bluuebunny/crossref_metadata_2025 huggingface dataset:
Melanocyte-Stimulating Hormone Directly Enhances UV-Induced DNA Repair in Keratinocytes by a Xeroderma Pigmentosum Group A–Dependent Mechanism
Authors: Dong Liang , Wen Ji , Pier Eric , Zhang Xiao , Zhang Bo , Dong Fangzheng , Ziegler Nick , Mysz Margaret , Armenta Rafael , Cui Rutao
Published: April 2010

Melanocyte-stimulating hormone (MSH) reduces UV-induced DNA damage through the induction of pigmentation. In this study, we provide evidence that MSH also enhances DNA repair in skin keratinocytes by modulating the function of DNA repair molecules. Intracutaneous injection of MSH prevented UV-induced DNA damage in human and mouse skin independent of its effects on melanogenesis. In keratinocytes, MSH bound to the melanocyte melanocortin receptor type 1 and activated adenylate cyclase activity, which in turn activated Xeroderma pigmentosum group A (XPA)–binding protein 1 and induced nuclear translocation of XPA, a critical factor controlling nucleotide excision repair signaling pathways. Together, our findings reveal a novel pigmentation-independent mechanism that underlies MSH–mediated DNA repair following UVB irradiation. Cancer Res; 70(9); 3547–56. ©2010 AACR.
Pharmacokinetic Analysis and Phase 1 Study of MRX-1024 in Patients Treated with Radiation Therapy with or without Cisplatinum for Head and Neck Cancer
Authors: Hamstra Daniel A. , Eisbruch Avraham , Naidu Maddireddy U.R. , Ramana Gogula V. , Sunkara Prasad , Campbell Kathleen C.M. , Ross Brian D. , Rehemtulla Alnawaz
Published: April 2010

Purpose: A previous study reported radiation protection from mucosal injury with D-methionine (D-met) in preclinical evaluation; therefore, the pharmacokinetics, safety, and utility of D-met were evaluated clinically.

Experimental Design: The pharmacokinetics of D-met following oral administration of a bioavailable formulation (MRX-1024) was evaluated in normal volunteers. Subsequently, 25 patients were enrolled on a phase 1 study of MRX-1024 concurrent with radiation therapy (RT) with or without weekly cisplatinum. Toxicity and mucosal events were evaluated weekly.

Results: Oral MRX-1024 resulted in rapid and dose-dependent increases in plasma D-met concentrations with a half-life of 3 hours. When administered concurrent with RT without chemotherapy, it was associated with a modest increase in grade 2 (two of six patients) and grade 3 (one of six patients) emesis. In those treated with MRX-1024 along with RT and weekly cisplatinum, there was no appreciable increase in emesis. Overall, five patients withdrew from the study due to emesis (four grade 2 and one grade 3). Only one incidence of dose-limiting toxicity (grade 3 emesis) was identified in 25 patients (4%). Finally, in 18 evaluable patients treated with MRX-1024 at 100 mg/kg twice daily (BID), the incidence of severe (grade 3) oral mucositis was 6% (1 of 18) with no grade 4 mucositis.

Conclusions: There is a dose-dependent increase in D-met exposure following MRX-1024 administration at 50 and 100 mg/kg, and MRX-1024 is safe for use concurrent with combined radiation and chemotherapy. The observed rate of mucositis seems less than that for similar treatment regimens within the published literature. Clin Cancer Res; 16(9); 2666–76. ©2010 AACR.
EphA2 Targeted Chemotherapy Using an Antibody Drug Conjugate in Endometrial Carcinoma
Authors: Lee Jeong-Won , Stone Rebecca L. , Lee Sun Joo , Nam Eun Ji , Roh Ju-Won , Nick Alpa M. , Han Hee-Dong , Shahzad Mian M.K. , Kim Hye-Sun , Mangala Lingegowda S. , Jennings Nicholas B. , Mao Shenlan , Gooya John , Jackson Dowdy , Coleman Robert L. , Sood Anil K.
Published: April 2010

Purpose: EphA2 overexpression is frequently observed in endometrial cancers and is predictive of poor clinical outcome. Here, we use an antibody drug conjugate (MEDI-547) composed of a fully human monoclonal antibody against both human and murine EphA2 (1C1) and the tubulin polymerization inhibitor monomethylauristatin F.

Experimental Design: EphA2 expression was examined in endometrial cancer cell lines by Western blot. Specificity of MEDI-547 was examined by antibody degradation and internalization assays. Viability and apoptosis were investigated in endometrial cancer cell lines and orthotopic tumor models.

Results: EphA2 was expressed in the Hec-1A and Ishikawa cells but was absent in the SPEC-2 cells. Antibody degradation and internalization assays showed that the antibody drug conjugate decreased EphA2 protein levels and was internalized in EphA2-positive cells (Hec-1A and Ishikawa). Moreover, in vitro cytotoxicity and apoptosis assays showed that the antibody drug conjugate decreased viability and increased apoptosis of Hec-1A and Ishikawa cells. In vivo therapy experiments in mouse orthotopic models with this antibody drug conjugate resulted in 86% to 88% growth inhibition (P < 0.001) in the orthotopic Hec-1A and Ishikawa models compared with controls. Moreover, the mice treated with this antibody drug conjugate had a lower incidence of distant metastasis compared with controls. The antitumor effects of the therapy were related to decreased proliferation and increased apoptosis of tumor and associated endothelial cells.

Conclusions: The preclinical data for endometrial cancer treatment using MEDI-547 show substantial antitumor activity. Clin Cancer Res; 16(9); 2562–70. ©2010 AACR.
Differential Functions of Growth Factor Receptor–Bound Protein 7 (GRB7) and Its Variant GRB7v in Ovarian Carcinogenesis
Authors: Wang Yajun , Chan David W. , Liu Vincent W.S. , Chiu PM , Ngan Hextan Y.S.
Published: April 2010

Purpose: Aberrant overexpression of growth factor receptor–bound protein 7 (GRB7) and its variant GRB7v has been found in numerous human cancers. The goal of this study was to characterize the functions of GRB7 and GRB7v in the ovarian carcinogenesis and to investigate the differential roles of GRB7 and GRB7v in the modulation of signaling pathways.

Experimental Design: Quantitative reverse transcription–PCR, Western blot, and immunohistochemical analyses were used to evaluate the levels of GRB7 and GRB7v. The cellular localization, functions, and signaling pathways regulated by GRB7 and GRB7v were investigated by enforced expression of GRB7 and GRB7v.

Results: Quantitative reverse transcription–PCR and Western blot analyses showed that GRB7 and GRB7v were frequently upregulated in ovarian cancer samples. The overexpressed GRB7 (P = 0.009) and GRB7v (P = 0.017) were significantly correlated with high-grade ovarian cancer. Immunohistochemical analysis on ovarian cancer tissue array confirmed that the upregulated GRB7 was significantly correlated with high-grade ovarian cancer (P = 0.001). Confocal microscopy analysis showed that GRB7 and GRB7v predominately localized in cytoplasm of ovarian cancer cells, consistent with their roles as signaling adaptors. Enforced expression of GRB7 promoted cell proliferation, migration, and invasion, whereas GRB7v only increased cell proliferation and anchorage-independent growth ability. With the treatment of specific kinase inhibitors, we showed that both GRB7 and GRB7v promoted cell proliferation through activating extracellular signal-regulated kinase signaling, whereas GRB7 enhanced cell migration/invasion by activating c-Jun NH2 terminal kinase signaling.

Conclusions: Our studies implicate that the overexpressed GRB7 and GRB7v are associated with high-grade tumors and exert distinct tumorigenic functions through regulating different signaling pathways in ovarian cancer cells. Clin Cancer Res; 16(9); 2529–39. ©2010 AACR.
Neuropsychological Predictors of Dementia in a Three-Year Follow-Up Period: Data from the LADIS Study
Authors: Madureira Sofia , Verdelho Ana , Moleiro Carla , Ferro José M. , Erkinjuntti Timo , Jokinen Hanna , Pantoni Leonardo , Fazekas Franz , Van der Flier Wiesje , Visser Marieke , Waldemar Gunhild , Wallin Anders , Hennerici Michael , Inzitari Domenico
Published: April 2010

Background: White matter changes (WMC) are related to cognitive deficits and dementia. Our aim was to determine the extent to which the performance in neuropsychological tests would be able to predict the clinical diagnosis of dementia. Methods: The LADIS (Leukoaraiosis and Disability) is a prospective study that evaluates the impact of WMC on the transition of independent elderly to disability. The subjects were evaluated at baseline and yearly during 3 years with a comprehensive clinical, functional and neuropsychological protocol. At each visit, dementia was classified according to clinical criteria. The performance in the neuropsychological batteries was compared according to the clinical diagnosis of dementia. Results: From the initially enrolled 639 subjects, 480 were evaluated at year 3. Dementia was diagnosed in 90 participants. The demented subjects had worse performance in almost all the baseline cognitive tests. Using receiver operating characteristic curves, we found that the Vascular Dementia Assessment Scale (VADAS) battery had higher sensitivity and specificity rates (area under the curve = 82%) to identify dementia compared with the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale. Worse performance on baseline MMSE (β = 0.33; p < 0.001) and VADAS (β = –0.07; p = 0.02) were predictors of dementia (regression analyses). Conclusion: Performance on the MMSE and the VADAS battery were important predictors of dementia at a 3-year period.
Bioavailability of Vitamins E and C: Does Helicobacter pylori Infection Play a Role?
Authors: Naja Farah , Kreiger Nancy , Mckeown Eyssen Gail , Allard Johane
Published: April 2010

Background: While the association between bioavailability of vitamins E and C and Helicobacter pylori infection has been extensively researched in gastritis and gastric cancer patients, little is known about this relationship in asymptomatic adults. Aim: To investigate the effect of H. pylori infection on bioavailability of vitamins E and C in asymptomatic adults. Methods: Volunteers from the University of Toronto, aged 18–45 years, were screened, for their H. pylori infection status. H. pylori-negative (n = 32) and asymptomatic H. pylori-positive (n = 27) participants received vitamin C (500 mg) and vitamin E (400 IU) supplements daily for 28 days. Plasma vitamins C, E and thiols concentrations were assessed before (baseline) and after supplementation. Results: Postsupplementation plasma levels of vitamin C and E were significantly higher than presupplementation levels in both groups. Yet, changes in plasma vitamins E and C were not significantly different between the two groups [vitamin C (µmol/l): 13.97 ± 16.86 vs. 20.87 ± 27.66, p > 0.05; vitamin E (µmol/l): 15.52 ± 9.4 vs. 14.47 ± 15.77; p > 0.05 for H. pylori-negative and H. pylori-positive groups, respectively]. In addition, no significant difference was found in plasma thiols levels between groups (p > 0.05). Conclusion: These findings suggest that H. pylori does not influence antioxidants bioavailability in its asymptomatic stages of infection until a factor or combination of factors triggers the inflammation cascade which may lead to increased oxidative stress and possibly reduced bioavailability of vitamins E and C.
Treatment of Ureteral Lithiasis with Tamsulosin: Literature Review and Meta-Analysis
Authors: Arrabal-Martin Miguel , Valle-Diaz de la Guardia Francisco , Arrabal-Polo Miguel Angel , Palao-Yago Francisco , Mijan-Ortiz Jose Luis , Zuluaga-Gomez Armando
Published: April 2010

Objective: Ninety percent of ureteral calculi <4 mm are expelled over a period of 3 months; if they are >6 mm the elimination possibilities are reduced to 30%. Presently, investigations in the treatment of ureteral lithiasis have the objective of modifying ureter contractibility with the aid of calcium antagonist and α-blocking drugs. The objective of this study is to analyze the effect of tamsulosin in the treatment of the distal ureter lithiasis and to make a systematic analysis of the literature. Patients and Methods: In a prospective study 70 cases of distal ureter lithiasis were divided into 2 groups: group 1 = 35 cases treated with ibuprofen (600 mg/12 h) and 2,000 ml water/24 h with tramadol on demand, and group 2 = 35 cases with the same treatment as described before plus tamsulosin 0.4 mg/day over 3 weeks. The number of stone-free patients, time to expulsion and the necessity for analgesia were evaluated. A literature review (2002–2007) and meta-analysis of 11 studies was performed. Statistical analysis included relative risk (RR), number needed to treat (NNT) and χ2 test. Results: Group 1 reported 19 stone expulsions (54.3%) and group 2 30 expulsions [85.7%, χ2 = 8.23 (p < 0.01), RR = 1.58, NNT = 3 (95% CI 2–9)]. The mean time to expulsion was 14 days in group 1 and 8 days in group 2. No side effects were detected. Meta-analysis included 792 patients: 392 patients in group 1 and 400 patients in group 2. Group 1 reported 211 stone expulsions (53.8%) and group 2 reported 332 expulsions [83%, χ2 = 78.17 (p < 0.01), RR = 1.54, absolute benefit = 29.2% (95% CI 23–35.3%), NNT = 3 (95% CI 3–4)]. The mean time to expulsion was 9.45 days in group 1 and 6.07 days in group 2 treated with tamsulosin; a significant difference was observed in all studies. Conclusions: Tamsulosin increases the elimination of distal ureter lithiasis of <10 mm.
Comparison of Perimeatal-Based Flap and Tubularized Incised Plate Urethroplasty Combined with Single- or Double-Layer Dartos Flap in Distal Hypospadias
Authors: Yıldız Abdullah , Bakan Vedat
Published: April 2010

Introduction: To determine whether the Mathieu technique with a single de-epithelized dartos flap, tabularized incised plate urethroplasty (TIPU) with a single de-epithelized dartos flap, or TIPU with double de-epithelized dartos flaps is the more appropriate treatment for distal hypospadias in terms of fistula rates. Methods: We present 2 surgeons’ experiences with 95 cases of hypospadias repair using dartos flap neourethra covering. The study includes patients who underwent Mathieu and TIPU repair of hypospadias. They were divided into 3 groups: group 1 was treated with Mathieu urethroplasty with a single de-epithelized dartos flap; groups 2 and 3 were treated with a modified Snodgrass technique (group 2 with a single flap and group 3 with double flaps). Results: The results were quite successful, and indicated the superiority of the double de-epithelized dartos flaps (with no fistulas). Conclusion: Double dartos flaps that are rotated around the penis are more effective than a single flap for prevention of urethrocutaneous fistulas.
The Combination of Vein Grafting and Two Different Types of Corporeal Plication in Complex Curvature due to Peyronie’s Disease
Authors: Kayıgil Onder , Agras Koray , Aldemir Mustafa , Okulu Emrah
Published: April 2010

Introduction: This study aimed to investigate the surgical results of incision and vein grafting combined with two types of plication sutures, including Essed-Schroeder and longitudinal imbrication, to correct the cavernous sacculation in complex curvature resulting from Peyronie’s disease. Material and Methods: Between 2004 and 2008, 15 patients with complex curvature resulting from Peyronie’s disease were surgically treated. Essed-Schroeder plication and venous grafting were performed in 10 patients. Five of the 15 patients had cavernous sacculation, which was defined as albugineal elongation, except for the normally morphological cavernosal structure, which caused some degree of penile torsion beside the angulation. Surgery was used to establish sufficient cosmetic results by performing longitudinal imbrication on the cavernous sacculation on the same side as that of the Essed-Schroeder plication combined with venous grafting in these five patients. Results: Complete penile straightening was achieved in all the patients. Two patients (13.3%) reported penile shortening without showing dissatisfaction about it. One patient complained of anesthesia on part of the skin of the penile shaft. All the patients were satisfied with the final surgical results. Conclusions: A combination of the surgical methods might be necessary to correct the complex deformities due to Peyronie’s disease. Further studies with larger patient populations are needed to standardize these procedures.
Use of Memokath 051 Metallic Stent in the Management of Ureteral Strictures: A Single-Center Experience
Authors: Papadopoulos Georgios I. , Middela Seshikanth , Srirangam Shalom J. , Szczesniak Cezary A. , Rao Poduri N.
Published: April 2010

Introduction: Memokath 051® represents a nickel-titanium stent that has been used to treat patients with incurable ureteral strictures. In the current study we present our experience in using this technique. Materials and Methods: Between 2003 and 2008, 19 metallic stents were placed in 13 patients. All of them had been previously treated by using JJ stents or dilatation. The etiology was benign in 10, while in 3 patients malignancy was involved. The mean age was 60.7 years. Mean stricture length was 3.2 cm while the median stent length was 6 cm. No severe complications were noticed postoperatively. Mean follow-up was 14.3 months. Results: Six patients (46%) experienced a satisfactory result after first insertion. Stent migration was observed in 6 patients and in 3 it was replaced successfully. One patient was offered a simple nephrectomy due to a poorly functioning kidney. Eventually, 10 of 13 patients (77%) had a successful outcome after the final stent insertion. Conclusion: Memokath stents suggest a possible alternative in treating chronic/recurrent ureteral strictures. Their most important disadvantage seems to be migration. Their role in endourological practice remains to be validated.
Sirolimus-Based Immunosuppression in Kidney Transplantation for Type 2 Diabetic Nephropathy
Authors: Veroux M. , Corona D. , Giuffrida G. , Gagliano M. , Vizcarra D. , Tallarita T. , Zerbo D. , Giaquinta A. , Sorbello M. , Macarone M. , Veroux P.
Published: April 2010

Introduction: Kidney transplantation is the best replacement therapy of type 2 diabetic patients and recently similar graft and patient survival between diabetic and nondiabetic recipients has been reported. However, standard immunosuppressive protocols are lacking. We present our experience with sirolimus-based immunosuppression in a population of 24 type 2 diabetic patients who underwent a kidney transplantation. Patients and Methods: From January 2001 to December 2006, 396 kidney transplantations were performed. Twenty-four patients had type 2 diabetes mellitus as a cause of end-stage renal disease. They were randomized in two groups: thirteen patients (group A) received an immunosuppressive treatment with sirolimus, low-dose tacrolimus and steroids, while 11 patients (group B) received sirolimus, mycophenolate mofetil and steroids. Results: Clinical characteristics were similar between the two groups. A slightly better kidney functionality was observed in group B patients. There were neither acute rejection episodes nor severe infectious complications in both groups. One patient in each group underwent a foot amputation. Graft and patient survival was 100% for both groups at a median follow-up of 29 months. Conclusions: Sirolimus-based immunosuppression is safe and efficacious in type 2 diabetic patients who underwent a kidney transplantation, allowing a better glucose metabolism control.
Percutaneous Adrenal Biopsy for Indeterminate Adrenal Lesion: Complications and Diagnostic Accuracy
Authors: Osman Yasser , El-Mekresh Mohsen , Gomha Abdul-Monem , Mohsen Tarek , Taha Noheir , Hussein Naser , Eraky Ibrahim
Published: April 2010

Purpose: To critically analyze the role, accuracy and safety of percutaneous adrenal biopsy for indeterminate adrenal lesions. Materials and Methods: Adrenal biopsies were performed in 15 among 214 patients (7%) diagnosed with adrenal masses being indeterminate on preoperative imaging. Definitive histopathology was obtained in all and overall sensitivity and negative predictive value were calculated. Safety of the procedure was reported. Results: The study included 8 male and 7 female patients with a mean age of 33.3 ± 20.3 years (range 7–65). Biopsy was carried out under computed tomography and ultrasound guidance in 12 and 3 patients, respectively. There were 2 nonrepresentative biopsies that were proved to be adrenocortical carcinoma and myelolipoma after adrenalectomy. Results of biopsy in the remaining 13 patients provided accurate diagnosis as proved by definitive histopathology in all but 2 in whom the final diagnosis was established as adrenocortical carcinoma while biopsy was paraganglioma in one and cortical adenoma in the other. Overall sensitivity and negative predictive value of adrenal biopsy was 73.3 and 60%, respectively. Apart from two mild hypertensive episodes following silent pheochromocytoma biopsy, no complications were reported. Conclusions: Percutaneous biopsy is a safe procedure for the diagnosis of pathologic conditions of the adrenal gland with a reasonable diagnostic aid.
Apoptotic Action of Botulinum Toxin on Detrusor Muscle in Rats
Authors: Watanabe Takeshi , Masago Toshihiko , Miyagawa Ikuo
Published: April 2010

Aims: To examine botulinum toxin A (BTX-A)-induced apoptosis in the detrusor muscle in male rats. Methods: The bladder wall and prostate in adult male Sprague-Dawley rats were injected with BTX-A (10 U at each site). Tissues were harvested after 2 weeks, then the effects of BTX-A on proliferative and apoptotic indices were determined using proliferative cell nuclear antigen and TUNEL staining, respectively. In addition, real-time polymerase chain reaction was used to measure mRNA expressions of the apoptosis-related gene, bcl-2, and BAX in detrusor muscle. Results: Although bladder weight was significantly increased in the BTX-A group compared to controls, no significant changes in prostate weight were identified. While significant increases in proliferative cells were apparent in the vesical mucosa after staining, no significant changes were noted in apoptotic or proliferative cells in detrusor muscle or prostate. In addition, no significant changes between the BTX-A group and controls were seen for mRNA expressions of bcl-2/β-actin or BAX/β-actin in detrusor muscle. Conclusions: The lack of significant changes in cellular dynamics of the detrusor muscle in the current study suggests that BTX-A injection into detrusor muscle for overactive bladder may not induce bladder atrophy.
Voiding Dysfunction due to Chronic Viral Encephalitis in a Young Woman
Authors: Abdel Hafez A.A.R. , Ali Salah E. , Rohrmann D. , Jakse G.
Published: April 2010

We record a case of a 37-year-old female with acute viral encephalitis, frequency and urgency incontinence. Video urodynamics showed small bladder capacity, sensory urgency, high residual urine and a Christmas tree appearance of the bladder. MRI showed inflammation and edema in the area of the thalamus and internal capsule in the early stage, then cavitation and gliosis in the same regions in the late stage.
Variability of Creatinine Measurements in Clinical Laboratories: Results from the CRIC Study
Authors: Joffe Marshall , Hsu Chi-yuan , Feldman Harold I. , Weir Matthew , Landis J.R. , Hamm L. Lee
Published: April 2010

Objectives: Estimating equations using serum creatinine (SCr) are often used to assess glomerular filtration rate (GFR). Such creatinine (Cr)-based formulae may produce biased estimates of GFR when using Cr measurements that have not been calibrated to reference laboratories. In this paper, we sought to examine the degree of this variation in Cr assays in several laboratories associated with academic medical centers affiliated with the Chronic Renal Insufficiency Cohort (CRIC) Study; to consider how best to correct for this variation, and to quantify the impact of such corrections on eligibility for participation in CRIC. Variability of Cr is of particular concern in the conduct of CRIC, a large multicenter study of subjects with chronic renal disease, because eligibility for the study depends on Cr-based assessment of GFR. Methods: A library of 5 large volume plasma specimens from apheresis patients was assembled, representing levels of plasma Cr from 0.8 to 2.4 mg/dl. Samples from this library were used for measurement of Cr at each of the 14 CRIC laboratories repetitively over time. We used graphical displays and linear regression methods to examine the variability in Cr, and used linear regression to develop calibration equations. We also examined the impact of the various calibration equations on the proportion of subjects screened as potential participants who were actually eligible for the study. Results: There was substantial variability in Cr assays across laboratories and over time. We developed calibration equations for each laboratory; these equations varied substantially among laboratories and somewhat over time in some laboratories. The laboratory site contributed the most to variability (51% of the variance unexplained by the specimen) and variation with time accounted for another 15%. In some laboratories, calibration equations resulted in differences in eligibility for CRIC of as much as 20%. Conclusions: The substantial variability in SCr assays across laboratories necessitates calibration of SCr measures to a common standard. Failing to do so may substantially affect study eligibility and clinical interpretations when they are determined by Cr-based estimates of GFR.
Obesity-Related Renal Injury in Childhood
Authors: Savino Alessandra , Pelliccia Piernicola , Chiarelli Francesco , Mohn Angelika
Published: April 2010

A significant increase in the prevalence of end-stage renal disease (ESRD) has been reported over the last three decades, paralleling the increasing prevalence of obesity and insulin resistance, also in the pediatric population. Overweight, obesity and the metabolic syndrome, which frequently coexist, contribute substantially to cardiovascular disease and ESRD. A higher body mass index, the presence of type 2 diabetes, hypertension and, of particular importance, reduced insulin sensitivity (IS), have recently emerged as strong independent risk factors for chronic kidney disease and ESRD. Of particular concern, the long-term cardiovascular impact of obesity, although deferred to adult life, has its origins in childhood. Clustering of cardiovascular risk factors is seen in children and adolescents with the highest degree of reduced IS, suggesting that adult consequences of obesity on target organs, including the kidney, are more likely to develop in these young people. This review will discuss the association between obesity and the risk of kidney disease, focusing on the way in which obesity and its metabolic complications may lead to renal involvement and injury, with particular regard to childhood. It is beyond the scope of this article to examine kidney disease as a component of syndromes that result in obesity in childhood.
Retinol-Binding Protein 4 Levels in Obese Children and Adolescents with Glucose Intolerance
Authors: Yeste D. , Vendrell J. , Tomasini R. , Gallart L.L. , Clemente M. , Simón I. , Albisu M. , Gussinyé M. , Audi L. , Carrascosa A.
Published: April 2010

Background: Retinol-binding protein 4 (RBP4) is known to be involved in obesity-associated insulin resistance. Aims: To study the relationships between the degree of adiposity, insulin resistance indices, plasma lipids, inflammatory parameters, glucose intolerance (GI) status and plasma RBP4 levels in obese children and adolescents. Patients and Methods: Prospective study comprising 199 obese patients (95 boys) aged 8–16 years (11.8 ± 1.9). Fifty-three subjects (23 boys) of similar mean age, 11.3 ± 2.1 years, served as controls. BMI, waist and hip circumferences, plasma lipids, and inflammatory parameters were measured and patients underwent an oral glucose tolerance test. Plasma RBP4 levels were determined by nephelometry. Results: Plasma RBP4 levels (pg/ml) in obese patients with GI (n = 15) were higher (45.0 ± 14.1) compared with those of obese patients without GI (35.9 ± 11.7, p = 0.02; n = 184) and controls (31.5 ± 12.3, p = 0.04) in a generalized linear model adjusted for age, sex, BMI and pubertal status. A negative correlation was found between the skeletal muscle insulin resistance index and RBP4; positive correlations were found between the RBP4 and BMI Z-score (r = 0.213, p < 0.001), waist circumferences (r = 0.135, p < 0.05), plasma triglycerides (r = 0.187, p = 0.005) and apolipoprotein B (0.187, p = 0.007). Conclusions: Our results suggest a direct relationship between circulating insulin and RBP4 levels, which indicates that this protein might contribute to the development of muscle insulin resistance.
Gender Dimorphic Associations between N-Terminal Pro-Brain Natriuretic Peptide, Body Mass Index and Blood Pressure in Children and Adolescents
Authors: Pervanidou Panagiota , Akalestos Athanassios , Sakka Sophia , Kanaka-Gantenbein Christina , Papassotiriou Ioannis , Chrousos George P.
Published: April 2010

Background: Obesity and hypertension are often comorbid, but the pathophysiologic mechanisms that link them are not fully understood. Natriuretic peptides might play a role in this association. The majority of studies show lower brain natriuretic peptide (BNP) concentrations as well as lower concentrations of the N-terminal of the prohormone (NT-proBNP) in obese than normal body mass index (BMI) adults and higher BNP concentrations in hypertensive than in normotensive individuals. In children, there are no studies examining the relations between NT-proBNP, BMI and blood pressure. Materials and Methods: Ninety-six children, 24 obese/25 normal BMI boys, and 23 obese/24 normal BMI girls, aged 10–16 years, were studied. Plasma NT-proBNP was measured using electrochemiluminescence. Results: In males, NT-proBNP concentrations were lower in the obese than the normal BMI group but higher in the obese hypertensive than the obese normotensive group (p = 0.04). In addition, a significant positive correlation was noted between plasma NT-proBNP and blood pressure (p = 0.03) only in obese males. In females, no correlations were detected between NT-proBNP, BMI and systolic or diastolic blood pressure. Conclusions: Longitudinal studies are needed to define the role of NT-proBNP as a screening biomarker in obese children, particularly males, to determine their risk for developing arterial hypertension.
Functional Characterization of Vasopressin Receptor 2 Mutations Causing Partial and Complete Congenital Nephrogenic Diabetes Insipidus in Thai Families
Authors: Sahakitrungruang Taninee , Tee Meng Kian , Rattanachartnarong Natthakorn , Shotelersuk Vorasuk , Suphapeetiporn Kanya , Miller Walter L.
Published: April 2010

Background:AVPR2 mutations cause most cases of nephrogenic diabetes insipidus (NDI); 211 AVPR2 mutations have been described, but only 7 are described causing partial NDI. Methods: Two unrelated Thai boys had polyuria and polydipsia in infancy but had normal electrolytes and serum osmolality at 2 years of age. Patient 1 could not concentrate his urine in response to water deprivation or 1-desamino-8-D-arginine vasopressin (DDAVP); patient 2 could concentrate to ∼600 mosm/l. The patients’ AVPR2 genes were sequenced and the identified mutations were re-created in AVPR2 cDNA expression vectors. AVPR2 activities were measured by stimulating transfected HEK293T cells with arginine vasopressin (AVP) or DDAVP, and assessing the resulting cAMP production by the activation of a luciferase reporter. Results: Patient 1 carried the previously described missense mutation R181C; patient 2 carried the novel missense mutation M311V. When transiently transfected into HEK293T cells, 6.8 × 10–12 M AVP induced the half-maximal response (EC50) of the wild-type, whereas the EC50 value for R181C was 5.9 × 10–9 M and for M311V was 2.6 × 10–10M. Responses to DDAVP were qualitatively similar but required 10-fold higher concentrations. Conclusion: The novel AVPR2 mutation M311V retains partial activity and results in a milder form of NDI.
Effects of Fat Supplementation on Postprandial GIP, GLP-1, Ghrelin and IGFBP-1 Levels: A Pilot Study on Adolescents with Type 1 Diabetes
Authors: Lodefalk M. , Carlsson-Skwirut C. , Holst J.J. , Åman J. , Bang P.
Published: April 2010

Aims: To compare the responses of GIP, GLP-1, ghrelin and IGFBP-1 between meals with different fat and energy content in adolescents with type 1 diabetes (T1DM) and to relate them to gastric emptying and glycaemia. Methods: On different days and in a random order, 7 adolescents with T1DM ingested a high- and low-fat meal (fat content: 38 and 2 g, energy content: 640 and 320 kcal, respectively). At normoglycaemia, the same prandial insulin dose was given at both meals and to all subjects. Postprandial blood samples were taken repeatedly over 4 hours. Gastric emptying was estimated by the paracetamol absorption method. Results: The area under the curve (AUC) for GIP0–240 min and for GLP-10–120 min was larger, but smaller for relative ghrelin0–240 min, after the high-fat meal (p = 0.002, 0.030 and 0.043, respectively). IGFBP-1 decreased significantly, but not differently, after the meals. Larger GLP-1 secretion correlated with slower gastric emptying (p = 0.029) and higher fasting ghrelin levels correlated with lower postprandial glycaemia (p = 0.007). Conclusion: In adolescents with T1DM, the postprandial responses of GIP, GLP-1 and ghrelin, but not that of IGFBP-1, depend more on meal size than on insulin.
Could Primary Hyperparathyroidism-Related Hypercalcemia Induce Hypercalcitoninemia?
Authors: Conte-Devolx B. , Morlet-Barla N. , Roux F. , Sebag F. , Henry J.F. , Niccoli P.
Published: April 2010

Aims: To determine if primary hyperparathyroidism (pHPT) per se may be responsible of hypercalcitoninemia. pHPT induces chronic hypercalcemia that should be expected to be a potential stimulatory pathway of calcitonin (CT) secretion and to cause hypercalcitoninemia. Method: We studied relationships between CT and pHPT-related chronic hypercalcemia in 122 patients aged 25–83 years who underwent parathyroid surgery. CT, calcium and PTH plasma levels were measured in all patients preoperatively. CT was measured by a current immunometric assay specific of mature CT monomer. Results: Of our 122 patients with pHPT-related hypercalcemia, 120 (98.4%) had normal CT values of less than 10 pg/ml and two (1.6%) exhibited a mildly increased CT above 10 pg/ml (11 and 12 pg/ml, respectively). We evidenced no relationship between CT and calcium level or PTH level. Conclusions: Chronic pHPT-related hypercalcemia per se does not cause hypercalcitoninemia. The finding of pHPT concomitant with high CT levels should raise suspicion of multiple endocrine neoplasia type 2A.
Effect of Treatment with Cyproterone Acetate on Uterine Bleeding at the Beginning of GnRH Analogue Therapy in Girls with Idiopathic Central Precocious Puberty
Authors: Seminara S. , Nanni L. , Generoso M. , Mirri S. , Leonardi V. , Slabadzianiuk T. , Vetrano M.L. , Buongiorno A. , Losi S. , Galluzzi F.
Published: April 2010

Background: The flare-up effect of GnRH analogues may cause transient uterine bleeding in girls affected with idiopathic central precocious puberty (ICPP). Aims: To assess the incidence of endometrial bleeding and verify whether pretreatment with cyproterone acetate could counteract it. Methods: Fifty-four girls affected by ICPP were divided into 2 groups. The first group (30 girls) was treated with triptorelin (3.75 mg, i.m. injection) every 28 days. The second group (24 girls) was treated with cyproterone acetate and triptorelin: cyproterone acetate (50 mg/m2) was administered every day for 8 weeks, and triptorelin (3.75 mg) was commenced 4 weeks after starting the cyproterone, then the intramuscular injection of triptorelin was repeated every 28 days. Results: Eight of 54 girls (15%) had mild withdrawal bleeding. There were no differences in incidence between groups 1 and 2. Girls with pubertal uterus at pelvic ultrasound had a higher incidence of uterine bleeding than girls with infantile uterus (25 vs. 7%), but this difference was not significant. Conclusion: Co-administration of cyproterone acetate and GnRH analogues does not significantly decrease the incidence of uterine bleeding.
Relationship of Muscle Function to Auxology in Preterm Born Children at the Age of Seven Years
Authors: Fricke Oliver , Roedder Daniela , Kribs Angela , Tutlewski Baerbel , von Kleist-Retzow Juergen-Christoph , Herkenrath Peter , Roth Bernhard , Schoenau Eckhard
Published: April 2010

Background/Aims: To characterize the relationship between muscle function and auxology in preterm born children. Methods: Forty-five preterm born children (birth weight ≤1,500 g with mean ± SD: 1,069 ± 281 g; median of gestational age: 29 weeks; 50% multiple births) were analyzed for auxological parameters (weight, height) and muscle function at the age of 7 years. Maximal isometric grip force (MIGF) and ground reaction forces of goal-directed counter-movement jumping were measured using the Preston dynamometer and the Leonardo force plate. MIGF, peak jump force (PJF), peak jump power (PJP) and the maximal velocity of take-off (Vmax) were analyzed for their relationship to perinatal risk factors and actual auxological parameters. Results: With reference to age, weight-standard deviation score (SDS) and height-SDS were lower than in the reference population. With reference to height, MIGF-SDS and PJP-SDS were lower than in reference individuals. Children with intraventricular hemorrhage (IVH) had lower PJP-SDS and Vmax than children without IVH. PJP-SDS was lower than PJF-SDS in children with IVH. Conclusion: Analyses showed a discrepancy between maximal force and power due to a decline of Vmax in children with IVH.
Ectopic Cushing’s Syndrome due to an Adrenal Ganglioneuroma
Authors: Corcuff Jean-Benoît , Deminiere Colette , Trouillas Jacqueline , Puel Olivier , Perel Yves , Barat Pascal
Published: April 2010

Background: Cushing’s syndrome (CS), rare in children, is due to pituitary or, less frequently, to adrenocortical tumors. Ectopic adrenocorticotropin (ACTH) secretion is exceptional. Method: A case of apparently ACTH-independent CS in a child is reported. Results: CS was due to an adrenal ganglioneuroma where neuroendocrine cells were immunopositive for ACTH responsible for the syndrome through a paracrine effect. Cortical cell hyperplasia was observed. Conclusion: Benign and differentiated tumors of the neural crest such as ganglioneuromas may be responsible for CS.
Autoimmune Thyroiditis, Pernicious Anaemia, Vitiligo and Scleroatrophic Lichen in a Boy with Short-Chain AcylCoA Dehydrogenase Deficiency
Authors: Stagi Stefano , Gasperini Serena , Manoni Cristina , Greco Antonella , Funghini Silvia , Donati Alice
Published: April 2010

Short-chain acylCoA dehydrogenase (SCAD) deficiency is a rare mitochondrial disorder involving the β-oxidation of fatty acylCoA compounds in chains of 4–6 carbons. Unlike other mitochondrial disorders, cases involving autoimmune diseases have not been described. We report a 15-year-old boy with SCAD deficiency who suffered from pernicious anaemia, vitiligo, scleroatrophic lichen and autoimmune thyroiditis. As has been reported in other mitochondrial disorders, we hypothesised that autoimmune diseases are also present in SCAD deficiency. Furthermore, we discuss the possible pathogenetic relationship between these diseases.
NREM Sleep Architecture and Relation to GH/IGF-1 Axis in Laron Syndrome
Authors: Verrillo Elisabetta , Bizzarri Carla , Cappa Marco , Bruni Oliviero , Pavone Martino , Cutrera Renato
Published: April 2010

Background: Laron syndrome (LS), known as growth hormone (GH) receptor deficiency, is a rare form of inherited GH resistance. Sleep disorders were described as a common feature of adult LS patients, while no data are available in children. Bi-directional interactions between human sleep and the somatotropic system were previously described, mainly between slow wave sleep and the nocturnal GH surge. Aims: To analyze the sleep macro- and microstructure in LS and to evaluate the influence of substitutive insulin-like growth factor 1 (IGF-1) therapy on it. Methods: Two young LS females underwent polysomnography; the first study was performed during IGF-1 therapy, the second one after a 3-month wash-out period. Results: In both patients, the sleep macrostructure showed that time in bed, sleep period time, total sleep time, sleep efficiency and rapid eye movement (REM) percentage were all increased during wash-out. The sleep microstructure (cyclic alternating pattern: CAP) showed significantly higher EEG slow oscillations (A1%) in NREM sleep, both during IGF-1 therapy and wash-out. Conclusions: Sleep macrostructure in LS children is slightly affected by substitutive IGF-1 therapy. Sleep microstructure shows an increase of A1%, probably related to abnormally high hypothalamic GHRH secretion, due to GH insensitivity.
What Have We Learnt from Experimental Renal Transplantation?
Authors: Brown K. , Phillips R.E. , Wong W.
Published: April 2010

The first series of kidney transplantation performed in the experimental setting over a century ago and its subsequent translation into humans has initiated a whole new facet of medical practice that has benefited a large number of patients with end-stage kidney and other organ failure. It has proven to be an indispensable tool in our quest to advance our skills and knowledge and continues to play a role in the development of better treatment protocols. Here, we discuss the advantages and drawbacks of this technique and use key examples to illustrate how it has been exploited to achieve our goals.
Serum and Urinary Biomarkers of Acute Kidney Injury
Authors: Lisowska-Myjak Barbara
Published: April 2010

Acute kidney injury (AKI) is a frequent clinical problem in critically ill patients and the associated mortality is high. Standard serum and urine biomarkers are insensitive and nonspecific for the detection of kidney injury in its early stages which limits the therapeutic options and may compromise the outcome. The study presents new candidates for biochemical markers of AKI, with potentially high sensitivity and specificity, causally related to its pathogenesis and development. Some of these biomarkers measured in serum or urine are well known in laboratory practice but have been used in other tests, while some novel biomarkers have been proposed as a result of experimental and clinical studies. In current clinical practice, identification and classification of AKI is based on elevations in serial serum creatinine concentrations, which are delayed and therefore unreliable in the acute setting. The most promising of the new serum AKI markers are cystatin C, neutrophil gelatinase-associated lipocalin and uric acid. Urinary AKI markers may be classified as enzymes released from damaged tubular cells (alkaline phosphatase, γ-glutamyl transpeptidase, alanine aminopeptidase, isoenzymes of glutathione transferase, N-acetyl-β-D-glucosaminidase), low-molecular-weight proteins (α1-microglobulin, β2-microglobulin, retinol-binding protein, cystatin C) and proteins specifically produced in the kidney and associated with the development of AKI [cysteine-rich protein 61, neutrophil gelatinase-associated lipocalin, kidney injury molecule 1, cytokines and chemokines (Gro-α, IL-18), and structural and functional proteins of renal tubules (F-actin, Na+/H+ exchange isoform 3)]. Based on the different expression of these markers, using a panel of serum and urine markers may potentially help to distinguish between various types of insults, establish the duration and severity of injury, predict the clinical outcome and help to monitor response to treatment in AKI.
Dialysis Prescription: A Modifiable Risk Factor for Chronic Kidney Disease Patients
Authors: Canaud Bernard , Wabel Peter , Tetta Ciro
Published: April 2010

Recent surveys of hemodialysis studies strongly support the fact that dialysis prescription is a modifiable risk factor. Six tracks to improve dialysis patient outcomes have been identified: change in vascular access option strategy and restricting catheter use; increasing time or frequency of dialysis sessions; assessment and management of fluid status; favoring removal of middle and large molecules by high-flux and convective clearance; considering ultrapurity of dialysis fluid purity as a new standard and a part of hemodialysis biocompatibility, and improving quality care and patient follow-up. By modifying dialysis prescription and by implementing a continuous quality assurance program it appears possible to improve dialysis patient survival.
Visual Assessment of Perfusion-Diffusion Mismatch Is Inadequate to Select Patients for Thrombolysis
Authors: Campbell Bruce C.V. , Christensen Søren , Foster Sarah J. , Desmond Patricia M. , Parsons Mark W. , Butcher Kenneth S. , Barber P. Alan , Levi Christopher R. , Bladin Christopher F. , Donnan Geoffrey A. , Davis Stephen M. ,   for the EPITHET Investigators
Published: April 2010

Background: For MR perfusion-diffusion mismatch to be clinically useful as a means of selecting patients for thrombolysis, it needs to occur in real time at the MRI console. Visual mismatch assessment has been used clinically and in trials but has not been systematically validated. We compared the accuracy of visually rating console-generated images with offline volumetric measurements using data from the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). Methods: Perfusion time-to-peak (TTP) and diffusion-weighted images (DWI) (as generated by commercial MRI console software) and Tmax perfusion maps (which required offline calculation) were visually rated. Perfusion-diffusion mismatch, defined as a ratio of perfusion:diffusion lesion volume of >1.2, was independently scored by 1 expert and 2 inexperienced raters blinded to calculated volumes and clinical information. Visual mismatch was compared with region-of-interest-based volumetric calculation, which was used as the gold standard. Results: Volumetric calculation demonstrated perfusion-diffusion mismatch in 85/99 patients. Visual TTP-DWI mismatch was correctly classified by the experienced rater in 82% of the cases (sensitivity: 0.86; specificity: 0.54) compared to 73% for the inexperienced raters (sensitivity: 0.75; specificity: 0.57). The interrater reliability for TTP-DWI mismatch was moderate (ĸ = 0.50). Visual Tmax-DWI mismatch performed better (agreement – 93 and 87%, sensitivity – 95 and 88%, specificity – 77 and 82% for the experienced and inexperienced raters, respectively). Conclusions: The assessment of visual TTP-DWI mismatch at the MRI console is insufficiently reliable for use in clinical trials. Differences in perfusion analysis technique and visual inaccuracies combine to make visual TTP-DWI mismatch substantially different to volumetric Tmax-DWI mismatch. Automated software that applies perfusion thresholds may improve the reproducibility of real-time mismatch assessment.