bluuebunny/crossref_metadata_2025 huggingface dataset:
High doses of dexamethasone induce increased β-cell proliferation in pancreatic rat islets
Authors: Rafacho Alex , Cestari Tânia M. , Taboga Sebastião R. , Boschero Antonio C. , Bosqueiro José R.
Published: January 2009

Activation of insulin signaling and cell cycle intermediates is required for adult β-cell proliferation. Here, we report a model to study β-cell proliferation in living rats by administering three different doses of dexamethasone (0.1, 0.5, and 1.0 mg/kg ip, DEX 0.1, DEX 0.5, and DEX 1.0, respectively) for 5 days. Insulin sensitivity, insulin secretion, and histomorphometric data were investigated. Western blotting was used to analyze the levels of proteins related to the control of β-cell growth. DEX 1.0 rats, which present moderate hyperglycemia and marked hyperinsulinemia, exhibited a 5.1-fold increase in β-cell proliferation and an increase (17%) in β-cell size, with significant increase in β-cell mass, compared with control rats. The hyperinsulinemic but euglycemic DEX 0.5 rats also showed a significant 3.6-fold increase in β-cell proliferation. However, DEX 0.1 rats, which exhibited the lowest degree of insulin resistance, compensate for insulin demand by improving only islet function. Activation of the insulin receptor substrate 2/phosphatidylinositol 3-kinase/serine-threonine kinase/ribosomal protein S6 kinase pathway, as well as protein retinoblastoma in islets from DEX 1.0 and DEX 0.5, but not in DEX 0.1, rats was also observed. Therefore, increasing doses of dexamethasone induce three different degrees of insulin requirement in living rats, serving as a model to investigate compensatory β-cell alterations. Augmented β-cell mass involves β-cell hyperplasia and, to a lower extent, β-cell hypertrophy. We suggest that alterations in circulating insulin and, to a lesser extent, glucose levels could be the major stimuli for β-cell proliferation in the dexamethasone-induced insulin resistance.
TRPMLs: in sickness and in health
Authors: Puertollano Rosa , Kiselyov Kirill
Published: January 2009

TRPML1, TRPML2 and TRPML3 belong to the mucolipin family of the TRP superfamily of ion channels. The founding member of this family, TRPML1, was cloned during the search for the genetic determinants of the lysosomal storage disease mucolipidosis type IV (MLIV). Mucolipins are predominantly expressed within the endocytic pathway, where they appear to regulate membrane traffic and/or degradation. The physiology of mucolipins raises some of the most interesting questions of modern cell biology. Their traffic and localization is a multistep process involving a system of adaptor proteins, while their ion channel activity possibly exemplifies the rare cases of regulation of endocytic traffic and hydrolysis by ion channels. Finally, dysregulation of mucolipins results in cell death leading to neurodegenerative phenotypes of MLIV and of the varitint-waddler mouse model of familial deafness. The present review discusses current knowledge and questions regarding this novel family of disease-relevant ion channels with a specific focus on mucolipin regulation and their role in membrane traffic and cell death. Since mucolipins are ubiquitously expressed, this review may be useful for a wide audience of basic biologists and clinicians.
Impairment of Postural Control in Rabbits With Extensive Spinal Lesions
Authors: Lyalka V. F. , Orlovsky G. N. , Deliagina T. G.
Published: January 2009

Our previous studies on rabbits demonstrated that the ventral spinal pathways are of primary importance for postural control in the hindquarters. After ventral hemisection, postural control did not recover, whereas after dorsal or lateral hemisection it did. The aim of this study was to examine postural capacity of rabbits after more extensive lesion (3/4 section of the spinal cord at T12 level), that is, with only one ventral quadrant spared (VQ animals). They were tested before (control) and after lesion on the platform periodically tilted in the frontal plane. In control animals, tilts of the platform regularly elicited coordinated electromyographic (EMG) responses in the hindlimbs, which resulted in generation of postural corrections and in maintenance of balance. In VQ rabbits, the EMG responses appeared only in a part of tilt cycles, and they could be either correctly or incorrectly phased in relation to tilts. Because of a reduced value and incorrect phasing of EMG responses on both sides, this muscle activity did not cause postural corrective movements in the majority of rabbits, and the body swayed together with the platform. In these rabbits, the ability to perform postural corrections did not recover during the whole period of observation (≤30 days). Low probability of correct EMG responses to tilts in most rabbits as well as an appearance of incorrect responses to tilts suggest that the spinal reflex chains, necessary for postural control, have not been specifically selected by a reduced supraspinal drive transmitted via a single ventral quadrant.
Inhibition of the Peptidyl-Prolyl-Isomerase Pin1 Enhances the Responses of Acute Myeloid Leukemia Cells to Retinoic Acid via Stabilization of RARα and PML-RARα
Authors: Gianni' Maurizio , Boldetti Andrea , Guarnaccia Valeria , Rambaldi Alessandro , Parrella Edoardo , Raska Ivan , Rochette-Egly Cecile , Del Sal Giannino , Rustighi Alessandra , Terao Mineko , Garattini Enrico
Published: January 2009

The peptidyl-prolyl-isomerase Pin1 interacts with phosphorylated proteins, altering their conformation. The retinoic acid receptor RARα and the acute-promyelocytic-leukemia–specific counterpart PML-RARα directly interact with Pin1. Overexpression of Pin1 inhibits ligand-dependent activation of RARα and PML-RARα. Inhibition is relieved by Pin1-targeted short interfering RNAs and by pharmacologic inhibition of the catalytic activity of the protein. Mutants of Pin1 catalytically inactive or defective for client-protein–binding activity are incapable of inhibiting ligand-dependent RARα transcriptional activity. Functional inhibition of RARα and PML-RARα by Pin1 correlates with degradation of the nuclear receptors via the proteasome-dependent pathway. In the acute myelogenous leukemia cell lines HL-60 and NB4, Pin1 interacts with RARα in a constitutive fashion. Suppression of Pin1 by a specific short hairpin RNA in HL-60 or NB4 cells stabilizes RARα and PML-RARα, resulting in increased sensitivity to the cytodifferentiating and antiproliferative activities of all-trans retinoic acid. Treatment of the two cell lines and freshly isolated acute myelogenous leukemia blasts (M1 to M4) with ATRA and a pharmacologic inhibitor of Pin1 causes similar effects. Our results add a further layer of complexity to the regulation of nuclear retinoic acid receptors and suggest that Pin1 represents an important target for strategies aimed at increasing the therapeutic index of retinoids. [Cancer Res 2009;69(3):1016–26
Glucocorticoid-Induced Tumor Necrosis Factor Receptor–Related Protein Ligand Subverts Immunosurveillance of Acute Myeloid Leukemia in Humans
Authors: Baessler Tina , Krusch Matthias , Schmiedel Benjamin Joachim , Kloss Mercedes , Baltz Katrin Miriam , Wacker Alexander , Schmetzer Helga Maria , Salih Helmut Rainer
Published: January 2009

The reciprocal interaction of tumor cells with the immune system is influenced by various members of the tumor necrosis factor (TNF)/TNF receptor (TNFR) family, and recently, glucocorticoid-induced TNFR-related protein (GITR) was shown to stimulate antitumor immunity in mice. However, GITR may mediate different effects in mice and men and impairs the reactivity of human natural killer (NK) cells. Here, we studied the role of GITR and its ligand (GITRL) in human acute myeloid leukemia (AML). Surface expression of GITRL was observed on AML cells in six of seven investigated cell lines, and 34 of 60 investigated AML patients whereas healthy CD34+ cells did not express GITRL. Furthermore, soluble GITRL (sGITRL) was detectable in AML patient sera in 18 of 55 investigated cases. While the presence of GITRL was not restricted to a specific AML subtype, surface expression was significantly associated with monocytic differentiation. Signaling via GITRL into patient AML cells induced the release of TNF and interleukin-10 (IL-10), and this was blocked by the inhibition of mitogen-activated protein kinases extracellular signal-regulated kinase 1/2. Furthermore, triggering GITR by surface-expressed and sGITRL impaired NK cell cytotoxicity and IFN-γ production in cocultures with leukemia cells, and NK cell reactivity could be restored by blocking GITR and neutralization of sGITRL and IL-10. Thus, whereas a stimulatory role of the GITR-GITRL system in mouse antitumor immunity has been reported, our data show that in humans GITRL expression subverts NK cell immunosurveillance of AML. Our results provide useful information for therapeutic approaches in AML, which, like haploidentical stem cell transplantation, rely on a sufficient NK cell response. [Cancer Res 2009;69(3):1037–45]
Tamoxifen Induces Expression of Immune Response–Related Genes in Cultured Normal Human Mammary Epithelial Cells
Authors: Schild-Hay Laura J. , Leil Tarek A. , Divi Rao L. , Olivero Ofelia A. , Weston Ainsley , Poirier Miriam C.
Published: January 2009

Use of tamoxifen is associated with a 50% reduction in breast cancer incidence and an increase in endometrial cancer incidence. Here, we documented tamoxifen-induced gene expression changes in cultured normal human mammary epithelial cells (strains 5, 16, and 40), established from tissue taken at reduction mammoplasty from three individuals. Cells exposed to 0, 10, or 50 μmol/L of tamoxifen for 48 hours were evaluated for (E)-α-(deoxyguanosine-N2-yl)-tamoxifen (dG-N2-TAM) adduct formation using TAM-DNA (DNA modified with dG-N2-TAM) chemiluminescence immunoassay, gene expression changes using National Cancer Institute DNA-oligonucleotide microarray, and real-time PCR. At 48 hours, cells exposed to 10 and 50 μmol/L of tamoxifen were 85.6% and 48.4% viable, respectively, and there were no measurable dG-N2-TAM adducts. For microarrays, cells were exposed to 10 μmol/L of tamoxifen and genes with expression changes of >3-fold were as follows: 13 genes up-regulated and 1 down-regulated for strain 16; 17 genes up-regulated for strain 5, and 11 genes up-regulated for strain 40. Interferon-inducible genes (IFITM1, IFIT1, MXI, and GIP3), and a potassium ion channel (KCNJ1) were up-regulated in all three strains. No significant expression changes were found for genes related to estrogen or xenobiotic metabolism. Real-time PCR revealed the up-regulation of IFNA1 and confirmed the tamoxifen-induced up-regulation of the five other genes identified by microarray, with the exception of GIP3 and MX1, which were not up-regulated in strain 40. Induction of IFN-related genes in the three normal human mammary epithelial cell strains suggests that, in addition to hormonal effects, tamoxifen exposure may enhance immune response in normal breast tissue. [Cancer Res 2009;69(3):1150–5]
MicroRNA-101, Down-regulated in Hepatocellular Carcinoma, Promotes Apoptosis and Suppresses Tumorigenicity
Authors: Su Hang , Yang Jian-Rong , Xu Teng , Huang Jun , Xu Li , Yuan Yunfei , Zhuang Shi-Mei
Published: January 2009

Although aberrant microRNA (miRNA) expressions have been observed in different types of cancer, their pathophysiologic role and their relevance to tumorigenesis are still largely unknown. In this study, we first evaluated the expression of 308 miRNAs in human hepatocellular carcinoma (HCC) and normal hepatic tissues and identified 29 differentially expressed miRNAs in HCC tissues. miR-101, a significantly down-regulated miRNA, was further studied in greater detail because the signal pathway(s) regulated by miR-101 and the role of miR-101 in tumorigenesis have not yet been elucidated. Interestingly, decreased expression of miR-101 was found in all six hepatoma cell lines examined and in as high as 94.1% of HCC tissues, compared with their nontumor counterparts. Furthermore, ectopic expression of miR-101 dramatically suppressed the ability of hepatoma cells to form colonies in vitro and to develop tumors in nude mice. We also found that miR-101 could sensitize hepatoma cell lines to both serum starvation– and chemotherapeutic drug–induced apoptosis. Further investigation revealed that miR-101 significantly repressed the expression of luciferase carrying the 3′-untranslated region of Mcl-1 and reduced the endogenous protein level of Mcl-1, whereas the miR-101 inhibitor obviously up-regulated Mcl-1 expression and inhibited cell apoptosis. Moreover, silencing of Mcl-1 phenocopied the effect of miR-101 and forced expression of Mcl-1 could reverse the proapoptotic effect of miR-101. These results indicate that miR-101 may exert its proapoptotic function via targeting Mcl-1. Taken together, our data suggest an important role of miR-101 in the molecular etiology of cancer and implicate the potential application of miR-101 in cancer therapy. [Cancer Res 2009;69(3):1135–42]
Positron Emission Tomography (PET) Imaging with [11C]-Labeled Erlotinib: A Micro-PET Study on Mice with Lung Tumor Xenografts
Authors: Memon Ashfaque A. , Jakobsen Steen , Dagnaes-Hansen Frederik , Sorensen Boe S. , Keiding Susanne , Nexo Ebba
Published: January 2009

Erlotinib (Tarceva) targets the epidermal growth factor receptor (EGFR), which is commonly overexpressed in human cancers, including lung cancer. We show that erlotinib can be labeled with [11C] by reacting the normethyl precursor with [11C]-methyl iodide. By using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, two lung cancer cell lines (A549 and NCI358) were shown to be less sensitive to erlotinib compared with the lung cancer cell line HCC827. This correlated with higher expression and activity of the EGFR in HCC827 cells as compared with the less sensitive cell lines. Micro–positron emission tomography (PET) and biodistribution of erlotinib was performed with [11C]-erlotinib in nude mice bearing xenografts of A549, NCI358, and HCC827 cells. Dynamic micro-PET showed that HCC827 tumors had the highest [11C]-erlotinib uptake and retained the activity significantly longer as compared with A549 and NCI358 tumors. Biodistribution of [11C]-erlotinib in the xenograft models of lung cancer showed the highest accumulation in the liver. In mice carrying the sensitive cancer cells, the accumulation of [11C]-erlotinib was higher in tumors than in the other organs. In contrast, the drug accumulated to a comparable extent in tumors from the less sensitive cancer cells and the other organs. Uptake of [11C]-erlotinib in the tumors was 1.6%, 0.7%, and 3.7% (percentage of injected dose/g), in A549, NCI358, and HCC827 cells, respectively. We show for the first time that [11C]-erlotinib identifies erlotinib-sensitive tumors. These results pave the road for studies examining the benefit of [11C]-erlotinib PET in patients with lung tumors or other tumors overexpressing EGFR. [Cancer Res 2009;69(3):873–8]
Transient Receptor Potential Type Vanilloid 1 Suppresses Skin Carcinogenesis
Authors: Bode Ann M. , Cho Yong-Yeon , Zheng Duo , Zhu Feng , Ericson Marna E. , Ma Wei-Ya , Yao Ke , Dong Zigang
Published: January 2009

Blockade of the transient receptor potential channel vanilloid subfamily 1 (TRPV1) is suggested as a therapeutic approach to pain relief. However, TRPV1 is a widely expressed protein whose function might be critical in various nonneuronal physiologic conditions. The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is overexpressed in many human epithelial cancers and is a potential target for anticancer drugs. Here, we show that TRPV1 interacts with EGFR, leading to EGFR degradation. Notably, the absence of TRPV1 in mice results in a striking increase in skin carcinogenesis. The TRPV1 is the first membrane receptor shown to have a tumor-suppressing effect associated with the down-regulation of another membrane receptor. The data suggest that, although a great deal of interest has focused on TRPV1 as a target for pain relief, the chronic blockade of this pain receptor might increase the risk for cancer development. [Cancer Res 2009;69(3):905–13]
Consistent Deregulation of Gene Expression between Human and Murine MLL Rearrangement Leukemias
Authors: Li Zejuan , Luo Roger T. , Mi Shuangli , Sun Miao , Chen Ping , Bao Jingyue , Neilly Mary Beth , Jayathilaka Nimanthi , Johnson Deborah S. , Wang Lili , Lavau Catherine , Zhang Yanming , Tseng Charles , Zhang Xiuqing , Wang Jian , Yu Jun , Yang Huanming , Wang San Ming , Rowley Janet D. , Chen Jianjun , Thirman Michael J.
Published: January 2009

Important biological and pathologic properties are often conserved across species. Although several mouse leukemia models have been well established, the genes deregulated in both human and murine leukemia cells have not been studied systematically. We performed a serial analysis of gene expression in both human and murine MLL-ELL or MLL-ENL leukemia cells and identified 88 genes that seemed to be significantly deregulated in both types of leukemia cells, including 57 genes not reported previously as being deregulated in MLL-associated leukemias. These changes were validated by quantitative PCR. The most up-regulated genes include several HOX genes (e.g., HOX A5, HOXA9, and HOXA10) and MEIS1, which are the typical hallmark of MLL rearrangement leukemia. The most down-regulated genes include LTF, LCN2, MMP9, S100A8, S100A9, PADI4, TGFBI, and CYBB. Notably, the up-regulated genes are enriched in gene ontology terms, such as gene expression and transcription, whereas the down-regulated genes are enriched in signal transduction and apoptosis. We showed that the CpG islands of the down-regulated genes are hypermethylated. We also showed that seven individual microRNAs (miRNA) from the mir-17-92 cluster, which are overexpressed in human MLL rearrangement leukemias, are also consistently overexpressed in mouse MLL rearrangement leukemia cells. Nineteen possible targets of these miRNAs were identified, and two of them (i.e., APP and RASSF2) were confirmed further by luciferase reporter and mutagenesis assays. The identification and validation of consistent changes of gene expression in human and murine MLL rearrangement leukemias provide important insights into the genetic base for MLL-associated leukemogenesis. [Cancer Res 2009;69(3):OF1109–16]
Chemotherapy in Patients with Penile Carcinoma
Authors: Protzel C. , Hakenberg O.W.
Published: January 2009

The prognosis of patients with advanced penile carcinoma is poor. There are only few studies, mostly with a low number of patients, which show a low response rate with severe toxicity. While adjuvant and palliative chemotherapy for penile cancer is universally characterized by low efficacy, neoadjuvant approaches for patients with fixed lymph node metastases have shown some response. Overall, recent experiences with new chemotherapeutic approaches (i.e. taxane-based combinations) have shown some encouraging results. Therefore, these combinations should be investigated in larger and multi-center studies.
Bicycle Saddle Pressure: Effects of Trunk Position and Saddle Design on Healthy Subjects
Authors: Carpes Felipe Pivetta , Dagnese Frederico , Kleinpaul Julio Francisco , de Assis Martins Elisandro , Bolli Mota Carlos
Published: January 2009

Objective: There is a common belief that seat pressure during cycling can compress specific neurovascular tissues over the perineum leading to genital pathologies. This topic has seldom been discussed for women. The present study was conducted to verify the effect of trunk position and saddle design on saddle pressure in both men and women. Methods: Recreational cyclists (11 men and 11 women) were evaluated while seated on a bicycle. Saddle pressure was measured with F-scan insoles adapted for two saddle models (with and without a hole), and two trunk positions (upright and forwards). Pressure values were compared between trunk positions and saddles employing ANOVA. Results: There were no statistical differences comparing saddle pressure between the two trunk positions for women. For men a statistical difference between the trunk positions for the saddle with a hole was found. Thus, the trunk forwards shift seems to affect the values of saddle pressure only for men using the ‘holed’ saddle. Conclusion: Saddle pressure for men was influenced by saddle design and trunk position only. This result indicates that the masculine anatomy may influence saddle pressure during bicycle.
Health-Related Quality of Life after Radical Prostatectomy and Low-Dose-Rate Brachytherapy for Localized Prostate Cancer
Authors: Wyler Stephen Frederic , Engeler Daniel Stephan , Seelentag Wolfhart , Ries Gerhard , Schmid Hans-Peter
Published: January 2009

Objective: To evaluate quality of life (QOL) after radical retropubic prostatectomy (RP) and low-dose-rate brachytherapy (BT). Methods: Between 2001 and 2004, RP or BT was performed in 212 patients. QOL data were evaluated with the European Organization for Research and Treatment of Cancer QLQ-C30 version 3.0, the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function-5 questionnaires. QOL data were compared. Results: RP and BT were performed in 142 and 70 patients, respectively. The mean follow-up was 24 months (5–53). The mean overall global health score for patients after RP was 78 (0–100) and after BT it was 83 (33–100), and it showed a trend in favour of BT. The follow-up lasted at most 53 months, and the period was divided into yearly categories. Patients who underwent BT showed worse global health in the first year after operation, but thereafter they showed better health. Patients who received BT showed a trend towards having lower functional-scale and symptom-scale scores in the first year after operation, and then higher scores for any subsequent year of follow-up. Only diarrhoea was temporarily worse in the second year after BT compared to RP. The mean total IPSS and QOL score for BT and RP patients during follow-up showed no significant difference. Conclusion: Patients treated with BT or RP have similar QOL scores. QOL after BT is worse in the first year after treatment, but thereafter it is better than QOL after RP.
Prostatitis-Like Symptoms: Diagnosis and Management in a Malaysian Primary Care Population
Authors: Lee Shaun Wen Huey , Liong Men Long , Yuen Kah Hay , Leong Wing Seng , Khan Nurzalina , Cheah Phaik Yeong , Krieger John N.
Published: January 2009

Background: Little is known about how primary care physicians (PCPs) in Asia diagnose and manage prostatitis-like symptoms. This study investigated the clinical diagnosis of and care provided for prostatitis-like symptoms by PCPs in a Malaysian population, and compared these findings to reports from other areas. Methods: All members of the Penang Private Medical Practitioners’ Society were asked to complete a self-administered survey. Nonresponders were contacted after 3 weeks and received a telephone request after 6 weeks. Results: Of the 786 practitioners contacted, 669 considered themselves to be PCPs, including 279 (42%) who responded to the survey. Adult males with prostatitis-like symptoms typically constitute <1% of the patients seen by PCPs. Most PCPs (72%) believe that prostatitis-like symptoms are caused by bacterial infection. 61% of PCPs base their diagnosis of prostatitis-like symptoms on clinical history, a physical examination and dipstick urinalysis. Standard management was to prescribe 1 or 2 courses of antimicrobials. Conclusions: Despite the 8.7% prevalence found in a previous survey in this population, prostatitis remains underdiagnosed in Malaysia. In contrast to many other clinical settings, urologists in Malaysia see a large proportion of newly diagnosed and treatment-naïve prostatitis patients, providing an opportunity for clinical diagnostic and treatment studies.
Cystic Nephroma, Cystic Partially Differentiated Nephroblastoma and Cystic Wilms’ Tumor in Children: A Spectrum with Therapeutic Dilemmas
Authors: van den Hoek Joop , de Krijger Ronald , van de Ven Kees , Lequin Maarten , van den Heuvel-Eibrink Marry M.
Published: January 2009

Background: Cystic renal tumors are a diagnostic and therapeutic challenge. Cystic nephroma (CN), cystic partially differentiated nephroblastoma (CPDN) and cystic Wilms’ tumor (CWT) are a spectrum with CN at the benign end, CWT at the malignant end and CPDN in the intermediate position. CN and stage 1 CPDN are often treated with surgery alone. International Society of Pediatric Oncology (SIOP) protocols for Wilms’ tumor (WT) advocate preoperative chemotherapy, which may be unnecessary and potentially harmful in CN and in stage 1 CPDN. There are difficulties in differentiating the three types using imaging techniques. Therefore, controversies exist regarding the optimal treatment. Methods: We describe 6 children, who each had a postoperative diagnosis of CN, CPDN or CWT, and we retrospectively evaluate the treatment strategies. Results: The three types cannot be differentiated using imaging techniques, although the presence of solid components in the tumor is indicative of WT. Conclusions: Surgery as first-line therapy should be seriously considered in children who have a cystic renal tumor, but further collaborative studies are needed since the distinction line between CPDN and CWT is not always clear.
Uroflow Findings in Older Boys with Tubularized Incised-Plate Urethroplasty
Authors: Tuygun Can , Bakirtas Hasan , Gucuk Adnan , Cakici Hakan , Imamoglu Abdurrahim
Published: January 2009

Aim: To analyze uroflow findings in older boys with tubularized incised-plate urethroplasty (TIPU). Materials and Methods: 79 toilet-trained patients who had TIPU were evaluated by studying their voiding history, a physical examination, suprapubic ultrasound and uroflowmetry, both pre- and postoperatively. The obstructive urinary flow pattern (OUFP) was accepted as low maximum urinary flow rate with plateau, staccato or intermittent shape. Results: The mean age was 7 years (range 5–11). The mean follow-up was 30 months (range 6–36). Of the 79 patients, 70 recovered. A permanent OUFP was found in 10 of 63 patients, as follows: 7 were detected in the 6th month after operation, and 1 each in the 9th, 18th and 36th months.Ten patients had no voiding abnormality and significant residual urine. The mean interval from initial surgery to presentation with an OUFP was 10.5 months. Conclusions: An occult urethral obstruction develops in some asymptomatic children with TIPU and commonly occurrs in the first year after operation.
Long-Term Efficiency of Skin Stretching and a Topical Corticoid Cream Application for Unretractable Foreskin and Phimosis in Prepubertal Boys
Authors: Ghysel Christophe , Vander Eeckt Kathy , Bogaert Guy A.
Published: January 2009

Objectives: To evaluate the long-term efficacy of topical application of a potent corticoid cream and skin stretching in the treatment of unretractable foreskin, pinpoint phimosis, balanopreputial adhesions and lichen sclerosus in prepubertal boys. Methods: 462 prepubertal boys (mean age 4.7 years) with unretractable foreskin applied a topical potent corticoid cream together with skin stretching twice daily for 6 weeks. Follow-up interview of all patients was performed to evaluate long-term results (median 22 months). Short- and long-term results were compared and evaluated. Results: 400/462 boys (86%) had a retractable prepuce after 6 weeks of treatment. 62/462 boys had no or only a partial response. After a median follow-up of 22 months, the treatment continued to be successful in 383/462 boys (83%). In 76/462 boys the foreskin was unretractable, of which 35 preferred surgical treatment. 12/462 boys presented with lichen sclerosus and the non-surgical treatment appeared efficient in 9/12 (67%). Conclusions: This study has shown that local application of a potent corticoid cream and skin stretching is a safe, simple and effective long-term treatment for all types of unretractable foreskin in prepubertal boys. The efficiency of the treatment was not related to the age of the patient or the type of unretractable foreskin.
Development of Sertoli Cells during Mini-Puberty in Normal and Cryptorchid Testes
Authors: Zivkovic Dragana , Hadziselimovic Faruk
Published: January 2009

Background: Only a few studies have dealt with quantitative changes of Sertoli cells during human development, and the results of these studies are conflicting. Our hypothesis is that the development of Sertoli cells during mini-puberty follows the same pattern as germ cells. Methods: We examined the biopsies of cryptorchid and normal testes from patients aged 1–12 months. Fifty complete, rounded tubules were examined and the number of Sertoli cells per tubule was determined. We compared the numbers in cryptorchid and normal testes, as well as the average number of Sertoli cells in each age group separately. Results: The number of Sertoli cells per tubule in the cryptorchid testes of patients aged 1–4 months was 22.38 ± 1.01 compared to cryptorchid patients aged 5–12 months (23.20 ± 1.41). This number in patients with spontaneously descended testes aged 1–4 months was 23.53 ± 1.98, while this number in the same group of patients aged 5–12 months was 26.20 ± 1.40. The difference between the two age groups was statistically significant (p < 0.001, two-tailed test). Conclusions: Our results suggest the number of Sertoli cells increases with the hormonal surge. In cryptorchid patients, the number of Sertoli cells is diminished compared to the normal testis.
Low Transscrotal Orchidopexy Is a Safe and Effective Approach for Undescended Testes Distal to the External Inguinal Ring
Authors: Takahashi Masayuki , Kurokawa Yasushi , Nakanishi Ryoichi , Koizumi Takahiro , Yamaguchi Kunihisa , Taue Ryuichi , Kishimoto Tomoteru , Kanayama Hiro-omi
Published: January 2009

Objectives: To review the results of a low transscrotal orchidopexy in patients with palpable undescended testes located distal to the external inguinal ring. Methods: Between July 1998 and June 2005, transscrotal orchidopexy with a single low scrotal incision was performed in 32 patients for 49 undescended testes. The indication was an undescended testis that lay distal to the external ring and could be pulled down manually into the scrotum under general anesthesia. Results: All testes that were treated with the low transscrotal approach were successfully fixed in the middle or lower portion of the scrotum. The mean operative time was significantly shorter for the low transscrotal orchidopexy (45.2 min) than for the inguinal orchidopexy (66.6 min) for 107 undescended testes at similar locations. The median follow-up duration was 39.1 months; all testes except 1 (97.7%) were located in a good position within the scrotum and had a good consistency; 1 testis ascended postoperatively and required inguinal orchidopexy. No inguinal hernias or hydroceles occurred after the surgery. Conclusions: Low transscrotal orchidopexy appears to be an excellent alternative to the standard inguinal orchidopexy for undescended testes located distal to the external inguinal ring.
New Guidelines for the Diagnosis of Growth Hormone Deficiency in Adults
Authors: Casanueva Felipe F. , Castro Ana I. , Micic Dragan , Kelestimur Fahrettin , Dieguez Carlos
Published: January 2009

Background: The task of diagnosing growth hormone deficiency (GHD) in adults is cumbersome because of the paucity of biological endpoints. Consequently, over the past decade different organizations have attempted to develop homogeneous criteria and methodology for worldwide use. GHD should be biochemically confirmed within an appropriate clinical context – but only if there is the intention to treat. Clinically, patients investigated for GHD should include those with signs and symptoms or a past history of hypothalamo-pituitary dysfunction and those with a history of cranial irradiation, tumour treatment, traumatic brain injury or subarachnoid haemorrhage. Conclusions: Subjects with ≥3 pituitary hormone deficiencies plus a low insulin-like growth factor I level do not need provocative testing. For those who must be tested, arguably the most commonly used provocative tests are the insulin tolerance test and the glucagon, GH-releasing hormone (GHRH) + arginine and GHRH + GH-releasing hexapeptide tests. Cutoffs differ across tests and results may be influenced by gender, age, body mass index and the assay reference preparation.
Bcl-2 Gene Therapy Prevents Aminoglycoside-Induced Degeneration of Auditory and Vestibular Hair Cells
Authors: Pfannenstiel Susanna C. , Praetorius Mark , Plinkert Peter K. , Brough Douglas E. , Staecker Hinrich
Published: January 2009

To evaluate the protective effects of bcl-2, we have developed an in vivo model of gentamicin ototoxicity in C57BL/6 mice using intratympanic delivery of gentamicin. Hair cell survival was evaluated using myosin VIIa immunohistochemistry, cytocochleogram and auditory brainstem response (ABR) testing. At 10 days after gentamicin application, a consistent loss of outer hair cells was seen. Mice were pretreated with an adenovector expressing human bcl-2 (Ad.11D.bcl-2) or a control vector (Ad.11D). Seventy-two hours after vector delivery mice were treated with intratympanic gentamicin and evaluated at 10 days after ototoxin delivery. Pretreatment with Ad.11D.bcl-2 resulted in morphologic protection of hair cells and preservation of hearing thresholds measured by ABR.
Endoscopic Repair of Supraorbital Ethmoid Cerebrospinal Fluid Leaks
Authors: Purkey Michael T. , Woodworth Bradford A. , Hahn Samuel , Palmer James N. , Chiu Alexander G.
Published: January 2009

Objective: To examine the clinical and anatomical characteristics of patients with supraorbital ethmoid (SOE) cerebrospinal fluid (CSF) leaks and encephaloceles and identify specific considerations unique to their management. Methods: Retrospective review of patients who underwent repair of SOE CSF leaks at our institution from 2003 to 2007. Results: The majority of patients were women (5/8), middle-aged (mean: 54.9 years) and had a high body mass index (mean 42.3). Intracranial pressures (ICPs) were elevated in 6/8 patients. Anatomically, 6/8 patients had defects medial to the medial orbital wall (MOW; mean distance: 4.15 mm) and 2/8 had defects lateral to the MOW (mean distance: 8.14 mm). Seven out of 8 were successfully repaired endoscopically, and 1 patient with a lateral defect required an adjunctive trephination. Conclusions: Patients with spontaneous SOE CSF leaks have unique clinical characteristics that include obesity and elevated ICP. Extension of a skull base defect lateral to the MOW and a narrow anterior-posterior diameter of the frontal recess are technical obstacles to endoscopic repair and may necessitate an adjunctive external approach.
The Potential of Phage Therapy in Bacterial Infections of the Eye
Authors: Górski Andrzej , Targońska Magdalena , Borysowski Jan , Weber-Dąbrowska Beata
Published: January 2009

Antibiotic resistance has become a major health challenge which poses a significant threat, also in ophthalmology. For example, methicillin-resistant Staphylococcus aureus may cause dramatic complications, including bilateral blindness as a consequence of orbital cellulitis and panophthalmitis. This menace has provoked a greatly revived interest in phage therapy. In recent years, a number of papers have been published suggesting its efficacy in animal and human bacterial infections, but none of them addressed the phage potential in ophthalmology, which is the subject of this mini review.
Measurements of Subcutaneous Tissue PO2 Reflect Oxygen Metabolism of the Small Intestinal Mucosa during Hemorrhage and Resuscitation
Authors: Mellström Å. , Månsson P. , Jönsson K. , Hartmann M.
Published: January 2009

Background: The first tissues to be deprived of perfusion and oxygenation in a hypovolemic situation and the last ones to be reperfused are the subcutaneous tissue and the gastrointestinal mucosa. We hypothesized that measurements of subcutaneous tissue gases and pH might reflect simultaneous changes in oxygenation of the intestinal mucosa. The aim of this study was to evaluate tissue gases and pH as measures of tissue oxygenation and tissue oxygen metabolism in subcutaneous and intestinal tissues simultaneously. Material and Methods: Five out of 17 domestic pigs (weight 21–25 kg) were used as controls without bleeding. Twelve animals were bled in 3 steps, 10% of their calculated blood volume at each step. The removed blood, crystalloid and colloid were thereafter infused, and animals were stabilized for 30 min. Measurements were made after each step of bleeding, retransfusion and stabilization. Before bleeding, all animals had a sensor (Paratrend 7™) implanted subcutaneously in the left groin for measurements of tissue gases and pH (PscO2, PscCO2 and pHsc). Catheters were positioned in the jugular vein, portal vein, carotid artery, pulmonary artery and femoral artery for infusion, bleeding and oxygen monitoring. Via a midline laparotomy, 2 silicon tonometers (TRIP™ sigmoid catheters) were positioned in the ileum and sigmoid colon for measurements of PCO2 and pH (PiICO2, PsiCO2, pHiI and pHsi). Blood flow in the portal vein was measured by an ultrasound probe (H6SB) and a Clark electrode (Cardiff tissue oxymeter) was used for serosal PO2 measurements of the ileum (PiIO2) and sigmoid colon (PsiO2). Results: After the first step of bleeding, PscO2 decreased from 64 ± 17 to 56 ± 22 mm Hg (SD; p < 0.05). PscCO2 and pHsc did not change. PiICO2 increased from 64 ± 14 to 79 ± 14 mm Hg (p < 0.05), PsiCO2 increased from 77 ± 16 to 90 ± 18 mm Hg (p < 0.05). pHiI decreased from 7.15 ± 0.09 to 7.03 ± 0.09 (p < 0.05). PiIO2 and PsiO2 decreased, but not significantly until steps of further bleeding. After re-transfusion and stabilization, PscO2 and PiICO2 returned to baseline. Conclusion: Measurements of subcutaneous PO2 are sensitive to bleeding and resuscitation and reflect oxygen metabolism in the small intestinal mucosa as measured by PCO2 and pH.
Factors Underlying Caregiver Stress in Frontotemporal Dementia and Alzheimer’s Disease
Authors: Mioshi Eneida , Bristow Matt , Cook Rachel , Hodges John R.
Published: January 2009

Background: Frontotemporal dementia (FTD) has devastating effects on patients and caregivers, yet the factors underlying caregiver stress are poorly understood. Methods: 108 caregivers (79 = FTD, 29 = Alzheimer’s disease) participated in a postal survey. Self-report measures of perceived stress, depression, social networks, as well as patient-based measures of behaviour change and activities of daily living were completed. Results: Depression was a cardinal feature in FTD caregivers, and it accounted for more than 58% of stress scores. Both depression and stress were significantly higher than in AD. Neither the severity of behaviour changes nor functional disability explained caregiver stress. Conclusion: Caregiver stress is a multidimensional construct, and FTD caregivers should receive more support than currently available. Depression plays a key role in coping ability.
Interleukin-1α –889 C/T Polymorphism in Turkish Patients with Late-Onset Alzheimer’s Disease
Authors: Dursun Erdinç , Gezen-Ak Duygu , Ertan Turan , Bilgiç Başar , Gürvit Hakan , Emre Murat , Eker Engin , Engin Funda , Uysal Ömer , Yilmazer Selma
Published: January 2009

Background/Aims: The polymorphism (rs1800587) in the 5′-flanking regulatory region at –889 of the interleukin-1α gene has been shown to be associated with inflammatory diseases and Alzheimer’s disease (AD). The aim of the current study is to determine whether there is an association between the promoter region polymorphism of the interleukin-1α gene and late-onset AD in a cohort of Turkish patients. Methods: One hundred and four subjects with dementia of the Alzheimer type and 103 age-matched controls were genotyped according to the PCR with confronting two-pair primers method. Results: Although the distribution of genotypes did not significantly differ (p = 0.107), the difference between allelic frequency was nearly significant according to a χ2 test (p = 0.05) when the controls and patients were compared. Conclusion: Our results showed that there is no association between the –889 C/T transition on the interleukin-1α gene and late-onset AD in the Turkish population.
Screening for Sterilizing Activity of Antibiotic Combinations in an Acid Model of Rapidly Growing Mycobacteria during the Stationary Phase of Growth
Authors: Cremades R. , Santos A. , Rodríguez J.C. , García-Pachón E. , Ruiz M. , Escribano I. , Royo G.
Published: January 2009

Background: In view of the problems of correlation between the data provided by classical microbiological studies and clinical response, we designed an in vitro method to screen for the sterilizing activity of various antibiotics, individually or in combinations, against clinical isolates of various rapidly growing mycobacteria in the stationary phase. Material and Methods: We screened a large number of antibiotic combinations (4–16 μg/ml) for their sterilizing capacity in 26 Mycobacterium fortuitum clinical isolates, 7 Mycobacterium chelonae and 2 Mycobacterium abscessus clinical isolates (105 CFU). Results: The best results against M. fortuitum were obtained with moxifloxacin, both on its own (13/26 strains) and in combination. This drug is also very active against M. chelonae (3/7 strains), and in combination with clarithromycin and amikacin exhibits sterilizing activity against all the strains studied. Combinations of clarithromycin with moxifloxacin or linezolid at high doses (16 μg/ml) exhibit activity against M. abscessus. Conclusions: The most relevant finding of our study is the good activity of moxifloxacin against these microorganisms in the stationary phase. This indicates the need to confirm these data in animal models or clinical trials in order to determine their true clinical importance.
Assessing the Value of Supportive Skin Care: Development and Validation of an Instrument for Evaluating Patient-Relevant Benefit
Authors: Augustin M. , Schäfer I. , Rabini S. , Lee-Seifert C. , Radtke M. , Rustenbach S.J.
Published: January 2009

Background: Supportive skin care for irritated and inflamed skin is one of the most important measures in the prevention and treatment of eczema and sensitive skin. Objectives: To develop and validate an instrument for the evaluation of patient-relevant benefit in the supportive care of irritated skin with nonpharmacological topical agents. Methods: Patient-defined treatment objectives and benefits of supportive skin care were determined in an open survey of patients with irritated skin. A pilot questionnaire was constructed according to the Patient Benefit Index (PBI). The questionnaire was tested for feasibility and validity in 1,886 patients with various irritated skin conditions. Results: From a total of 90 characteristics of basic therapy benefit, a 23-item questionnaire was constructed. This questionnaire (‘PBI-k’) proved to be feasible, reliable and was associated with a high level of patient acceptance in the surveillance field. The questionnaire showed good internal consistency, distribution characteristics and convergent validity with patient satisfaction. Conclusion: The PBI-k is the first specific instrument developed for the evaluation of patient-defined benefit in supportive skin care with nonpharmacological topical agents. Feasibility and psychometric properties make this questionnaire suitable for application in studies involving patients with irritated, sensitive skin.
Neurovascular Pulsatile Compression and Neurosurgical Decompression of the Rostral Ventrolateral Medulla in Medically Resistant Hypertensive Patients
Authors: Legrady Peter , Voros Erika , Bajcsi Dora , Sonkodi Sandor , Barzo Pal , Abraham Gyorgy
Published: January 2009

Background/Aims: In cases of severe primary hypertension not responding to conventional medical therapy, neurovascular pulsatile compression of the rostral ventrolateral medulla on the left side may be considered as an etiological factor in the hypertension. Through neurosurgical decompression, the blood pressure can be reduced in these cases, and the conventional medication can also become more effective. Methods:The authors retrospectively analysed the changes in the blood pressure and therapy of patients with or without neurosurgical decompression over a 2-year period. The 2-year data were available for 9 operated and 7 non-operated patients with neurovascular compression. The data of control examinations performed 1, 3, 6, 12 and 24 months after the intervention (or after MR-angiography in the non-operated cases) were analysed. Results: After the decompression, both the systolic and diastolic blood pressure decreased significantly and permanently in all cases, and there was an improved response to the medication. In the non-operated group, the blood pressure did not change significantly during the 2 years. Conclusion: In severe hypertension that does not respond to conventional therapy, neurosurgical decompression of the brain stem on the left side can guarantee a long-lasting blood pressure reduction and a better response to antihypertensive medication.
Implications of Measuring Soluble Receptor Activators of Nuclear Factor-κB Ligand and Osteoprotegerin in Bone Metabolism of Elderly Women
Authors: Chiba Yuko , Onouchi Tsuneko , Ikeda Toru , Adachi Junichiro , Tamura Yoshiaki , Horiuchi Toshiyuki
Published: January 2009

Background/Aim: The discovery of a signaling system consisting of a soluble receptor activator of the NF-κB ligand (sRANKL) and its decoy receptor osteoprotegerin (OPG) has provided a valuable key to understanding the pathophysiology of the bone microenvironment. We conducted a cross-sectional study of the role of sRANKL and OPG levels as they relate to bone metabolism in elderly postmenopausal women with and without osteoporosis. Subjects and Methods: Fifty-one elderly women with or without osteoporosis were enrolled in the study. Bone alkaline phosphatase, osteocalcin, urinary deoxypyridinoline and urinary type I collagen N-terminal telopeptide (NTx) were measured as bone metabolic markers. Serum levels of OPG and sRANKL were measured by sandwich enzyme-linked immunosorbent assay and the lumbar spine bone mineral density (LSBMD) with dual-energy X-ray absorptiometry. Furthermore, we compared the sRANKL and OPG levels in elderly women with and without vertebral fractures (VFs). Results: In elderly postmenopausal women, there was a significant positive association between OPG levels and the T score and Z score of LSBMD (r = 0.345 and p = 0.014 for T score; r = 0.438 and p = 0.001 for Z score). sRANKL levels were not significantly correlated with T score, Z score of LSBMD, or any of the four bone metabolic markers. There were no significant differences in the sRANKL levels among the three groups (normal bone mineral density, osteopenia, and osteoporosis), but a trend toward a higher value in the osteoporosis group. The sRANKL/OPG ratio was negatively correlated with the T score and Z score of LSBMD (r = –0.336, p = 0.017; r = –0.384, p = 0.006, respectively), but not with any of the four bone metabolic markers. OPG levels in elderly women with VFs were lower than in those without VFs (p = 0.05). Multiple regression analysis showed that OPG and NTx are contributing factors to bone loss in elderly women (p = 0.014 and 0.012, respectively). Conclusion: The OPG level provides a good predictor of osteoporosis as well as NTx in elderly women; additionally, the findings suggest that OPG might protect elderly women from bone loss or fractures.