction of a large variety of human malignancies, including melanoma. Here we investigated the effects of CD133 downregulation in vitro and in vivo in human metastatic melanoma. The average number of CD133 molecules on the cell surface of FEMX-I melanoma cells was decreased by 8.7-fold and 1.8-fold using two different short hairpin RNAs. Downregulation of CD133, confirmed by immunocytochemistry, Western blotting, microarray analysis, and reverse transcription-polymerase chain reaction, resulted in slower cell growth, reduced cell motility, and decreased capacity to form spheroids under stem cell-like growth conditions. Clonal analysis revealed that the reduction in growth rate was proportional to the extent of CD133 downregulation. Monoclonal antibodies directed against two different epitopes of the CD133 protein induced a specific, dose-dependent cytotoxic effect in FEMX-I cells. The downregulation of CD133 severely reduced the capacity of the cells to metastasize, particularly to the spinal cord. In the CD133 downregulated cells, microarray analysis revealed expression changes for only 143 annotated genes (76 up- and 67 downregulated). Ten of the 76 upregulated genes coded for Wnt inhibitors, suggesting an interaction between CD133 and the canonical Wnt pathway. We conclude that CD133, in addition to its role as a CSC marker, is an important therapeutic target for metastatic melanoma and, potentially, for other CD133-expressing cancer types.
Disclosure of potential conflicts of interest is found at the end of this article.
Enteroviral meningitis in children in Turkey
Authors: Şensoy Gülnar , Sel Kutay , Özkaya Ethem , Çuhaci Çakir Bahar , Vidinlisan Sadi , Doganci Levent 
Published: September 2008

Abstract
In the indexed medical literature, there have been a very limited number of studies to investigate the epidemiologic and clinical features of enteroviral meningitis in Turkey. The aim of the present retrospective study is to update the actual situation to recognize the spectrum and magnitude of this important clinical entity. Between June 1999 and December 2004, 612 cases of aseptic meningitis were followed up at our hospital. Enteroviral meningitis was defined by isolation of enteroviruses from cerebrospinal fluid (CSF) and/or stool samples. Mumps virus was detected in 310 cases (50.7%) and enteroviruses were the etiologic agents in 104 (17%) of the patients with aseptic meningitis. Most of the enteroviral meningitis cases (36 cases, 34.6%) were diagnosed in August and 70 (67.3%) of them were male. The mean age was 5.6 ± 3.4 years. The most common initial symptoms were fever (81.7%), vomiting (77.9%) and headache (57.7%). In the physical examination, 46.2% of the cases had neck stiffness and 38.5% had pharyngitis. Echovirus 30 was the most frequently (38 cases, 36.5%) isolated enterovirus with peaks in 1999, 2002 and 2004. The other frequently isolated enteroviruses were Coxsackie virus type B (17 cases, 16.3%), echovirus 6 (11 cases, 10.6%), echovirus 11 (6 cases, 5.8%), and echovirus 13 (4 cases, 3.8 %). Mean hospitalization time was 6.2 ± 2.4 days. All patients recovered without any sequelae. Enteroviruses have an important role in childhood aseptic meningitis cases in Turkey too, and the predominant serotypes vary according to years.
Effect of Weight-Bearing Activity on Foot Ulcer Incidence in People With Diabetic Peripheral Neuropathy: Feet First Randomized Controlled Trial
Authors: LeMaster Joseph W , Mueller Michael J , Reiber Gayle E , Mehr David R , Madsen Richard W , Conn Vicki S 
Published: September 2008

BackgroundWeight-bearing exercise has been contraindicated among people with diabetic peripheral neuropathy (DM+PN). However, recent cohort studies have suggested that daily weight-bearing activity is associated with lower risk for foot ulceration.ObjectiveThe objective of this study was to determine the effect of a lower-extremity exercise and walking intervention program on weight-bearing activity and foot ulcer incidence in people with DM+PN.DesignThis was an observer-blinded, 12-month randomized controlled trial.SettingThe settings were physical therapy offices in part 1 of the intervention and the community in part 2 of the intervention.ParticipantsThe participants were 79 individuals with DM+PN who were randomly assigned either to a control group (n=38) or an intervention group (n=41) group.InterventionIntervention components included leg strengthening and balance exercises; a graduated, self-monitored walking program (part 1); and motivational telephone calls every 2 weeks (part 2). Both groups received diabetic foot care education, regular foot care, and 8 sessions with a physical therapist.MeasurementsTotal and exercise bout–related daily steps at baseline and at 3, 6, and 12 months were measured by accelerometers. Foot lesions/ulcers were photographed and classified by an independent panel of dermatologists. Use of adequate footwear was monitored.ResultsAt 6 months, bout-related daily steps increased 14% from baseline in the intervention group and decreased 6% from baseline in the control group. Although the groups did not differ statistically in the change in total daily steps, at 12 months steps had decreased by 13% in the control group. Foot ulcer rates did not differ significantly between groups.ConclusionPromoting weight-bearing activity did not lead to significant increases in foot ulcers. Weight-bearing activity can be considered following adequate assessment and counseling of patients with DM+PN.
Excessive Adipose Tissue Infiltration in Skeletal Muscle in Individuals With Obesity, Diabetes Mellitus, and Peripheral Neuropathy: Association With Performance and Function
Authors: Hilton Tiffany N , Tuttle Lori J , Bohnert Kathryn L , Mueller Michael J , Sinacore David R 
Published: September 2008

Background and Purpose
The primary purpose of this study was to report differences in calf intermuscular adipose tissue (IMAT), muscle strength (peak torque), power, and physical function in individuals with obesity, diabetes mellitus (DM), and peripheral neuropathy (PN) compared with those without these impairments. A secondary purpose was to assess the relationship between IMAT and muscle strength, power, and physical function.

Subjects and Methods
Six participants with obesity, DM, and PN (2 women, 4 men; mean age=58 years, SD=10; mean body mass index=36.3, SD=5; mean modified Physical Performance Test [PPT] score=22, SD=3) and 6 age- and sex-matched control subjects without these impairments were assessed and compared in muscle strength, muscle power, physical functioning, and muscle and fat volume, including IMAT in the calf muscles. Muscle, adipose tissue, and IMAT volumes of each calf were quantified by noninvasive magnetic resonance imaging. Muscle strength and power of the plantar-flexor and dorsiflexor muscles were quantified using isokinetic dynamometry. The modified PPT was used to assess physical function.

Results
Leg muscle and fat volumes were similar between groups, although IMAT volumes were 2.2-fold higher in the subjects with obesity, DM, and PN (X̅=120 cm3, SD=47) than in the control subjects (X̅=54 cm3, SD=41). Muscle strength, muscle power, ratio of leg muscle power to leg muscle volume, and modified PPT scores were lower in subjects with obesity, DM, and PN compared with the control subjects.

Discussion and Conclusion
The data indicate that excess fat infiltration in leg skeletal muscles is associated with low calf muscle strength, low calf muscle power, and impaired physical function in individuals who are obese with DM and PN.