bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo
Authors: Liu Ta-Jen , LaFortune Tiffany , Honda Toshiyuki , Ohmori Osamu , Hatakeyama Shinji , Meyer Thomas , Jackson Dowdy , de Groot John , Yung W.K. Alfred
Published: April 2007

Multiple genetic aberrations in human gliomas contribute to their highly infiltrative and rapid growth characteristics. Focal adhesion kinase (FAK) regulates tumor migration and invasion. Insulin-like growth factor-I receptor (IGF-IR), whose expression correlates with tumor grade, is involved in proliferation and survival. We hypothesized that inhibiting the phosphorylation of FAK and IGF-IR by NVP-TAE226 (hereafter called TAE226), a novel dual tyrosine kinase inhibitor of FAK and IGF-IR, would suppress the growth and invasion of glioma cells. In culture, TAE226 inhibited extracellular matrix–induced autophosphorylation of FAK (Tyr397). TAE226 also inhibited IGF-I–induced phosphorylation of IGF-IR and activity of its downstream target genes such as MAPK and Akt. TAE226 retarded tumor cell growth as assessed by a cell viability assay and attenuated G2-M cell cycle progression associated with a decrease in cyclin B1 and phosphorylated cdc2 (Tyr15) protein expression. TAE226 treatment inhibited tumor cell invasion by at least 50% compared with the control in an in vitro Matrigel invasion assay. Interestingly, TAE226 treatment of tumor cells containing wild-type p53 mainly exhibited G2-M arrest, whereas tumor cells bearing mutant p53 underwent apoptosis. Induction of apoptosis by TAE226 was substantiated by detection of caspase-3/7 activation and poly(ADP-ribose) polymerase cleavage and by an Annexin V apoptosis assay. More importantly, TAE226 treatment significantly increased the survival rate of animals in an intracranial glioma xenograft model. Collectively, these data show that blocking the signaling pathways of FAK and IGF-IR with TAE226 has the potential to be an efficacious treatment for human gliomas. [Mol Cancer Ther 2007;6(4):1357–67]
Activation of clinically used anthracyclines by the formaldehyde-releasing prodrug pivaloyloxymethyl butyrate
Authors: Cutts Suzanne M. , Swift Lonnie P. , Pillay Vinochani , Forrest Robert A. , Nudelman Abraham , Rephaeli Ada , Phillips Don R.
Published: April 2007

The anthracycline group of compounds is extensively used in current cancer chemotherapy regimens and is classified as topoisomerase II inhibitor. However, previous work has shown that doxorubicin can be activated to form DNA adducts in the presence of formaldehyde-releasing prodrugs and that this leads to apoptosis independently of topoisomerase II–mediated damage. To determine which anthracyclines would be useful in combination with formaldehyde-releasing prodrugs, a series of clinically relevant anthracyclines (doxorubicin, daunorubicin, idarubicin, and epirubicin) were examined for their capacity to form DNA adducts in MCF7 and MCF7/Dx (P-glycoprotein overexpressing) cells in the presence of the formaldehyde-releasing drug pivaloyloxymethyl butyrate (AN-9). All anthracyclines, with the exception of epirubicin, efficiently yielded adducts in both sensitive and resistant cell lines, and levels of adducts were similar in mitochondrial and nuclear genomes. Idarubicin was the most active compound in both sensitive and resistant cell lines, whereas adducts formed by doxorubicin and daunorubicin were consistently lower in the resistant compared with sensitive cells. The adducts formed by doxorubicin, daunorubicin, and idarubicin showed the same DNA sequence specificity in sensitive and resistant cells as assessed by λ-exonuclease–based sequencing of α-satellite DNA extracted from drug-treated cells. Growth inhibition assays were used to show that doxorubicin, daunorubicin, and idarubicin were all synergistic in combination with AN-9, whereas the combination of epirubicin with AN-9 was additive. Although apoptosis assays indicated a greater than additive effect for epirubicin/AN-9 combinations, this effect was much more pronounced for doxorubicin/AN-9 combinations. [Mol Cancer Ther 2007;6(4):1450–9]
Phospholipid hydroperoxide glutathione peroxidase plays a role in protecting cancer cells from docosahexaenoic acid–induced cytotoxicity
Authors: Ding Wei-Qun , Lind Stuart E.
Published: April 2007

Docosahexaenoic acid (DHA; 22:6, n-3) is known to exert cytotoxic effects against various types of tumors via lipid peroxidation. Whereas several enzymes influence the response of cells to oxidative stress, only one enzyme, phospholipid hydroperoxide glutathione peroxidase (GPx-4), directly reduces lipid hydroperoxides in mammalian cells. The present study was designed to examine the involvement of GPx-4 in determining the effects of DHA addition to various human cancer cell lines. Although baseline levels of GPx-4 did not correlate with the relative sensitivity of human cancer cell lines to DHA, DHA reduced the level of protein expression of GPx-4 by at least 50% in all six lines. Knockdown of GPx-4 by small interfering RNA technique in a human ovarian cancer cell line significantly enhanced the cytotoxic effect of DHA in a time- and concentration-dependent manner. This cytotoxic effect of DHA was reversed by pretreatment with vitamin E, suggesting that the enhanced toxicity of GPx-4 knockdown is due to changes in the ability of the cells to handle oxidative stress. Neither baseline superoxide dismutase-1 nor catalase expression correlated with the relative sensitivity of the cells to DHA treatment. These results illustrate that susceptibility to the oxidative stress imposed by DHA, and possibly other therapeutic agents, is due to complex interactions among multiple antioxidant systems. The modulation of GPx-4 levels by DHA administration is of potential importance and may influence the cellular response to other oxidant stresses. [Mol Cancer Ther 2007;6(4):1467–74]
Combined effects of retinoic acid and histone deacetylase inhibitors on human neuroblastoma SH-SY5Y cells
Authors: De los Santos Maxy , Zambrano Alberto , Aranda Ana
Published: April 2007

All-trans retinoic acid (RA) causes differentiation of neuroblastoma cells, and retinoids have been used in clinical trials in children with advanced neuroblastoma. Combination of RA with histone deacetylase inhibitors (HDACi) could result in improved antitumorigenic activity. We have examined the effect of the HDACi trichostatin A (TSA), sodium butyrate, and suberoylanilide hydroxamic acid (SAHA), alone and in combination with RA in human neuroblastoma SH-SY5Y cells. At concentrations that cause sustained increase of histone H3 acetylation, HDACi produced extensive apoptotic cell death as shown by flow cytometry analysis and induction of poly(ADP-ribose) polymerase proteolysis. HDACi inhibited SH-SY5Y cell growth at a much larger extent than RA. This compound did not cause apoptosis and did not further increase HDACi-mediated cell death. In contrast, both types of drugs cooperated to inhibit cell growth, although synergistic effects were not found. In surviving cells, HDACi repressed cyclin D1 expression and increased the cyclin kinase inhibitors (CKI) p21Waf1/Cip1 and p27Kip1. Cyclin D1 was not affected by RA, but this retinoid also increased CKI levels. Induction of p21Waf1/Cip1 and p27Kip1 by HDACi was further enhanced in the presence of RA. This effect seems to be at least partially due to transcriptional stimulation of CKI gene expression because both types of drugs cooperated to increase CKI mRNA levels and to activate the CKI promoters in transient transfection assays. These results show the strong antitumorigenic effects of HDACi in neuroblastoma cells and reinforce the idea that combination therapy could be useful to inhibit tumor growth. [Mol Cancer Ther 2007;6(4):1425–32]
Use of fluorescent labeled anti–epidermal growth factor receptor antibody to image head and neck squamous cell carcinoma xenografts
Authors: Rosenthal Eben L. , Kulbersh Brian D. , King Teresa , Chaudhuri Tandra R. , Zinn Kurt R.
Published: April 2007

Physicians and surgeons rely on subtle tissue changes to detect the extent of tumors and the presence of residual disease in the clinical setting. The development of a cancer-specific fluorescent contrast agent has the potential to provide real-time tumor imaging in the clinic or operating room. Because epidermal growth factor receptor (EGFR) is highly overexpressed on the surface of head and neck squamous cell carcinoma (HNSCC), we sought to determine if fluorescently labeled anti-EGFR antibody could be used to image HNSCC xenografts in vivo. Cetuximab or control isotype-matched IgG1 was conjugated with the Cy5.5 fluorochrome and systemically injected into mice bearing human split thickness skin grafts, tumor cell line xenografts, transplanted human tumor xenografts, or mouse mesothelioma tumors. Xenografts were imaged by time-domain fluorescence imaging or fluorescence stereomicroscopy. Both imaging modalities detected specific uptake of cetuximab-Cy5.5 in HNSCC xenografts with significantly higher fluorescence levels relative to control IgG1-Cy5.5. Tumor xenograft fluorescence was higher compared with background (before injection), human split thickness skin grafts, or mouse mesothelioma tumors at 24, 48, and 72 h. Fluorescence was detected in multiple HNSCC tumor cell lines with variable EGFR expression levels. Mock resections of flank tumors using fluorescence stereomicroscopy showed that small (2 mm) specimens could be detected in the surgical wound bed. These results show the feasibility of using fluorescently labeled anti-EGFR antibody to detect human tumors in the surgical setting. [Mol Cancer Ther 2007;6(4):1230–8]
Brainstem Tumors: Where Are We Today?
Authors: Recinos Pablo F. , Sciubba Daniel M. , Jallo George I.
Published: April 2007

Brainstem tumors comprise 10–20% of all pediatric central nervous system tumors. The management of these tumors has evolved dramatically in the past century. Once considered uniformly fatal, it is now known that brainstem tumors have distinguishing characteristics and do not behave identically. The focality and location of the lesion is determined from the clinical history, presentation, and associated imaging. Based on these findings, it is possible to predict the behavior of the tumor and choose an appropriate intervention. Focal lesions have a good prognosis and are treated operatively while diffuse lesions have a poor prognosis and are managed medically. This article reviews the current classification of brainstem tumors, current management options and future directions for the treatment of these rare tumors.
Endoscopic Fenestration of Middle Fossa Arachnoid Cysts: A Technical Description and Case Series
Authors: Elhammady Mohamed Samy A. , Bhatia Sanjiv , Ragheb John
Published: April 2007

Background: Arachnoid cysts are intra-arachnoidal cerebrospinal fluid collections most frequently seen in the middle cranial fossa. The optimal method of treatment for symptomatic arachnoid cysts remains controversial and includes cyst shunting, open craniotomy and endoscopic fenestration. All these techniques, however, have been associated with the development of postoperative subdural fluid collections. We describe a new endoscopic transcortical technique that attempts to avoid this complication. Methods: Six patients with middle cranial fossa arachnoid cysts were treated with endoscopic fenestration at our institution between January 2002 and December 2005. Three cases were approached directly through the cyst, while the other 3 were approached by passing the endoscope through the rim of adjacent cortex. Results: All six endoscopic fenestrations were successful in treating the arachnoid cysts. Among the 3 patients treated via a direct cyst entry, 2 cases developed significant subdural hygromas, 1 of which required aspiration. On the other hand, 1 of the 3 cases treated using a transcortical technique developed an insignificant postoperative extra-axial collection that resolved at 3 months without intervention. Conclusion: Endoscopic fenestration is an effective treatment for symptomatic arachnoid cysts. Endoscopic fenestration via a transcortical approach attempts to minimize cerebrospinal fluid drainage into the subdural space, avoiding the development of significant postoperative extra-axial collections, while promoting flow into the basal cisterns.
Clinical Significance of Terminal Syringomyelia in Association with Pediatric Tethered Cord Syndrome
Authors: Beaumont Andrew , Muszynski Cheryl A. , Kaufman Bruce A.
Published: April 2007

An association between terminal syringomyelia (TS) and tethered cord syndrome (TCS) has been recognized. The clinical significance of TS and the need for concurrent treatment is not known. Thirty-four patients with TCS undergoing surgery for tethered cord release were evaluated for the incidence of TS. The clinical and radiological response to untethering with and without syrinx drainage was assessed. The group incidence of TS was 29.4%. There were no significant differences in the sex, age, underlying pathology or preoperative symptoms between the TCS group (TCS, n = 24) and the TCS group with TS (TCS + TS, n = 10). In the TCS group, 37.5% of the patients were asymptomatic preoperatively, and in the TCS + TS group 50% were asymptomatic preoperatively. After surgery, none of these asymptomatic patients developed symptoms. All of the symptomatic TCS + TS patients improved clinically, 12 of 15 symptomatic TCS patients improved, 2 patients were unchanged and 1 had worsening scoliosis. Syrinx did not develop in patients lacking it preoperatively. In patients where postoperative imaging was available, preoperative syringes improved. TS is clearly associated with TCS. Tethered cord release alone may be sufficient to improve preoperative symptoms and TS may be an associated phenomenon that does not mandate separate treatment.
Influence of Social and Environmental Factors on Nesting Behaviour in Captive Gorillas (Gorilla gorilla gorilla)
Authors: Weiche Iris , Anderson James R.
Published: April 2007

Field studies on gorilla sleeping sites usually emphasize environmental influences on nest site selection, as individual nesting behaviours are usually not observed directly. In captivity, nesting behaviour and influencing factors are often overlooked. In the present study, the sleeping sites of members of a captive group of 16–21 gorillas were analysed, based on 152 nights over a 5-year period. Subadults tended to sleep apart from adults but clustered around the oldest blackback male. Full siblings and mothers with offspring were often nearest neighbours. Some sleeping dyads notably endured. Neither age of offspring nor rank of adult females influenced neighbour choice or distances; an interadult distance of 1.5–3 m was typical. Group dynamics were reflected in nesting arrangements. We suggest that possibilities for co-nesting and choice of sleeping sites should be provided to improve the welfare of captive gorillas and other great apes.
Can a Group Elicit Duets from Its Neighbours? A Field Study on the Black-Crested Gibbon (Nomascus concolor jingdongensis) in Central Yunnan, China
Authors: Fan Pengfei , Liu Changming , Luo Wenshou , Jiang Xuelong
Published: April 2007

We tested the intergroup spacing hypothesis with a 13-month field study of the interaction of singing behaviour between 3 neighbouring groups of black-crested gibbons (Nomascus concolor jingdongensis) at Mt. Wuliang, Central Yunnan, China. Neighbouring groups tended not to sing on the same day. While it did happen occasionally, a group seldom started a duet while its neighbour was singing, or within 5 min of the singing ceasing. The intersong intervals of 2 groups calling on the same day were similar or significantly longer than the intervals between any song bouts randomly selected from the same 2 groups when calling on different days. Groups did not sing in intergroup encounters and showed similar responses to neighbouring groups and groups with no common border. These results did not support the intergroup spacing hypothesis. The possible reasons are discussed.
Effect of an Alcohol-Free, 1% Chlorhexidine Gel as an Adjunct to a Fluoridated Dentifrice Using an Intraoral Crown Model
Authors: Timmons S.R. , Harless J.D. , Hogan M.M. , Eckert G.J. , Marek C.L. , Drake D.R. , Wefel J.S.
Published: April 2007

Background/Aims: The use of chlorhexidine as a topically applied oral antiseptic is well documented; however, clinical studies examining the effects of chlorhexidine gel on in situ dental caries are limited. This study utilized an in situ caries model and a modified crossover design to examine whether the addition of a biweekly topical, alcohol-free, 1% chlorhexidine digluconate gel to a daily fluoridated dentifrice inhibited artificial caries in dental tissues better than the fluoridated dentifrice alone when compared to a nonfluoridated placebo dentifrice. Methods: Thirty patients were recruited based on their need for a mandibular, full crown. Artificial caries lesions were created in extracted human teeth and enamel and root tissue sections 100 µm in thickness were characterized using polarized light microscopy. The sections were fixed in the crown and placed on the prepared tooth. The participants were assigned a placebo toothpaste, a toothpaste with 1,100 ppm F or a 1,100 ppm F toothpaste followed by 1 ml of 1% chlorhexidine gel at day 1 and day 14 (chlorhexidine+). Patients were instructed to brush twice daily for 4 weeks. Following each round, the sections in the crown were replaced with new sections. The sections were recharacterized and the mean changes were compared using ANOVA at α = 0.05. Results: The chlorhexidine + Fdentifrice and the F dentifrice alone significantly reduced lesion area in enamel tissue when compared to the placebo dentifrice. Both treatments also inhibited lesion progression and initiation in root tissue better than control in this model system. Although the chlorhexidine+ group enhanced remineralization and inhibited lesion progression better than the F– dentifrice alone for all outcomes measured, the differences were not significant. Conclusions: The chlorhexidine, in conjunction with a fluoride dentifrice, was no more effective than the fluoride dentifrice alone. Further study is needed before this 1% alcohol-free chlorhexidine gel should be recommended as an adjunct to a fluoride dentifrice in the treatment of dental caries.
Histomorphometric Analysis of Tissue Responses to Bioactive Glass Implants in Critical Defects in Rat Calvaria
Authors: Cardoso Ana Karina M.V. , de Almeida Barbosa Jr. Aryon , Borges Miguel Fúlvio , Marcantonio Jr. Elcio , Farina Marcos , de Almeida Soares Glória Dulce , Paim Rosa Fabiana
Published: April 2007

The aim of this study was to evaluate the osteogenic behavior of two chemically similar bioactive glass products (Biogran®and Perioglas®) implanted in critical bone defects in rat calvaria. Thirty-six transfixed bone defects of 8 mm diameter were made surgically in adult male Wistar rats. The animals were distributed equally into three groups: Biogran (GI), Perioglas (GII) and without implant material (control; GIII). The morphology and composition of both bioactive glasses were analyzed by scanning electron microscopy and energy-dispersive spectrometry. Tissue specimens were analyzed at the biological time points of 15, 30 and 60 days by optical microscopy and morphometry, demonstrating biocompatibility for the tested materials with moderate chronic inflammation involving their particles. Bone neoformation resulted only as a reparative reaction to an intentionally produced defect and was limited to the defect’s edges. No statistically significant differences among the groups were observed. At the scar interstice, abundant deposits of collagenous fibers enveloping the particles were noted. The present results indicated that the bioactive glasses, under the experimental conditions analyzed, did not show osteogenic behavior.
Changes in Bone Microarchitecture and Bone Mineral Density following Experimental Osteonecrosis of the Hip in Rabbits
Authors: Hofstaetter Jochen G. , Wang Jinxi , Yan Jun , Glimcher Melvin J.
Published: April 2007

Background: Osteonecrosis of the femoral head is a common disorder which can lead to hip joint destruction usually necessitating total hip replacement. Methods: Quantitative micro-computed tomography, digital radiography and histology were used to characterize changes in bone microarchitecture and bone mineral density during the repair of the osteonecrotic femoral head as well as during the development of secondary osteoarthritis in the ipsilateral acetabulum. Osteonecrosis was induced surgically in 17 adult, male rabbits and the contralateral side was used as control. Results: At 4 weeks no changes in microarchitecture in the femoral head nor in the acetabulum were found. At 6 months the repair process led to an increase in bone mass in the trabecular region of the femoral head. However, a decrease in volumetric bone mineral density and an increase in apparent porosity were seen in the compact subchondral and cortical region of the osteonecrotic femoral head. At 6 months the subchondral bone of the osteoarthritic ipsilateral acetabulum was thicker, but had a lower volumetric bone mineral density and a higher apparent porosity. Conclusion: Resorption of necrotic compact bone may weaken the structural properties of the femoral head. Moreover, remodeling and resorption of subchondral bone may play a critical role in the disease process of osteoarthritis.
Comparison of Polyester Scaffolds for Bioengineered Intestinal Mucosa
Authors: Chen David C. , Avansino Jeffrey R. , Agopian Vatche G. , Hoagland Vicki D. , Woolman Jacob D. , Pan Sheng , Ratner Buddy D. , Stelzner Matthias
Published: April 2007

Introduction: Biodegradable polyester scaffolds have proven useful for growing neointestinal tissue equivalents both in vitro and in vivo. These scaffolds allow cells to attach and grow in a 3-dimensional space while nutrient flow is maintained throughout the matrix. The purpose of this study was to evaluate different biopolymer constructs and to determine mucosal engraftment rates and mucosal morphology. Hypothesis: We hypothesized that different biopolymer constructs may vary in their ability to provide a good scaffolding onto which intestinal stem cell organoids may be engrafted. Study Design: Eight different microporous biodegradable polymer tubes composed of polyglycolic acid (PGA), polylactic acid, or a combination of both, using different fabrication techniques were seeded with intestinal stem cell clusters obtained from neonatal rats. Three different seeded polymer constructs were subsequently placed into the omentum of syngeneic adult recipient rats (n = 8). Neointestinal grafts were harvested 4 weeks after implantation. Polymers were microscopically evaluated for the presence of mucosal growth, morphology, scar formation and residual polymer. Results: Mucosal engraftment was observed in 7 out of 8 of the polymer constructs. A maximal surface area engraftment of 36% (range 5–36%) was seen on nonwoven, randomly entangled, small fiber PGA mesh coated with aerosolized 5% poly-L-lactic acid. Villous and crypt development, morphology and created surface area were best on PGA nonwoven mesh constructs treated with poly-L-lactic acid. Electrospun microfiber PGA had poor overall engraftment with little or no crypt or villous formation. Conclusion: Intestinal organoids can be engrafted onto biodegradable polyester scaffoldings with restitution of an intestinal mucosal layer. Variability in polymer composition, processing techniques and material properties (fiber size, luminal dimensions and pore size) affect engraftment success. Future material refinements should lead to improvements in the development of a tissue-engineered intestine.
Three-Dimensional Surface Structure of Macrophages in Fetal and Adult Mouse Liver: An Immunohistochemical Light Microscopic Study
Authors: Sonoda Yuji , Sasaki Kazunobu
Published: April 2007

Using 100-µm-thick paraffin sections stained by F4/80 antibody, the three-dimensional surface morphology of macrophages in fetal and adult livers was examined by conventional light microscope equipped with a computer-controlled z-axis stepping motor. Hematopoietic macrophages in fetal livers were located in the center of erythroid cell clusters, forming cell sockets which consisted of two different kinds of projections. The primary cytoplasmic processes were membranous projections and the secondary processes were finger-like projections extending from the primary processes. Erythroids in the cell sockets were linearly arranged on the macrophage surface. Adult sinusoidal macrophages possessed a few pseudopod-like processes, ridge-like profiles and numerous ruffle or spike-like processes, and cell contact with neighboring macrophages could be recognized. Compared to confocal laser scanning microscopy and scanning electron microscopy, this study provided information about cell surface structures at reasonably low cost, although the resolution was limited in z axis due to the stepping interval.
ALCAM (CD166) Is a Surface Marker for Early Murine Cardiomyocytes
Authors: Hirata Hirokazu , Murakami Yoshinobu , Miyamoto Yoshiaki , Tosaka Mako , Inoue Kayoko , Nagahashi Ayako , Jakt Lars Martin , Asahara Takayuki , Iwata Hiroo , Sawa Yoshiki , Kawamata Shin
Published: April 2007

ALCAM (activated leukocyte cell adhesion molecule, CD166) belongs to the immunoglobulin superfamily and is involved in axon guidance, hematopoiesis, immune response and tumor metastasis. During embryogenesis, mRNA encoding ALCAM was expressed in the cardiac crescent and the neural groove at embryonic day (E) 7.75 and predominately in the tubular heart at E8.5. A newly generated monoclonal antibody against the ALCAM molecule (ALC-48) exclusively stained cardiomyocytes at E8.25–10.5. However, ALCAM expression was lost by cardiomyocytes by E12.5 and its expression shifts to a variety of organs during later stages. ALCAM was found to be a prominent surface marker for cardiomyocytes in early embryonic hearts. The transient expression of ALCAM during early developmental stages marks specific developmental stages in cardiomyocyte differentiation.
Aquaporin 1: Examination of Its Expression and Localization in Normal Human Skeletal Muscle Tissue
Authors: Jimi Takahiro , Wakayama Yoshihiro , Inoue Masahiko , Kojima Hiroko , Oniki Hiroaki , Matsuzaki Yoko , Shibuya Seiji , Hara Hajime , Takahashi Joji
Published: April 2007

To examine aquaporin 1 (AQP1) expression in skeletal muscle tissue precisely, we performed reverse transcription-polymerase chain reaction (RT-PCR) at RNA level and immunoblot analysis, immunohistochemistry and immunoelectron microscopy at protein level. The RT-PCR study of total RNA from normal human skeletal muscle showed a strong single band of AQP1. At the protein level we used two commercially available antibodies, both of which recognize the cytoplasmic domain of the AQP1 molecule. One antibody gave positive results. Immunoblot of muscle extract showed a 30-kDa band protein, the molecular weight of which corresponded to that of AQP1. Immunohistochemically, AQP1 was immunostained at the myofiber surface both in type 1 and type 2 myofibers with almost the same intensity, and its staining pattern was rather diffuse and irregular compared with that of the anti-dystrophin antibody. The endomysial endothelial cells were also immunolabeled. Immunoelectron microscopy revealed that the immunogold particles indicating the presence of the AQP1 molecule were present along the inside surface of the muscle plasma membrane. However, another antibody showed negative results except for the endomysial endothelial cells which were positively stained. We drew the conclusion that AQP1 is expressed at the endomysial capillary endothelial cell and further AQP1 may be expressed at the human skeletal myofiber plasma membrane.
The Prevention of Vocal Fold Scarring Using Autologous Adipose Tissue-Derived Stromal Cells
Authors: Lee Byung Joo , Wang Soo Geun , Lee Jin Choon , Jung Jin Sup , Bae Yong Chan , Jeong Hae Jin , Kim Hwal Woong , Lorenz Robert R.
Published: April 2007

Prevention and treatment of vocal fold scarring and atrophy remain challenging. The aim of this study was to treat injured vocal folds using autologous adipose tissue-derived stromal cells (ADSCs) and evaluate the ability to prevent vocal fold scarring and atrophy by ADSCs in a canine animal model. Ten adult dogs were used for this experiment. ADSCs from the adipose tissue from the inguinal area were isolated and cultured in all dogs. Immediately after being mixed with atelocollagen, the ADSCs (1–3 × 106) were injected into the right vocal fold of each animal, using a syringe with a 23-gauge needle. As a control, atelocollagen was injected into the left vocal fold of the same dog. The effects of the prevention of vocal fold scarring and atrophy were measured by morphological and histological assessment. At 8 weeks, there was a difference in granuloma and atrophic changes between the ADSC-injected and control sides in the majority of the dogs. This difference continued to be present at the 24 weeks’ follow-up. On histopathologic examination, a large number of cells labeled with a fluorochrome were observed in ADSC-injected vocal folds 8 weeks after the initial treatment. This study demonstrates the multipotential ability of ADSCs in the regeneration of injured vocal folds. Injecting ADSCs into a damaged vocal fold appears to be useful in preventing vocal fold scarring and atrophy 24 weeks after initial damage.
Sexual Symptoms in Endocrine Diseases: Psychosomatic Perspectives
Authors: Balercia Giancarlo , Boscaro Marco , Lombardo Francesco , Carosa Eleonora , Lenzi Andrea , Jannini Emmanuele A.
Published: April 2007

Background: Not only the most frequent causes of endocrine sexual dysfunction, such as hypogonadism and hyperprolactinemia, but almost all extragonadal endocrinopathies (hyper- and hypothyroidism, hyper- and hypocortisolism, steroidal secreting tumors, etc.) may have a greater or lesser effect on sexual function. Methods: We analyzed scientific literature on the correlations between hormones and sexual behavior, analyzing the most important issue from a practical point of view. The aim of this review article was thus to summarize the sexual symptoms that may be observed with endocrine diseases. Results: Hormones directly or indirectly regulate all human sexual functions (desire, erection/lubrication, ejaculation, orgasm). Some sexual symptoms may occur as a psychosomatic consequence of hormonal impairment. However, in other cases, endocrine failure may be generated by the psychosomatic involvement. Conclusions: The endocrinologist, as an expert in body chemistry, is ideally positioned to identify and evaluate the full range of medical, physical, and psychiatric problems disrupting sexual function.
Intrapersonal Conflict in Goals and Values of Patients with Unipolar Depression
Authors: Stangier Ulrich , Ukrow Uwe , Schermelleh-Engel Karin , Grabe Martin , Lauterbach Wolf
Published: April 2007

Background: Although increased conflicts between attitudes and beliefs about certain goals or values are often discussed as important factors in depression, there are only few empirical studies investigating these relations among patients with depressive disorders. Methods: In the present study, we used the Intrapersonal Conflict Test to assess cognitive inconsistencies in goals or values. A total of 53 inpatients with unipolar depression and 24 nondepressed controls (inpatients of an internal and a surgery ward) participated in the study. In addition to the Intrapersonal Conflict Test, patients completed the Beck Depression Inventory, the Dysfunctional Attitude Scale, the Inventory of Interpersonal Problems as well as the Problem Solving Inventory. Results: Compared with controls, patients with depressive disorders showed significantly higher scores for global inconsistencies, inconsistencies within different goals/values, as well as between goals/values and their perceived realization. Significant correlations were found between conflict measures and the Inventory of Interpersonal Problems, as well as the Problem Solving Inventory. Path analyses show that group differences in intrapersonal conflicts were partially mediated by interpersonal problems but not by depressive symptoms or cognitive vulnerability factors. Conclusions: Given the cross-sectional design of the study, the findings of this exploratory study do not allow for conclusions regarding the role of intrapersonal conflicts in the development and course of depression. Nevertheless, the high levels of intrapersonal conflicts observed in the study suggest that inconsistencies in goals or values should be considered in the psychological treatment of depression.
Is a Full Recovery Possible after Cognitive Behavioural Therapy for Chronic Fatigue Syndrome?
Authors: Knoop Hans , Bleijenberg Gijs , Gielissen Marieke F.M. , van der Meer Jos W.M. , White Peter D.
Published: April 2007

Background: Cognitive behavioural therapy (CBT) for chronic fatigue syndrome (CFS) leads to a decrease in symptoms and disabilities. There is controversy about the nature of the change following treatment; some suggest that patients improve by learning to adapt to a chronic condition, others think that recovery is possible. The objective of this study was to find out whether recovery from CFS is possible after CBT. Methods: The outcome of a cohort of 96 patients treated for CFS with CBT was studied. The definition of recovery was based on the absence of the criteria for CFS set up by the Center for Disease Control (CDC), but also took into account the perception of the patients’ fatigue and their own health. Data from healthy population norms were used in calculating conservative thresholds for recovery. Results: After treatment, 69% of the patients no longer met the CDC criteria for CFS. The percentage of recovered patients depended on the criteria used for recovery. Using the most comprehensive definition of recovery, 23% of the patients fully recovered. Fewer patients with a co-morbid medical condition recovered. Conclusion: Significant improvement following CBT is probable and a full recovery is possible. Sharing this information with patients can raise the expectations of the treatment, which may enhance outcomes without raising false hopes.
Low Control at Work and the Risk of Suicide in Japanese Men: A Prospective Cohort Study
Authors: Tsutsumi Akizumi , Kayaba Kazunori , Ojima Toshiyuki , Ishikawa Shizukiyo , Kawakami Norito
Published: April 2007

Background: Although adverse psychosocial job characteristics are suspected predictors of suicide death, prospective studies based on established stress instruments are limited. Methods: In a multicenter community-based Japanese cohort study, we prospectively investigated the association between psychosocial job characteristics and the risk of death from suicide among male workers. Baseline examination was conducted from 1992 to 1995 to determine the socioeconomic, behavioural and biological variables in addition to the psychosocial job characteristics of 3,125 male workers aged 65 and under and free from major illness. Low job control and high job demands were measured as adverse psychosocial job characteristics according to a job demand-control model questionnaire. Suicide deaths were identified using the Cause-of-Death Register. Results: During the 9-year follow-up, 14 suicides were identified. The suicide death rate was 48.1 per 100,000 person years. Multivariate analysis revealed a more than fourfold increase in the risk of suicide among men with low control at work (relative risk: 4.10; 95% confidence interval: 1.31–12.83) compared with counterpart men after adjustment for age, marital status, educational attainment, occupation, smoking status, alcohol consumption, total cholesterol level, and study area. Job demands were not associated with risk of death from suicide. Conclusions: By using a job demand-control model questionnaire, low control at work was revealed as a predictor of suicide death among Japanese male workers. The finding implies that job redesign aimed at increased worker control could be a worthwhile strategy in preventing, or at least reducing, the risk of suicide death.
Governing Sex Determination in Fish: Regulatory Putsches and Ephemeral Dictators
Authors: Volff J.-N. , Nanda I. , Schmid M. , Schartl M.
Published: April 2007

In contrast to the rather stable regulatory regimes established over more that 100 million years in birds and mammals, sex determination in fish might frequently undergo evolutionary changes bringing the sex-determining cascade under new master sex regulators. This phenomenon, possibly associated with the emergence of new sex chromosomes from autosomes, would explain the frequent switching between sex determination systems observed in fish. In the medaka Oryzias latipes, the Y-specific master sex-determining gene dmrt1bY has been formed through duplication of the autosomal gene dmrt1 onto another autosome, thus generating a new Y chromosome. Dmrt1bY emerged about 10 million years ago and is restricted to several Oryzias species, indicating that the Y chromosome of the medaka is evolutionarily much younger than mammalian and bird sex chromosomes. Fertile males without dmrt1bY have been detected in some medaka populations, and this gene might even have been inactivated in one Oryzias species, indicating the existence of sexual regulators already able to supplant dmrt1bY. Studies on other models have confirmed that fish sex chromosomes are generally young and occurred independently in different fish lineages. The identification of new sex-determining genes in these species will shed new light on the exceptional evolutionary instability governing sex determination in fish.
Characterisation of Urogenital Ridge Gene Expression in the Human Embryonal Carcinoma Cell Line NT2/D1
Authors: Knower K.C. , Sim H. , McClive P.J. , Bowles J. , Koopman P. , Sinclair A.H. , Harley V.R.
Published: April 2007

The study of the mammalian sex-determining pathway has been hampered by the lack of cell culture systems to investigate the underlying molecular relationships between sex-determining genes. Recent approaches using high-throughput genome-wide studies have revealed a number of sexually dimorphic genes expressed in the developing mouse gonad. Here, we investigated a human testicular cell line in terms of its expression of known sex-determining genes and newly identified candidates. The human embryonal carcinoma cell line NT2/D1 was screened for the expression of 46 genes with known or potential roles in the sex-determining and differentiation pathway. Forty genes tested were expressed in NT2/D1 cells including the testis-determining genes SRY, SOX9, SF-1, DHH and FGF9. Genes not expressed included WT1, DAX1 and the ovary-specific genes FOXL2 and WNT4. Cell-specific markers demonstrate that NT2/D1 cells reflect a number of cell types in the gonad including Sertoli, Leydig and germ cells. Our results suggest that male pathways initiated by SRY, SOX9 and SF-1 remain intact in these cells. Lack of expression of ovary-specific genes is consistent with a commitment of these cells to the male lineage. Manipulation of gene expression in this cell line could be an important new in vitro tool for the discovery of new human sex-determining genes.
Bmp7 Regulates Germ Cell Proliferation in Mouse Fetal Gonads
Authors: Ross A. , Munger S. , Capel B.
Published: April 2007

Relatively little is known regarding the signals that regulate the proliferation and sex-specific development of germ cells during mammalian fetal gonad differentiation. Members of the bone morphogenetic protein (BMP) family have been identified as key regulators of germ cells in the Drosophila gonad. Here we show that in mice Bmp7 is expressed in gonads of both sexes and is required for germ cell proliferation during a narrow window of development between 10.5–11.5 days post coitum (dpc). The proliferation defect is more severe in male than in female embryos suggesting that there are sexually dimorphic compensatory pathways. BMP signaling appears to be an evolutionarily conserved pathway regulating embryonic germ cell proliferation in vertebrate and invertebrate species.
Temperature-Dependent Sex Determination in Hd-rR Medaka Oryzias latipes: Gender Sensitivity, Thermal Threshold, Critical Period, and DMRT1 Expression Profile
Authors: Hattori R.S. , Gould R.J. , Fujioka T. , Saito T. , Kurita J. , Strüssmann C.A. , Yokota M. , Watanabe S.
Published: April 2007

The developmental time and thermal threshold for temperature-dependent sex determination (TSD), gender differences in temperature sensitivity, the fertility of thermally sex reversed fish, and the effect of temperature on the expression of two major sex determination/differentiation genes (DMY/DMRT1bY and DMRT1) were examined in the Hd-rR strain of medaka, Oryzias latipes. Fertilized eggs were exposed from either shortly after fertilization (8–16 cells; embryonic stages 5–6) or from middle embryogenesis (heart development stage; stage 36) until hatching to temperatures ranging from 17°C to 34°C. Secondary sexual characteristics, gonadal histology, progeny testing, sex-linked body coloration and gene expression were used to determine phenotypic and genotypic sex. Sex determination was unaffected by low or high temperatures in genotypic (XY) males. In contrast, genotypic (XX) females treated from stages 5–6 showed increasing rates of sex reversal into phenotypic males at temperatures above 27°C up to 100% at 34°C. Thermal manipulation of sex was ineffective after stage 36, indicating that gonadal fate in medaka is determined considerably earlier than histological differentiation (stage 39). High temperature induced DMRT1 expression in genotypic females, which was observed already from stage 36. Sex-reversed males had histologically normal testes, were capable of sexual courtship and, with the exception of fish from 34°C, sired viable progeny when mating with fertile females. These results clarify the pattern of TSD in medaka and provide important clues to understand the mechanism of sex determination in this species. They also suggest that a brief exposure to high temperature early in life could impair the fertility of medaka as adults.
Bacterial Meningitis: The Role of Transforming Growth Factor-Beta in Innate Immunity and Secondary Brain Damage
Authors: Malipiero Ursula , Koedel Uwe , Pfister Walter , Fontana A.
Published: April 2007

Project 6 of the NCCR ‘Neural Plasticity and Repair’ focuses on mechanisms of immunity and tissue damage in autoimmune and infectious diseases of the central nervous system (CNS). In one of the subprojects, the influence of transforming growth factor-β (TGF-β) on the immune reactivity of the CNS was investigated. In mice with Streptococcus pneumoniae-induced meningitis, a deletion of TGF-β receptor II on leukocytes is found to enhance recruitment of neutrophils to the site of infection and to promote bacterial clearance. The improved host defense against S. pneumoniae was associated with an almost complete prevention of meningitis-induced vasculitis, a major intracranial complication leading to brain damage. The data show that endogenous TGF-β suppresses host defense against bacterial infection in the CNS. This contrasts with findings from other body compartments that suggested that TGF-β is a powerful chemotactic cytokine and increases microbial clearance.
Repair of the Injured Spinal Cord
Authors: Buchli Anita D. , Rouiller Eric , Mueller Roland , Dietz Volker , Schwab Martin E.
Published: April 2007

The myelin protein Nogo-A is a potent inhibitor of neurite outgrowth in the central nervous system, thus contributing to the incapacity of fiber tracts in the adult spinal cord to regenerate after injury. In this review we report on a joint approach of different research groups to develop a therapy applying anti-Nogo-A antibodies to the injured spinal cord. While basic researchers took the initiative to provide means of neutralizing the inhibitory effect of Nogo-A and demonstrated enhanced fiber growth, regeneration and functional recovery both in rodent and primate models, clinical groups and rehabilitation engineers have sought to translate this novel strategy into a clinical setting.
The Application of an Enamel Matrix Protein Derivative (Emdogain®) in Regenerative Periodontal Therapy: A Review
Authors: Sculean Anton , Schwarz Frank , Becker Jürgen , Brecx Michel
Published: April 2007

Regenerative periodontal therapy aims at reconstitution of the lost periodontal structures such as new formation of root cementum, periodontal ligament and alveolar bone. Findings from basic research indicate that enamel matrix protein derivative (EMD) has a key role in periodontal wound healing. Histological results from animal and human studies have shown that treatment with EMD promotes periodontal regeneration. Moreover, clinical studies have indicated that treatment with EMD positively influences periodontal wound healing in humans. This review aims to present an overview of evidence-based clinical indications for regenerative therapy with EMD.
Low Back Ache Treatment with Botulinum Neurotoxin Type A
Authors: Nagarajan Venkatesan , Al-Shubaili Asmahan , Ayad Yasser M. , Alexander John , Al-Ramezi Khadijah
Published: April 2007

Objective: To investigate the efficacy, safety and tolerability of paraspinal administration of botulinum neurotoxin type A (BoNT-A) in patients with chronic low back ache (LBA). Subjects and Methods: Eight patients with chronic LBA were injected with BoNT-A at three sites on either side of lumbar paraspinal muscles. The patients rated their pain intensity using a visual analogue scale (VAS) from 0 to 10, and our physiotherapist assessed the paraspinal muscle spasm using a functional scale (FS) from 0 to 5. The improvement in both VAS and FS 30, 60 and 90 days after BoNT-A from baseline was analyzed separately using paired t test. The correlation between the muscle spasm (FS) and pain relief (VAS) was analyzed using the Spearman’s rank correlation coefficient test. The level of statistical significance was p < 0.05. Results: Five (63%) patients showed a remarkable recovery in VAS and FS, whereas 2 (25%) patients showed improvement only in FS. Statistically significant improvement was achieved in VAS and FS independently 30 days (p < 0.02 and p < 0.02, respectively), 60 days (p < 0.01 and p < 0.001, respectively) and 90 days (p < 0.02 and p < 0.001, respectively) after treatment. Pain relief started early and it was independent of relief of muscle spasm 30 days after treatment (r = 0.685; p > 0.05). Conclusion: With this limited study, we have demonstrated that the paraspinal injection of BoNT-A is effective in relieving chronic LBA without producing side effects. The injection is an easy procedure, well tolerated and did not require anesthesia or imaging technique.