bluuebunny/crossref_metadata_2025 huggingface dataset:
VEGFA-VEGFR Pathway Blockade Inhibits Tumor-Induced Regulatory T-cell Proliferation in Colorectal Cancer
Authors: Terme Magali , Pernot Simon , Marcheteau Elie , Sandoval Federico , Benhamouda Nadine , Colussi Orianne , Dubreuil Olivier , Carpentier Antoine F. , Tartour Eric , Taieb Julien
Published: October 2012

Multitarget antiangiogenic tyrosine kinase inhibitors (TKI) have been shown to reduce regulatory T cells (Treg) in tumor-bearing animals and patients with metastatic renal carcinomas. However, a direct role of the VEGF-A/VEGFR pathway inhibition in this phenomenon is a matter of debate and molecular mechanisms leading to Treg modulation in this setting have not been explored to date. Treg proportion, number, and proliferation were analyzed by flow cytometry in peripheral blood of patients with metastatic colorectal cancer (mCRC) treated with bevacizumab, a monoclonal antibody targeting specifically VEGF-A, and in colon cancer–bearing mice (CT26) treated with drugs targeting the VEGF/VEGFR axis. The direct impact of VEGF-A on Treg induction was assessed together with specific blockade of different isoforms of VEGFRs that may be involved. In CT26-bearing mice, anti-VEGF antibody and sunitinib treatments reduced Treg but masitinib, a TKI not targeting VEGFR, did not. Targeting VEGF-A/VEGFR axis seems sufficient to affect Treg percentages, without any changes in their function. Similarly, bevacizumab inhibited Treg accumulation in peripheral blood of patients with mCRCs. In vitro, Treg expressing VEGFR from tumor-bearing mice directly proliferated in response to VEGF-A. Anti-VEGF-A treatment decreased Treg proliferation in mice as well as in patients with mCRCs. VEGFR-2- but not VEGFR-1–specific blockade led to the same results. We identified a novel mechanism of tumor escape by which VEGF-A directly triggers Treg proliferation. This proliferation is inhibited by VEGF-A/VEGFR-2 blockade. Anti-VEGF-A therapies also have immunologic effects that may be used with a therapeutic goal in the future. Cancer Res; 73(2); 539–49. ©2012 AACR.
Bortezomib with Thalidomide plus Dexamethasone Compared with Thalidomide plus Doxorubicin and Dexamethasone as Induction Therapy in Previously Untreated Multiple Myeloma Patients
Authors: Buda Gabriele , Orciuolo Enrico , Carulli Giovanni , Galimberti Sara , Ghio Francesco , Cervetti Giulia , Pelosini Matteo , Petrini Mario
Published: October 2012

We conducted a retrospective study to compare thalidomide, bortezomib and dexamethasone (VTD) with thalidomide plus doxorubicin and dexamethasone (TAD). Until now, first-line treatment with these combinations has not been reported in any comparative study. The principal objective of this study was to determine whether VTD would improve the complete response (CR) and CR plus very good partial response rates compared with TAD. Second, using additional methods, such as flow cytometric assays and polymerase chain reaction technology, we evaluated the molecular residual disease in the subgroup of patients that obtained CR. Our study shows that VTD is a superior induction regimen compared with TAD, with a higher response rate after induction, translating into greater CR plus very good partial response.
Enthesitis in Psoriatic Disease
Authors: McGonagle Dennis G. , Helliwell Philip , Veale Douglas
Published: October 2012

Enthesitis is increasingly recognized as an important component in psoriatic arthritis (PsA). Improved imaging techniques have expanded our understanding of the role of enthesitis in PsA and provided methods for earlier detection and assessment. Increased knowledge about the extent of tendon and ligament involvement has led to the theory that enthesitis may be the primary event in PsA. Given the historical difficulties in detecting and measuring enthesitis, its inclusion as an endpoint in PsA trials has been limited. Current trial data suggest that tumour necrosis factor inhibitors can successfully treat PsA-related enthesitis, which may have implications for the long-term prognosis of PsA. In this article, we review methods for detecting and assessing enthesitis, current thinking regarding the role of enthesitis in the pathogenesis of PsA, and trial evidence for the treatment of PsA and, therefore, enthesitis.
Adipocytokines and Hepatocellular Carcinoma
Authors: Wieser Verena , Moschen Alexander R. , Tilg Herbert
Published: October 2012

Adipocytokines are primarily adipocyte-derived products, although certain members are also synthesized by other cell types. These adipocytokines, similarly to classical cytokines, are characterized by very pleiotropic functions affecting biological processes throughout the body. An increasing number of adipocytokines has recently been recognized, such as adiponectin, leptin, pre-B cell colony-enhancing factor/Nampt/visfatin, resistin, progranulin, and others. Adiponectin has emerged as the most abundant circulating adipocytokine, is produced almost exclusively by adipocytes, and has mainly anti-inflammatory and anti-diabetic functions. In contrast, leptin is produced by many cell types beyond adipocytes, regulates immunity and T cell functions, and acts in a more pro-inflammatory fashion. Adipocytokines play a fundamental role in adipose tissue homeostasis (i.e. health) and disease, especially in obesity-related disorders such as non-alcoholic fatty liver diseases (NAFLD) and their complications, including hepatocellular carcinoma (HCC). Lack of adiponectin as observed in NAFLD drives steatosis and inflammation in the liver, and evidence is increasing that this adipocytokine has many anti-tumor properties and might play a rather protective role in HCC. The role of leptin in NAFLD is still unclear and this adipocytokine seems to have opposite effects in HCC, acting more as a tumor promoter. Evidence is increasing that HCC tissue produces various adipocytokines, and adiponectin expression in HCC seems to be decreased whereas leptin expression is rather increased. In conclusion, adipocytokines are increasingly recognized as pleiotropic molecules involved in the pathophysiology of HCC, which might lead to therapeutic approaches targeting these mediators.
Epidermal Growth Factor Receptor Signaling in Hepatocellular Carcinoma: Inflammatory Activation and a New Intracellular Regulatory Mechanism
Authors: Berasain Carmen , Nicou Alexandra , Garcia-Irigoyen Oihane , Latasa M. Ujue , Urtasun Raquel , Elizalde Maria , Salis Fabiana , Perugorría María J. , Prieto Jesús , Recio Juan A. , Corrales Fernando J. , Avila Matías A.
Published: October 2012

Background/Aims: Hepatocellular carcinoma (HCC) is a chemoresistant tumor strongly associated with chronic hepatitis. Identification of molecular links connecting inflammation with cell growth/survival, and characterization of pro-tumorigenic intracellular pathways is therefore of therapeutic interest. The epidermal growth factor receptor (EGFR) signaling system stands at a crossroad between inflammatory signals and intracellular pathways associated with hepatocarcinogenesis. We investigated the regulation and activity of different components of the EGFR system, including the EGFR ligand amphiregulin (AR) and its sheddase ADAM17, and the modulation of intracellular EGFR signaling by a novel mechanism involving protein methylation. Methods: ADAM17 protein expression was examined in models of liver injury and carcinogenesis. Crosstalk between tumor necrosis factor (TNF)-α, AR and EGFR signaling was evaluated in human HCC cells and mouse hepatocytes. Modulation of EGFR signaling and biological responses by methylation reactions was evaluated in AML12 mouse hepatocytes. Results: ADAM17 was upregulated in liver injury and hepatocarcinogenesis. TNF-α triggered AR shedding and EGFR transactivation in HCC cells. AR was necessary for TNF-α activation of ERK1/2 and Akt signaling in hepatocytes. Inhibition of methylation reactions increased the ERK1/2 signal amplitude triggered by AR/EGFR and reduced DNA synthesis in AML12 cells. Conclusions: Increased ADAM17 in pre-neoplastic liver injury further supports its implication in hepatocarcinogenesis. AR release and EGFR transactivation by TNF-α constitutes a novel link between inflammatory signals and pro-tumorigenic mechanisms in liver cells. Finally, the identification of a new mechanism controlling growth factor signaling, and biological responses, involving methylation reactions within the RAS/RAF/MEK/ERK pathway, exposes a new target for antineoplastic intervention.
Adherence with Oral Oncologic Treatment in Cancer Patients: Interest of an Adherence Score of All Dosing Errors
Authors: Thivat E. , Van Praagh I. , Belliere A. , Mouret-Reynier M.A. , Kwiatkowski F. , Durando X. , Mahammedi H. , Dillies A.F. , Chollet P. , Chevrier R.
Published: October 2012

Purpose: Patient nonadherence to oral antineoplastic therapy is a well-recognized barrier to effective treatment. In order to identify patients who may need additional support to become adherent, it is important to have a useful tool that takes into account all the parameters of adherence to prescription. The aim of this prospective study was to evaluate adherence of oral antineoplastic agents and to investigate two calculation methods of adherence score. Patients and Methods: Twenty-nine cancer patients were enrolled in this study. Fourteen were treated by capecitabine and 15 patients by aromatase inhibitors. Adherence was measured using a medication event monitoring system and adherence score was calculated by a usual method and a composite adherence score that takes into account missed doses and also intake interval errors (between 2 doses and between meals). Results: Across the 6-month evaluation period, average adherence was 95% with the standard calculation (capecitabine group: 89%; aromatase inhibitor group: 99%) versus 83% with the composite index (capecitabine group: 62%; aromatase inhibitor group: 99%) (p = 0.030). The composite calculation permits to highlight more nonadherent patients (29.6 vs. 7.4%), particularly in the capecitabine group (73 vs. 18%, p = 0.001). We report 2 cases identified as nonadherent with composite adherence rate. Conclusion: The composite adherence score permits to better evaluate adherence to prescription and to identify barriers to adherence and persistence.
Prospective Short-Term Evaluation of Transurethral Needle Ablation Procedure in an Ambulatory Setting
Authors: Cornu Jean-Nicolas , Desgrandchamps François , de la Taille Alexandre , Vicaut Eric , Aout Mounir , Lukacs Bertrand
Published: October 2012

Objective: To assess the results of transurethral needle ablation (TUNA) (Prostiva®, Medtronic, France) performed in an ambulatory setting in men with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH). Materials and Methods: A multicenter open-label study was conducted. Short-term success was defined by ability to leave the hospital on the evening of the intervention, and absence of rehospitalization due to complications during the first postoperative month. Sexual and urinary functions were evaluated by validated questionnaires. Results: The procedure was successful in 44/49 patients. Sexual and ejaculatory function was not affected or slightly improved in the majority of patients. Urinary parameters improved with a 32% decrease in the International Prostate Symptom Score. At 1 month postoperation, more than 80% of patients were satisfied, and 36/41 patients were prepared to undergo the procedure again if needed. Our study was limited by the short follow-up duration. Conclusions: TUNA can be successfully performed in an ambulatory setting under local and/or general anesthesia with a high level of patient satisfaction and a low short-term morbidity, especially on sexual function. Thus, the procedure is a suitable mini-invasive option for patients who cannot/do not want to take medical therapy or undergo invasive surgical procedures, or want to preserve their sexual function.
Reduction in Body Weight but Worsening Renal Function with Late Ultrafiltration for Treatment of Acute Decompensated Heart Failure
Authors: Dev Sandesh , Shirolkar Shailesh C. , Stevens Susanna R. , Shaw Linda K. , Adams Patricia A. , Felker G. Michael , Rogers Joseph G. , O’Connor Christopher M.
Published: October 2012

Objectives: The safety, effectiveness and indications for ultrafiltration (UF) are not well established. We hypothesized that UF would not worsen renal function in patients with heart failure (HF) who were not responding to medical therapy. Methods: Data was collected for patients who underwent UF between 2006 and 2010 (n = 72, median age 61 years, 54% males, 61% Caucasian, 54% left ventricular ejection fraction ≥40%). Results: Baseline GFR was 38 ml/min/ 1.73 m2. All patients were initially treated with loop diuretics and 58% required a thiazide-like diuretic or vasoactive agent. UF resulted in total fluid removal of 11.3 liters and weight loss was 9.7 kg. The median decrease in eGFR during UF was 4.5 ml/min/m2 (IQR –13, 0; p <0.01) and 43% of patients experienced a ≥20% decrease in eGFR. Ten percent of patients required dialysis and 13% died, received a ventricular assist device/cardiac transplant or were discharged to hospice. Conclusions: In a cohort of HF patients who did not respond to medical therapy, UF was associated not only with a significant reduction of body weight and fluid removal, but also acute worsening of renal function. Further research to identify the appropriate population for UF, long-term outcomes and the intensity of treatment is required if UF is to gain wide acceptance for HF management.
Cathepsin C Gene 5′-Untranslated Region Mutation in Papillon-Lefèvre Syndrome
Authors: Kosem Rok , Debeljak Maruša , Repič Lampret Barbka , Kansky Aleksej , Battelino Tadej , Trebušak Podkrajšek Katarina
Published: October 2012

Background: Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder characterized by palmoplantar keratoderma together with a severe form of generalized aggressive periodontitis and associated with mutations in cathepsin C gene (CTSC). Objective: To investigate the clinical and mutational characteristics of 6 PLS patients from 4 unrelated Slovenian families. Methods:CTSC mutational and functional analyses were performed. Results: In all patients, a novel homozygous substitution, c.-55C>A, in the CTSC 5′-untranslated region (UTR) was detected on genomic DNA level and confirmed by mRNA analysis, resulting in the almost complete loss of CTSC mRNA expression and CTSC activity. In silico analysis revealed the potential of the mutation to disrupt putative transcription factor binding sites (TFBSs) for AP-2 and Sp families of transcription factors. Conclusion: Identification of a novel CTSC 5′-UTR mutation together with a severe reduction of CTSC mRNA expression and virtually nonexistent CTSC activity was suggestive of a novel mechanism of TFBS dysfunction associated with PLS.
The Smallest Active Carbamoyl Phosphate Synthetase Was Identified in the Human Gut Archaeon Methanobrevibacter smithii
Authors: Popa Elena , Perera Nirosha , Kibédi-Szabó Csaba Z. , Guy-Evans Hedeel , Evans David R. , Purcarea Cristina
Published: October 2012

The genome of the major intestinal archaeon Methanobrevibacter smithii contains a complex gene system coding for carbamoyl phosphate synthetase (CPSase) composed of both full-length and reduced-size synthetase subunits. These ammonia-metabolizing enzymes could play a key role in controlling ammonia assimilation in M. smithii, affecting the metabolism of gut bacterial microbiota, with an impact on host obesity. In this study, we isolated and characterized the small (41 kDa) CPSase homolog from M. smithii. The gene was cloned and overexpressed in Escherichia coli, and the recombinant enzyme was purified in one step. Chemical cross-linking and size exclusion chromatography indicated a homodimeric/tetrameric structure, in accordance with a dimer-based CPSase activity and reaction mechanism. This small enzyme, MS-s, synthesized carbamoyl phosphate from ATP, bicarbonate, and ammonia and catalyzed the same ATP-dependent partial reactions observed for full-length CPSases. Steady-state kinetics revealed a high apparent affinity for ATP and ammonia. Sequence comparisons, molecular modeling, and kinetic studies suggest that this enzyme corresponds to one of the two synthetase domains of the full-length CPSase that catalyze the ATP-dependent phosphorylations involved in the three-step synthesis of carbamoyl phosphate. This protein represents the smallest naturally occurring active CPSase characterized thus far. The small M. smithii CPSase appears to be specialized for carbamoyl phosphate metabolism in methanogens.
Primitive Neuroectodermal Tumor of the Kidney: A Single-Institute Series of Six Patients from China
Authors: Huang Jiwei , Zhang Jin , Dong Baijun , Chen Yonghui , Kong Wen , Liu Qiang , Xue Wei , Liu Dongming , Huang Yiran
Published: October 2012

Objective: Renal primitive neuroectodermal tumor (PNET) is a rare and highly malignant neoplasm. Our study aims to present the clinical findings and prognosis of 6 patients with renal PNET from China. Material and Methods: From January 2003 to February 2012, 6 patients with renal PNET confirmed by immunohistochemical staining and fluorescence in situ hybridization (FISH) treated in our institution were reviewed retrospectively and our data compared with the literature. Results: There were 4 male and 2 female patients with a mean age of 35.0 years. The mean diameter was 13.3 cm. Five of the masses had renal vein thrombosis, and 3 extended into the inferior vena cava. A lymph node metastasis was detected in 1 patient and a liver metastasis in another patient. Radical nephrectomy was performed in all cases, with 5 patients following chemotherapy and 1 receiving Sutent treatment. Within a median follow-up of 7.5 months (range 1-71), median overall survival was 22.1 months. Conclusions: The diagnosis of renal PNET should be considered in young patients presenting with renal mass and venous thrombosis. It seems that Asian renal PNET patients had a higher rate of venous thrombosis than Caucasian populations. CD99 positivity on immunohistochemistry and EWS-FL1 chimera gene detected by FISH support the diagnosis. The prognosis is poor despite multimodal treatment.
Activation of AMP-Activated Protein Kinase Inhibits Albumin-Induced Endoplasmic Reticulum Stress and Apoptosis through Inhibition of Reactive Oxygen Species
Authors: Lee Eun Kyoung , Jeong Jin Uk , Chang Jai Won , Yang Won Seok , Kim Soon Bae , Park Su Kil , Park Jung Sik , Lee Sang Koo
Published: October 2012

Background: Endoplasmic reticulum (ER) stress induced by urinary albumin plays an important role in tubulointerstitial injury. We have shown that albumin-induced ER stress is regulated through reactive oxygen species (ROS)-c-Src kinase-mTOR signaling pathways. We postulated that peroxisome proliferator-activated receptor-γ (PPAR-γ) might also act as an upstream signaling molecule between c-Src kinase and mTOR. It has been suggested that AMP-activated protein kinase (AMPK) is involved in attenuation of ER stress. We examined whether and how activation of AMPK suppressed the albumin-induced ER stress and apoptosis in tubular epithelial cells. Method: HK-2 cells, a proximal tubular cell line, were used. Protein expressions were measured by Western blot analysis. Intracellular ROS and apoptosis were analyzed by flow cytometry. Results: Albumin-induced PPAR-γ expression and PPAR-γ inhibitor (GW9662) suppressed the albumin-induced ER stress. c-Src kinase inhibitor and GW9662 reduced the albumin-induced PPAR-γ and mTOR, respectively. Metformin (the best known clinical activator of AMPK) and another AMPK activator (AICAR) suppressed the albumin-induced ER stress via inhibition of ROS through induction of endogenous antioxidant thioredoxin. AMPK inhibitor blocked the effect of metformin and AICAR. Our in vivo animal study showed that metformin reduced the renal cortical expression of ER stress protein (GRP78) in protein-overload proteinuria rats. Metformin also reduced the caspase 3-dependent apoptosis induced by albumin. Conclusion: PPAR-γ was involved in albumin-induced ER stress as an upstream signaling molecule between c-Src kinase and mTOR. AMPK activation might be beneficial in attenuating the tubulointerstitial injury induced by albumin.
Early Development of Secondary Hyperparathyroidism following Renal Transplantation
Authors: Isaksson Elin , Sterner Gunnar
Published: October 2012

Background: Optimal levels of intact parathyroid hormone (iPTH) in the post-transplant period are not known due to insufficient data. Therefore, we aimed to describe secondary hyperparathyroidism (SHPT) in Swedish renal transplant (RT) recipients and also report events of fractures and vascular events potentially related to levels of iPTH. Methods: Medical charts from 132 RT recipients were retrospectively reviewed. Laboratory/clinical data were obtained at regular points up to 12 months post RT. Three groups were created based on pre-RT levels of iPTH based on KDOQI recommended levels of iPTH in CKD 5. Results: One year post RT 69% had iPTH above levels recommended by KDOQI. A multiple regression analysis showed a strong relation between pre-transplant iPTH levels and iPTH levels at 12 months (β coefficient = 0.323, p < 0.001). Patients with low pre-transplant levels of iPTH had a higher rate of fractures during follow up compared to patients with higher pre-transplant levels of iPTH had a higher rate of fratures during follow-up compared to patients with higher pre-transplant levels of iPTH (p = 0.034). Conclusion: SHPT is common in Swedish RT recipients. Pre-transplant regulation of SHPT is of great importance to determine outcome post RT. Low levels of iPTH in the pre-transplant period could be associated with a high risk of fracture in the first post-transplant year.
Early Abdominal Ectopic Pregnancies: A Systematic Review of the Literature
Authors: Poole Aaron , Haas David , Magann Everett F.
Published: October 2012

Objective: To define abdominal ectopic pregnancy outcomes by both location and treatment. Methods: Literature review of abdominal pregnancies from 1965 to August of 2009. Ectopic pregnancy exclusions were interstitial, tubal, cervical, ovarian, or those beyond 20 weeks at diagnosis/treatment. Results: There were 511 cases identified with 225 meeting the inclusion criteria. There were 7 maternal deaths (3.0%) with 18 (8%) of the early abdominal ectopic pregnancies occurring with an intrauterine device in place. Mean gestational age at the time of treatment was 10 weeks 0 days and mean maternal age was 29.7 years. The average blood loss associated with treatment was 1,450 ml. The top three sites of early abdominal ectopic pregnancies were pouches around the uterus (24.3%), serosal surface of the uterus and tubes (23.9%), and multiple sites (12.8%). Primary surgical management was performed in 208 cases (87.8%). Nonsurgical adjuvant or primary therapy included intramuscular methotrexate, intralesional methotrexate, intracardiac KCl, and artery embolization. Conclusion: Abdominal pregnancies should be considered in all patients until an intrauterine location can be confirmed. Understanding treatment options by pregnancy location may be helpful in the management of this potentially life-threatening condition.
Infection-Related Cancers in Sub-Saharan Africa: A Paradigm for Cancer Prevention and Control
Authors: Okuku Fred , Omoding Abrahams , Walusansa Victoria , Origa Martin , Mutungi Gerald , Orem Jackson
Published: October 2012

There is much commonality between chronic noncommunicable and communicable diseases which is best exemplified by cancers of infectious origin. It provides the perfect opportunity for harnessing the advances that have been made in the control of communicable diseases to attempt the control of noncommunicable diseases. There are possibilities at various levels of intervention, at primary, secondary and tertiary levels, which fit well within a well-planned national cancer control strategy. Prevention should proceed through steps of disruption of transmission, improvement in disease recognition and diagnosis, as well as through prompt effective treatment. This principle should work for both infection and the resultant cancer. Research is very important in understanding how best to use the available knowledge and how best to sequentially implement strategies. Finally, policies that acknowledge infection-related cancers as a major problem in the region should be in place.
Characteristics of Methylcellulose Acid Gel Lesions Created in Human and Bovine Enamel
Authors: Lippert F. , Butler A. , Lynch R.J.M.
Published: October 2012

Acid gel caries lesions were created in 3,100 human and bovine enamel specimens and studied with transverse microradiography. Small, significant differences were found. Human enamel lesions were found to be less demineralized, shallower, had a higher ratio of integrated mineral loss (ΔZ) to lesion depth (L), a lower degree of surface zone mineralization (SZmax) and showed less variability than those in bovine enamel. SZmax showed the highest variability. Between tissues, L differed the most, ΔZ the least. Biological variation within bovine enamel is perhaps not only bigger than previously assumed, it may also overshadow any structural and chemical differences between tissues.
Sphingoid Bases Are Taken Up by Escherichia coli and Staphylococcus aureus and Induce Ultrastructural Damage
Authors: Fischer C.L. , Walters K.S. , Drake D.R. , Blanchette D.R. , Dawson D.V. , Brogden K.A. , Wertz P.W.
Published: October 2012

Sphingoid bases found in the outer layers of the skin exhibit antimicrobial activity against gram-positive and gram-negative bacteria. We investigated the uptake of several sphingoid bases by Escherichia coli and Staphylococcus aureus, and assessed subsequent ultrastructural damage. E. coli and S. aureus were incubated with d-sphingosine, dihydrosphingosine, or phytosphingosine at ten times their MIC for 0.5 and 4 h, respectively, to kill 50% of viable bacteria. Treated bacterial cells were immediately prepared for SEM, TEM, and analyzed for lipid content by QTLC. E. coli and S. aureus treated with sphingoid bases were distorted and their surfaces were concave and rugate. Significant differences were observed in the visual surface area relative to controls for both E. coli and S. aureus when treated with dihydrosphingosine and sphingosine (p < 0.0001) but not phytosphingosine. While sphingoid base-treated S. aureus exhibited disruption and loss of cell wall and membrane, E. coli cytoplasmic membranes appeared intact and the outer envelope uncompromised. Both E. coli and S. aureus cells contained unique internal inclusion bodies, likely associated with cell death. QTLC demonstrated extensive uptake of sphingoid bases by the bacteria. Hence, sphingoid bases induce both extracellular and intracellular damage and cause intracellular inclusions that may reflect lipid uptake.
Topical Treatment with Basic Fibroblast Growth Factor Promotes Wound Healing and Barrier Recovery Induced by Skin Abrasion
Authors: Nakamizo S. , Egawa G. , Doi H. , Natsuaki Y. , Miyachi Y. , Kabashima K.
Published: October 2012

It has been reported that basic fibroblast growth factor (bFGF) promotes the healing of skin ulceration by inducing fibroblast proliferation, yet the role of bFGF on epidermal barrier function, especially from the perspective of scratch-induced skin abrasion, remains unknown. To this end, we initially developed an epidermal abrasion mouse model induced by scratching with a stainless-steel wire brush, and examined the effects of bFGF on the wound healing induced by skin abrasion. This procedure induced a significant elevation of transepidermal water loss (TEWL) in a scratch-count-dependent manner. This elevated TEWL was significantly decreased following topical application of bFGF to the skin. In addition, bFGF increased the expression of Ki67 in keratinocytes following mechanical scratching. These results suggest that bFGF enhances keratinocyte proliferation, which, in turn, repairs the skin barrier disruption and wounds caused by scratching in mice. Consistently, bFGF stimulated proliferation of normal human epidermal keratinocytes (NHEK). Intriguingly, the effect of bFGF and other growth factors on NHEK proliferation was additive. However, high cell density diminished the effect of bFGF on NHEK proliferation. This particular result can be explained by our observation that FGF receptor mRNA expression in NHEK was low under conditions of high cell density. Our findings suggest that bFGF stimulates keratinocyte proliferation, especially in a lower cell density environment, to repair skin wound in accord with skin barrier recovery.
The K-P Algorithm: A New First-Trimester Growth Model – Comparison with Other Formulae and Correlations with Recorded Embryonic Lengths
Authors: Mongelli M. , Riemke J. , Casikar I. , Alhamdan D. , Benzie R. , Condous G.
Published: October 2012

Objective: To generate and validate individually fitted first-trimester growth curves using a new growth model. Secondary aims were to compare this new model with actual recorded embryonic measurements and validate its predictive accuracy. Methods: A prospective study of women presenting to the Early Pregnancy Unit in the first trimester. Women with viable singleton pregnancies at the end of the first trimester who had had at least two crown-rump length (CRL) measurements were selected. An individual power function of CRL was derived from serial CRL measurements. Individual curves were fitted using computer software to estimate a dating adjustment factor (‘k’), and a growth coefficient (‘P’) for each case. The predictive accuracy of the growth curves was then tested in a validation subset of the population that had a third CRL measurement. The population average curve from the developed model was also extrapolated to day 27 menstrual age (Carnegie stage 6), day 30 menstrual age (Carnegie stage 7) and day 84 menstrual age, and values were compared to previously reported measurements. Results: 326 viable pregnancies were selected for CRL growth curve development. The mean time interval between CRL measurements was 20.5 days (range 2–44). The mean value for ‘P’ was 2.058, and for ‘k’ 24.6. Testing the model on a subset of 81 cases showed that the average error in predicting a third CRL measurement was 1% (SD 9.1%). Conclusions: These new, individually fitted growth curves for the first trimester correlate more closely with the recorded embryonic lengths than other standards.
Spermatic Cord Sarcoma: Our Experience and Review of the Literature
Authors: Guttilla Andrea , Crestani Alessandro , Zattoni Fabio , Secco Silvia , Iafrate Massimo , Vianello Fabio , Valotto Claudio , Prayer-Galetti Tommaso , Zattoni Filiberto
Published: October 2012

Introduction: Spermatic cord tumors represent 4% of scrotal tumors. The most common neoplasms are lipomas. Spermatic cord sarcomas (SCS) of the genitourinary tract account for 2% of all urological tumors. Herein we presented our experience in the treatment of these tumors and a review of the literature. Patients and Methods: A review of the literature was performed using the Medline database with no restriction on language and date of published papers. The literature search used the following terms: epidemiology, surgery, chemotherapy, radiotherapy and spermatic cord sarcomas. Four cases treated from December 2009 to May 2010 are described. Results: All patients were treated with radical orchiectomy. The final pathological report showed different types of sarcomas. Two of the patients were treated with adjuvant chemotherapy. 12 months after surgery, 2/4 patients were alive without signs of relapse. Conclusion: SCS are very rare tumors with a poor prognosis. SCS’s prognostic factors have been identified in grading, size, depth of invasion and surgical margin status. Age and performance status of the patient are however very important. Lymphatic and hematogenous dissemination is uncommon. Surgery is the most important treatment both in the first approach and in local relapse. The role of adjuvant chemotherapy and radiation therapy is still debated.
Emerging Therapies for Diabetic Nephropathy Patients: Beyond Blockade of the Renin-Angiotensin System
Authors: Tanios Bassem Y. , Ziyadeh Fuad N.
Published: October 2012

Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. The mainstay of treatment has been glycemic control and blood pressure lowering using agents blocking the renin-angiotensin system. Clinical trials are currently under way using novel agents for the treatment of patients with diabetic nephropathy. Promising agents emerging from some of the completed trials include pirfenidone and bardoxolone methyl, which have been shown in two recent randomized controlled trials in patients with diabetic nephropathy to result in an improved estimated glomerular filtration rate compared to placebo. Also, paricalcitol has been shown to decrease the urinary albumin-to-creatinine ratio, whereas sulodexide failed to do so in a large randomized double-blind placebo-controlled trial. Of note, pyridoxamine has also shown promise in the treatment of diabetic nephropathy if started early in the disease course. These preliminary trials have shown significant promise for managing patients with diabetic nephropathy, sparking active research in this field and providing the rationale for further clinical testing in long-term, hard-outcomes trials.
Tolerating Increases in the Serum Creatinine following Aggressive Treatment of Chronic Kidney Disease, Hypertension and Proteinuria: Pre-Renal Success
Authors: Hirsch Sheldon , Hirsch Jackie , Bhatt Udayan , Rovin Brad H.
Published: October 2012

Background: Blood pressure (BP) reduction in patients with chronic kidney disease (CKD), particularly with a renin-angiotensin system inhibitor (RASI), commonly leads to an initial decrease in glomerular filtration rate. The current clinical guideline, based on studies with single RASIs, is to tolerate an increase in the serum creatinine only up to 30%. This guideline has aptly guided CKD care for over a decade, but should be updated in the contemporary context of more aggressive RASI and diuretic use. Methods: This study is a retrospective review of 48 mostly African-American patients with CKD treated with multiple and/or high-dose renin-angiotensin system (RAS) inhibition and diuretics, targeting both low BP and reduction of urine protein. RASI was not reduced in response to initial increases in serum creatinine greater than 30%. Results: A clinically well-tolerated increase in serum creatinine over 30% during the first year occurred in 41% of the patients. Treatment was unaltered, and target goals for BP and urine protein were typically achieved. After the point of maximal serum creatinine in the first year, these patients had minimal progression of disease over the next 6 years, with a long-term estimated glomerular filtration rate slope of only –0.52 ml/min/year/1.73 m2. Only 25% progressed to end-stage renal disease or death. Conclusion: The 30% limitation to initial increases in the serum creatinine still pertains for single RASI at usual doses. However, favorable long-term outcomes suggest that initial increases over 30% should be tolerated in the context of dual goal-directed, more aggressive RASI and diuretic use.
Effects of Exercise Intervention on Vascular Risk Factors in Older Adults with Mild Cognitive Impairment: A Randomized Controlled Trial
Authors: Uemura Kazuki , Doi Takehiko , Shimada Hiroyuki , Makizako Hyuma , Yoshida Daisuke , Tsutsumimoto Kota , Anan Yuya , Suzuki Takao
Published: October 2012

Aims: The purpose of this study is to clarify the effects of exercise intervention on vascular risk factors in older adults with mild cognitive impairment (MCI). Methods: Community-dwelling older adults who met the definition of MCI using the Petersen criteria (n = 100; mean age = 75.3 years) were randomly allocated to the exercise (n = 50) or education control group (n = 50). Participants in the exercise group exercised under the supervision of physiotherapists for 90 min/day, 2 days/week, 80 times for 12 months. Anthropometric profiles, blood markers, blood pressure, and physical fitness (the 6-min walking test) were measured. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and TC/HDL-C risk ratio measurements were taken from blood samples. Results: The exercise group showed significantly reduced TC and TC/HDL-C risk ratio after training compared with baseline levels (p < 0.001, p = 0.004). However, no significant reduction was found for the control group (p = 0.09, p = 0.09). Physical fitness also significantly improved after exercise intervention compared with the control group (p < 0.0001). Conclusion: Exercise intervention was associated with positive changes in important vascular risk factors related to cognitive decline and vascular disease in older adults with MCI.
Renoprotection by Continuous Erythropoietin Receptor Activator in Puromycin Aminonucleoside-Induced Nephrotic Syndrome
Authors: Aizawa Ken , Takeda Satoshi , Tashiro Yoshihito , Yorozu Keigo , Hirata Michinori , Kanada Hirotaka , Moriguchi Yoshiyuki , Endo Koichi
Published: October 2012

Background/Aims: Recent studies have demonstrated that erythropoiesis-stimulating agents (ESAs) induce a tissue-protective effect in the kidney. In this study, we examined whether continuous erythropoietin receptor activator (CERA), a long-acting ESA, could prevent kidney injury, especially podocyte damage, in a rat model of nephrotic syndrome induced by puromycin aminonucleoside (PAN). Methods: Rats were injected with CERA (30 µg/kg) or vehicle 4 h before the injection of PAN (50 mg/kg). Renal function, kidney injury, and podocyte damage were assessed at 7 days. Results: The levels of proteinuria, BUN, and plasma creatinine significantly increased in rats with PAN-induced nephrosis. Treatment with CERA significantly prevented these deteriorations induced by PAN. Glomerular lesions, especially vacuolation of podocytes, and the increase of desmin expression in PAN-treated rats were significantly ameliorated by treatment with CERA. Treatment with CERA also significantly prevented the decrease in the protein productions of nephrin and podocin in the kidneys of PAN-treated rats. We found persistent activation of the Akt signaling pathway in the kidneys of CERA-treated rats. Conclusion: CERA could ameliorate renal dysfunction in PAN-induced nephrosis, which might be due to the amelioration of podocyte injury. CERA inhibited the depletion of nephrin and podocin, key components of the glomerular filtration barrier, and alleviated proteinuria. Activation of the Akt signaling pathway might be involved in the renoprotective effect of CERA
Methods of Administering Superimposed High-Frequency Jet Ventilation and the Associated Risk for Aspiration in a Model of Tracheal Bleeding
Authors: Nowak Andreas , Usichenko Taras , Wendt Michael , Klemm Eckart
Published: October 2012

Background: To determine the suitability of different superimposed high-frequency jet ventilation (SHFJV) application methods during tracheal bleeding. Objective: To determine the effect of SHFJV on the aspiration of blood during tracheal bleeding. Methods: A test lung was ventilated using SHFJV via a rigid endoscope, a jet laryngoscope and a 4-lumen jet catheter. Packed red blood cells (PRBCs) were injected into the artificial trachea caudally to the rigid endoscope and jet laryngoscope ventilation, and both caudally and cranially during ventilation via the 4-lumen jet catheter, and the migration of PRBCs during ventilation was studied using continuous video recording. Results: Migration of blood into the lower respiratory tract did not occur during SHFJV via the rigid endoscope and jet laryngoscope and via the 4-lumen jet catheter with the bleeding caudal to ventilation source. If the bleeding was cranial to the 4-lumen jet catheter ventilation, migration of blood into the lower respiratory tract was seen when reflux of blood reached the entrainment area. From this area, blood is transported within the jet stream into the lower respiratory tract. Conclusions: SHFJV protects the lower respiratory tract from blood aspiration in case of tracheal bleeding. During SHFJV via the 4-lumen jet catheter, aspiration of blood only occurs if bleeding is localized cranial to the 4-lumen jet catheter ventilation. In case of heavy tracheal bleeding, the jet sources should be positioned cranial to the site of bleeding.
Subablative Er:YAG Laser Effect on Enamel Demineralization
Authors: Liu Y. , Hsu C.-Y.S. , Teo C.M.J. , Teoh S.H.
Published: October 2012

Objectives: To characterize the cariostatic potential of a low-energy Er:YAG laser treatment. Methods: Twelve sound premolars were selected. Two 2 × 1 mm windows were created on each tooth and randomly assigned to L1 and L2 groups. Three sites in each window were chosen with the middle site as the control and the left and right ones receiving Er:YAG laser treatment of 5.1 J/cm2 (L1) or 2.0 J/cm2 (L2), respectively. The teeth were further subjected to 4-day pH cycling to create caries-like lesions. After mineral quantification using a micro-computed tomography scanner, the preventive effects (ΔML = mineral loss of the control area minus that of the lased area) of L1 and L2 treatments were calculated based on the difference in the gray value of the control and lased sites. Results: Significant inhibitory effects of L1 and L2 on enamel demineralization were demonstrated (both p ≤ 0.001), with the L1 treatment having a greater effect (45.2%) than the L2 treatment (25.2%, p = 0.004). Conclusions: Subablative low-energy Er:YAG laser irradiation can significantly prevent enamel demineralization potentially through the retardation of enamel diffusion. This study confirmed that high-energy laser treatment, which may damage the peripheral and underlying tissues, may not be needed for caries prevention.
Superparamagnetic Iron Oxide-Enhanced Magnetic Resonance Imaging in a Case of Spleen Hamartoma
Authors: Bulakci Mesut , Yilmaz Erdem , Yahyayev Aghakishi , Bulakci Betul Bozkurt , Yekeler Ensar
Published: October 2012

Objective: To emphasize the contribution of superparamagnetic iron oxide (SPIO) contrast agent in the diagnosis of the splenic hamartoma. Clinical Presentation and Intervention: A 63-year-old female was admitted to our hospital with diffuse abdominal pain. An ultrasound examination revealed a 5 × 4 cm solid lesion in the spleen. Dynamic gadolinium-enhanced magnetic resonance imaging (MRI) of the abdominal findings was consistent with a splenic hamartoma. SPIO-enhanced MRI was then performed and it confirmed the diagnosis. The lesion showed a decrease of signal intensity on T2-weighted images. Conclusion: This case showed that SPIO-enhanced MRI was useful for establishing a noninvasive diagnosis of the splenic hamartomas.
Pheochromocytoma Mimicking both Acute Coronary Syndrome and Sepsis: A Case Report
Authors: Lee Ting-Wei , Lin Ke-Hsun , Chang Chun-Jen , Lew Wei-Han , Lee Ting-I
Published: October 2012

Objective: To present an atypical manifestation in a patient with pheochromocytoma. Clinical Presentation and Intervention: A 48-year-old man presented with chest pain, fever and leukocytosis. Elevated cardiac biomarkers and diffuse ST-T abnormalities on electrocardiography suggested myocardial infarction. However, coronary angiography showed normal coronary arteries. Abdominal computed tomography revealed a left adrenal tumor of 6.7 × 6.8 cm. Paroxysmal fluctuation of blood pressure raised the suspicion of pheochromocytoma, which was further supported by elevated urine catecholamine levels. He underwent left adrenalectomy and pathological findings confirmed the diagnosis. Conclusion: Pheochromocytoma should be considered as part of the differential diagnosis in a patient with symptoms suggestive of both acute coronary syndrome and sepsis.
Dominant Expansion of a Cryptic Subclone with an Abnormal Karyotype in B Lymphoblastoid Cell Lines during Culture
Authors: Danjoh I. , Shirota R. , Hiroyama T. , Nakamura Y.
Published: October 2012

Although B lymphoblastoid cell lines (B-LCLs) are thought to maintain their original genomic structures during long-term culture, there has been considerable disagreement on the actual genomic stability of these cells. This study was initiated to determine whether B-LCLs develop cell populations with abnormal genomes during culture and to search for factors important to the maintenance of the original genome. We established continuous cultures of B-LCLs for more than 6 months and analyzed the cells using array-based comparative genome hybridization (CGH) analysis, conventional karyotyping and analysis of V(D)J recombination in the immunoglobulin (Ig) gene. We found that one B-LCL acquired an extra chromosome 4 without any other genomic rearrangements at passage 16 of continuous culture. At the Ig light- and heavy-chain loci, analysis of the major cell population showed a difference between cultures at early and later passages. Another aneuploid line was detected among B-LCLs established elsewhere and deposited previously into the RIKEN Cell Bank. Our findings indicate that some of the genomic rearrangements in B-LCLs are not caused by gradual accumulation of mutations and rearrangements during the B-LCL establishment processes, but rather as a result of a change in the cell population from clones with a normal genome to clones with de novo rearrangements. It is therefore feasible to maintain B-LCLs with a normal genomic structure by cell cloning or similar treatment.
Endoscopic versus Open Resection of Tuberculum Sellae Meningiomas: A Decision Analysis
Authors: Bohman Leif-Erik , Stein Sherman C. , Newman Jason G. , Palmer James N. , Adappa Nithin D. , Khan Aamir , Sitterley T.T. , Chang Diana , Lee John Y.K.
Published: October 2012

Background/Aims: Tuberculum sellae meningiomas (TSMs) are challenging tumors for surgical resection. Endoscopic endonasal (EE) approaches to these lesions have not been directly compared to open craniotomy in a controlled trial. Methods: We searched Medline and Embase online databases for English-language articles containing key words related to TSMs. Data were pooled, including 5 of our own patients reported here for the first time. Metaregression was used and a decision-analytical model was constructed to compare outcomes between open microsurgery and EE approaches. Results: The overall quality of life (QOL) was not significantly different between the approaches (p = 0.410); however, there were large differences in individual complication rates. The Monte Carlo simulation yielded an overall average QOL in craniotomy patients of 0.915 and in endoscopic patients of 0.952. Endoscopy had a higher CSF leak rate (26.8 vs. 3.5%, p < 0.001) but a lower rate of injury to the optic apparatus (1.4 vs. 9.2%, p < 0.001) compared with craniotomy. The 3-year recurrence rates were not statistically different (p = 0.529). Conclusion: EE resection of TSMs appears to be a comparable alternative to traditional open microsurgical resection with respect to overall QOL based on available publications. A meaningful comparison of recurrence rates will require a longer follow-up.