bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered de novo lipogenesis contributes to low adipose stores in cystic fibrosis mice
Authors: Bederman Ilya , Perez Aura , Henderson Leigh , Freedman Joshua A. , Poleman James , Guentert Dana , Ruhrkraut Nicholas , Drumm Mitchell L.
Published: June 2012

Cystic fibrosis (CF) mouse models exhibit exocrine pancreatic function, yet they do not develop adipose stores to the levels of non-CF mice. CF mice homozygous for the Cftr mutation (F508del) at 3 wk (postweaning) and 6 wk (young adult) of age had markedly less adipose tissue than non-CF mice. Food intake was markedly lower in 3-wk-old CF mice but normalized by 6 wk of age. Both 3- and 6-wk-old mice had dietary lipid absorption and fecal lipid excretion comparable to non-CF mice. Hepatic de novo lipogenesis (DNL), determined by2H incorporation, was reduced in CF mice. At 3 wk, F508del mice had significantly decreased DNL of palmitate and stearate, by 83% and 80%, respectively. By 6 wk, DNL rates in non-CF mice remained unchanged compared with 3-wk-old mice, while DNL rates of F508del mice were still reduced, by 33% and 40%, respectively. Adipose tissue fatty acid (FA) profiles were comparable in CF and non-CF mice, indicating that adipose differences are quantitative, not qualitative. A correspondingly lower content of2H-labeled FA was found in CF adipose tissue, consistent with reduced deposition of newly made hepatic triglycerides and/or decreased adipose tissue lipogenesis. Hepatic transcriptome analysis revealed lower mRNA expression from several genes involved in FA biosynthesis, suggesting downregulation of this pathway as a mechanism for the reduced lipogenesis. These novel data provide a model for altered lipid metabolism in CF, independent of malabsorption, and may partly explain the inability of pancreatic enzyme replacement therapy to completely restore normal body mass to CF patients.
Melanocortin receptor expression is associated with reduced CRP in response to resistance training
Authors: Henagan Tara M. , Forney Laura , Dietrich Marilyn A. , Harrell Brian R. , Stewart Laura K.
Published: June 2012

The existing paradigm of exercise-induced decreases in chronic inflammation focuses on the expression of inflammatory receptors on systemic monocytes in response to exercise training, with the role of anti-inflammatory receptors largely ignored. Our recent preliminary studies indicate that the anti-inflammatory melanocortin receptors (MCRs) may play a role in modulating exercise-induced decreases in chronic inflammation. Here, we present a study designed to determine the effect of intense, resistance exercise training on systemic monocyte MCR expression. Because low-grade chronic inflammation is associated with elevated cardiometabolic risk in healthy populations and exercise decreases chronic inflammation, we investigated the associations between systemic monocyte cell surface expression of MCRs and inflammatory markers as a possible mechanism for the beneficial anti-inflammatory effects of resistance training. To this end, the present study includes 40 adults (aged 19–27 yr) and implements a 12-wk periodized, intensive resistance training intervention. Melanocortin 1 and 3 receptor expression on systemic monocytes and inflammatory markers, including C-reactive protein (CRP), interleukin (IL)-6, IL-1β, and IL-10, were measured before and after the intervention. Resistance training significantly altered MCR systemic monocyte cell surface expression, had no chronic effects on IL-6, IL-1β, or IL-10 expression, but significantly decreased CRP levels from a moderate to a low cardiovascular disease risk category. More specifically, decreased melanocortin 3 receptor expression significantly correlated with decreased CRP, independent of changes in adiposity. These data suggest that the observed responses in MCR expression and decreases in cardiovascular disease risk in response to resistance training represent an important anti-inflammatory mechanism in regulating exercise-induced decreases in chronic inflammation that occur independent of chronic changes in systemic cytokines.
Noninvasive determination of local pulse wave velocity and wave intensity: changes with age and gender in the carotid and femoral arteries of healthy human
Authors: Borlotti Alessandra , Khir Ashraf W. , Rietzschel Ernst R. , De Buyzere Marc L. , Vermeersch Sebastian , Segers Patrick
Published: June 2012

We recently introduced noninvasive methods to assess local pulse wave velocity (PWV) and wave intensity (ndI) in arteries based on measurements of flow velocity (U) and diameter (D). Although the methods were validated in an experimental setting, clinical application remains lacking. The aim of this study was therefore to investigate the effect of age and gender on PWV andndI in the carotid and femoral arteries of an existing population. We measured D and U in the carotid and femoral arteries of 1,774 healthy subjects aged 35-55 yr, a subgroup of the Asklepios population. With the use of the lnDU-loop method, we calculated local PWV, which was used to determine arterial distensibility (nDs). We then used the new algorithm to determine maximum forward and backward wave intensities (ndI+maxandndI−min, respectively) and the reflection index (nRI). On average, PWV was higher, andnDs was lower in the femoral than at the carotid arteries. At the carotid artery, PWV increased with age, butnDs,ndI+max, andndI−mindecreased;nRI did not change with age. At the femoral artery, PWV was higher, andnDs was lower in male, but all parameters did not change significantly with age in both women and men. We conclude that the carotid artery is more affected by the aging process than the femoral artery, even in healthy subjects. The new techniques provide mechanical and hemodynamic parameters, requiring only D and U measurements, both of which can be acquired using ultrasound equipment widely available today, hence their advantage for potential use in the clinical setting.
Mechanisms of sympathetic regulation in orthostatic intolerance
Authors: Stewart Julian M.
Published: June 2012

Sympathetic circulatory control is key to the rapid cardiovascular adjustments that occur within seconds of standing upright (orthostasis) and which are required for bipedal stance. Indeed, patients with ineffective sympathetic adrenergic vasoconstriction rapidly develop orthostatic hypotension, prohibiting effective upright activities. One speaks of orthostatic intolerance (OI) when signs, such as hypotension, and symptoms, such as lightheadedness, occur when upright and are relieved by recumbence. The experience of transient mild OI is part of daily life. However, many people experience episodic acute OI as postural faint or chronic OI in the form of orthostatic tachycardia and orthostatic hypotension that significantly reduce the quality of life. Potential mechanisms for OI are discussed including forms of sympathetic hypofunction, forms of sympathetic hyperfunction, and OI that results from regional blood volume redistribution attributable to regional adrenergic hypofunction.
Motor cortex excitability does not increase during sustained cycling exercise to volitional exhaustion
Authors: Sidhu Simranjit K. , Cresswell Andrew G. , Carroll Timothy J.
Published: June 2012

The excitability of the motor cortex increases as fatigue develops during sustained single-joint contractions, but there are no previous reports on how corticospinal excitability is affected by sustained locomotor exercise. Here we addressed this issue by measuring spinal and cortical excitability changes during sustained cycling exercise. Vastus lateralis (VL) and rectus femoris (RF) muscle responses to transcranial magnetic stimulation of the motor cortex (motor evoked potentials, MEPs) and electrical stimulation of the descending tracts (cervicomedullary evoked potentials, CMEPs) were recorded every 3 min from nine subjects during 30 min of cycling at 75% of maximum workload (Wmax), and every minute during subsequent exercise at 105% of Wmax until subjective task failure. Responses were also measured during nonfatiguing control bouts at 80% and 110% of Wmax prior to sustained exercise. There were no significant changes in MEPs or CMEPs ( P > 0.05) during the sustained cycling exercise. These results suggest that, in contrast to sustained single-joint contractions, sustained cycling exercise does not increase the excitability of motor cortical neurons. The contrasting corticospinal responses to the two modes of exercise may be due to differences in their associated systemic physiological consequences.
Speed and incline during Thoroughbred horse racing: racehorse speed supports a metabolic power constraint to incline running but not to decline running
Authors: Self Z. T. , Spence A. J. , Wilson A. M.
Published: June 2012

We used a radio tracking system to examine the speed of 373 racehorses on different gradients on an undulating racecourse during 33 races, each lasting a few minutes. Horses show a speed detriment on inclines (0.68 m·s−1·1% gradient−1, r2= 0.97), the magnitude of which corresponds to trading off the metabolic cost (power) of height gain with the metabolic cost (power) of horizontal galloping. A similar relationship can be derived from published data for human runners. The horses, however, were also slower on the decline (−0.45 m·s−1·1% gradient−1, r2= 0.92). Human athletes run faster on a decline, which can be explained by the energy gained by the center of mass from height loss. This study has shown that horses go slower, which may be attributable to the anatomical simplicity of their front legs limiting weight support and stability when going downhill. These findings provide insight into limits to athletic performance in racehorses, which may be used to inform training regimens, as well as advancing knowledge from both veterinary and basic science perspectives.
Effect of regional lung inflation on ventilation heterogeneity at different length scales during mechanical ventilation of normal sheep lungs
Authors: Wellman Tyler J. , Winkler Tilo , Costa Eduardo L. V. , Musch Guido , Harris R. Scott , Venegas Jose G. , Vidal Melo Marcos F.
Published: June 2012

Heterogeneous, small-airway diameters and alveolar derecruitment in poorly aerated regions of normal lungs could produce ventilation heterogeneity at those anatomic levels. We modeled the washout kinetics of 13NN with positron emission tomography to examine how specific ventilation (sV̇) heterogeneity at different length scales is influenced by lung aeration. Three groups of anesthetized, supine sheep were studied: high tidal volume (Vt; 18.4 ± 4.2 ml/kg) and zero end-expiratory pressure (ZEEP) ( n = 6); low Vt (9.2 ± 1.0 ml/kg) and ZEEP ( n = 6); and low Vt (8.2 ± 0.2 ml/kg) and positive end-expiratory pressure (PEEP; 19 ± 1 cmH2O) ( n = 4). We quantified fractional gas content with transmission scans, and sV̇ with emission scans of infused 13NN-saline. Voxel 13NN-washout curves were fit with one- or two-compartment models to estimate sV̇. Total heterogeneity, measured as SD[log10(sV̇)], was divided into length-scale ranges by measuring changes in variance of log10(sV̇), resulting from progressive filtering of sV̇ images. High-Vt ZEEP showed higher sV̇ heterogeneity at <12- ( P < 0.01), 12- to 36- ( P < 0.01), and 36- to 60-mm ( P < 0.05) length scales compared with low-Vt PEEP, with low-Vt ZEEP in between. Increased heterogeneity was associated with the emergence of low sV̇ units in poorly aerated regions, with a high correlation ( r = 0.95, P < 0.001) between total heterogeneity and the fraction of lung with slow washout. Regional mean fractional gas content was inversely correlated with regional sV̇ heterogeneity at <12- ( r = −0.67), 12- to 36- ( r = −0.74), and >36-mm ( r = −0.72) length scales ( P < 0.001). We conclude that sV̇ heterogeneity at length scales <60 mm increases in poorly aerated regions of mechanically ventilated normal lungs, likely due to heterogeneous small-airway narrowing and alveolar derecruitment. PEEP reduces sV̇ heterogeneity by maintaining lung expansion and airway patency at those small length scales.
Vismodegib
Authors: Rudin Charles M.
Published: June 2012

Vismodegib (GDC-0449), an orally bioavailable small-molecule inhibitor of Hedgehog signaling, was recently approved by the U.S. Food and Drug Administration for the treatment of basal cell carcinoma that is either metastatic or locally advanced in patients who are not candidates for surgical resection or radiation. Given the absence of previously defined effective drug therapy for this disease, approval was granted primarily on the basis of outcome of a nonrandomized parallel cohort phase II study of 99 patients with advanced basal cell carcinoma, with a primary endpoint of objective response rate. Response rates of 30.3% and 42.9% were observed in metastatic and locally advanced cohorts in this study, respectively, associated with median progression-free survival in both cohorts of 9.5 months. Ongoing clinical investigations include evaluation of the potential efficacy of vismodegib in a variety of diseases and in combination with other agents. The mechanism of action, preclinical and clinical data, and potential utility in other disease contexts are reviewed here. Clin Cancer Res; 18(12); 3218–22. ©2012 AACR.
Mind the Gap: Potential for Rebounds during Antiangiogenic Treatment Breaks
Authors: Ebos John M.L. , Pili Roberto
Published: June 2012

VEGF pathway inhibitors have shown benefits in many cancers, yet many (often controversial) questions remain about whether vascular and tumor regrowth can occur when therapy is stopped. Marked increases in endothelial cell proliferation could play a role in putative rebounds, potentially influencing overall efficacy, dosing schedules, and presurgical intervention strategies. Clin Cancer Res; 18(14); 3719–21. ©2012 AACR.
How to Develop Treatments for Biologically Heterogeneous “Diseases”
Authors: Simon Richard M.
Published: June 2012

The standard paradigm for the design of phase III clinical trials is not suitable for evaluation of molecularly targeted treatments in biologically heterogeneous groups of patients. Here, we comment on alternative clinical trial designs and propose a prospective discovery/evaluation framework for using tumor genomics in the design of phase III trials. Clin Cancer Res; 18(15); 4001–3. ©2012 AACR.
Phase I Study of Pazopanib in Combination with Paclitaxel and Carboplatin Given Every 21 Days in Patients with Advanced Solid Tumors
Authors: Burris Howard A. , Dowlati Afshin , Moss Rebecca A. , Infante Jeffrey R. , Jones Suzanne F. , Spigel David R. , Levinson Kelly T. , Lindquist Diana , Gainer Shelby D. , Dar Mohammed M. , Suttle A. Benjamin , Ball Howard A. , Tan Antoinette R.
Published: June 2012

Several phase III trials have shown that the addition of an antiangiogenic agent to conventional chemotherapy can improve clinical benefit in patients with advanced solid tumors. This study examined the feasibility of combining pazopanib (Votrient), an oral antiangiogenic agent, with paclitaxel and carboplatin. This 3 + 3 dose-escalation phase I study evaluated the maximum-tolerated regimen (MTR) of daily pazopanib in combination with paclitaxel 175 mg/m2 and carboplatin [dosed at area under the curve (AUC) 5 or 6] given every 21 days in patients with advanced solid tumors. Plasma samples were collected to evaluate the effect of pazopanib on the pharmacokinetics of paclitaxel and carboplatin. Thirty-four patients were enrolled. The MTR was paclitaxel 175 mg/m2 and carboplatin AUC5 with pazopanib 200 mg. The most common dose-limiting toxicities were neutropenia and thrombocytopenia. Two patients with esophageal cancer had a complete response and four patients, one each with breast, small-cell lung, pancreatic, and gastroesophageal junction cancer, had partial responses. Pazopanib at 200 mg increased paclitaxel maximal concentration (Cmax) by 43% and carboplatin (AUC5 or AUC6) Cmax by 54%. Paclitaxel and carboplatin given every 21 days at standard doses was not feasible in combination with the monotherapy pazopanib dose of 800 mg daily because of dose-limiting myelosuppression. Coadministration of pazopanib increased exposure to paclitaxel and carboplatin and likely contributed to this effect. Given the antitumor activity of this regimen, further studies are underway to determine a clinically tolerable schedule of pazopanib with paclitaxel and carboplatin. Mol Cancer Ther; 11(8); 1820–8. ©2012 AACR.
miR-23a, a Critical Regulator of “migR”ation and Metastasis in Colorectal Cancer
Authors: Wang Zhiwei , Wei Wenyi , Sarkar Fazlul H.
Published: June 2012

Jahid and colleagues have shown that miR-23a promotes the transition from indolent to invasive colorectal cancer through inhibition of the MTSS1 tumor suppressor. This study reveals a novel role of miR-23a in the acceleration of colorectal cancer progression. Cancer Discov; 2(6); 489–91. ©2012 AACR

Commentary on Jahid et al., p. 540.
Tracking Evolution of BRCA1-Associated Breast Cancer
Authors: Jonkers Jos
Published: June 2012

Summary: Single-cell profiling and computational identification of evolutionary paths to BRCA1-associated tumorigenesis predict that PTEN loss and TP53 mutation precede loss of wild-type BRCA1 in basal-like and luminal tumors, respectively. Cancer Discov; 2(6); 486–8. ©2012 AACR.

Commentary on Martins et al., p. 503.
Frequency and Determinants of Using Pharmacological Enhancement in the Clinical Practice of In-Hospital Stroke Rehabilitation
Authors: Engelter Stefan T. , Urscheler Niklaus , Baronti Fabio , Vuadens Philippe , Koch Joachim , Frank Matthias , Disserens Karin , Jenni Walter
Published: June 2012

Background: Pharmacological enhancement in stroke rehabilitation (PESR) is promising. Data about its use in clinical practice are missing. Methods: In a prospective, explorative study of four rehabilitation centers, we systematically observed the frequency and determinants of using PESR in consecutive patients. PESR was defined as using agents potentially enhancing post-stroke recovery exclusively to aid rehabilitation without an established indication. Results: 257 (55.4%) of 464 patients had agents potentially enhancing recovery. Selective serotonin reuptake inhibitors (SSRI) (n = 125, 26.9%), levodopa (n = 114, 24.6%), serotonin-noradrenaline reuptake inhibitors (SNRI) (n = 52, 11.2%), and acetylcholinesterase inhibitors (n = 48, 10.3%) were used most often. SSRI in 102/125 patients and SNRI in 46/52 patients were mostly used for accompanying depressive symptoms. 159 (34.3%) patients had PESR (without an otherwise established indication). In PESR patients, levodopa (n = 102, 64.1%) was used most commonly. PESR was primarily used for aphasia (36.5%) and paresis (25.2%). PESR patients did not differ from non-PESR patients in age, gender and stroke type. However, the utilization rates of PESR differed significantly across centers (2, 4, 38 and 55%). Conclusion: SSRI and SNRI were predominately used for accompanying depression, while levodopa was nearly exclusively used to aid stroke rehabilitation in the absence of an otherwise established indication. The differences in utilization rates for PESR between centers suggest therapeutic uncertainty and indicate the need for additional studies.
Effect of Local Environment, Fibrin, and Basic Fibroblast Growth Factor Incorporation on a Canine Autologous Model of Bioengineered Cartilage Tissue
Authors: Morotomi T. , Wada M. , Uehara M. , Enjo M. , Isogai N.
Published: June 2012

We developed a technique to form a bioabsorbable synthetic polymer (polyglycolic acid, PGA) combined with a natural polymer (fibrin) to serve as a scaffold to help retain seeded cells and improve the seeding efficiency of chondrocytes in an implantable construct. This approach was evaluated in a canine autologous implant model of bioengineered cartilage. The implantation site (subcutaneous or intrafascial) and the use of basic fibroblast growth factor (b-FGF) were also evaluated with this system. The intrafascial implantation site yielded optimal results, especially when used in conjunction with fibrin and a b-FGF sustained-release system incorporated into the complex. A thicker, more sustained cartilagenous layer was formed, with a more vascularized outer fibrous supporting tissue layer. This combined approach of implant environment selection, natural polymer for cell retention, and growth factor supplementation offers a more optimized method for generating bioengineered auricular cartilage.
Effect of the Direct Renin Inhibitor Aliskiren in the Prevention of Experimental Contrast-Induced Nephropathy in the Rat
Authors: Kedrah Alla Eldeen , Ari Elif , Alahdab Yesim , Gul Cuma Bulent , Macunluoglu Beyza , Atakan Aydin , Asicioglu Ebru , Cakalagaoglu Fulya , Koc Mehmet
Published: June 2012

Background: Renal vasoconstriction, activated by the renin-angiotensin system, plays a pivotal role in the pathogenesis of contrast-induced nephropathy (CIN). The purpose of this study was to evaluate the effect of aliskiren, a direct renin inhibitor, for the prophylaxis of experimental CIN in the rat. Methods: Thirty-two Wistar albino rats were divided into four groups of 8 rats each, namely the control (C), aliskiren (A), contrast media (CM) and aliskiren plus contrast media (ACM) groups. Aliskiren was given orally at a dose of 50 mg/kg/day once daily for 5 consecutive days. CIN was induced by intravenous administration of indomethacin, N-nitro-L-arginine methyl ester and high-osmolar contrast medium meglumine amidotrizoate. Renal function parameters, kidney histology and tubular expression of vascular endothelial growth factor were determined. Results: Mean serum creatinine was significantly lower (p < 0.001) and mean creatinine clearance was higher (p < 0.001) in the ACM group compared with the CM group. However, there were no differences between the ACM and CM groups in terms of tubular necrosis, proteinaceous casts, medullary congestion and vascular endothelial growth factor expression. Conclusion: Our preliminary data seem to suggest a potential role of aliskiren for the prophylaxis of CIN in an experimental rat model.
Organotypic Modeling of Human Keratinocyte Response to Peroxisome Proliferators
Authors: Zhang Carmen , Gurevich Igor , Aneskievich Brian J.
Published: June 2012

Peroxisome proliferators (PPs) are a diverse chemical group including hypolipidemic drugs and some fatty acids. Their stimulation of PP-activated receptors (PPARs) and subsequent control of gene expression regulates metabolism and differentiation in many cells. PPs have multiple opportunities to target human epidermal keratinocytes because of delivery through dietary, clinical, and/or topical exposure routes. PPAR knockout mice and PP treatment of mouse skin or human keratinocytes in monolayer culture have established some effects for PPs in cutaneous differentiation. However, incomplete epidermal maturation characteristic of monolayer keratinocytes and rodent-specific effects may limit our full understanding of human keratinocyte responses to PPs. To address these issues, we investigated PP influence on primary human keratinocytes in organotypic cultures that recapitulate biochemical markers of epidermis. We found that the PPARα agonists clofibrate, docasohexaenoic acid, and WY-14,643 produced mild to moderate keratinocyte hyperplasia, increased stratification (particularly of granular and cornified layers), and enhanced levels of the differentiation markers filaggrin, ABCA12, and phosphorylated HSP27. Several PP effects generated in the organotypic system, however, were distinct from those previously reported for rodent skin and human keratinocyte monolayer cultures, suggesting that the species and growth context of target cells can impact exposure outcomes. Given the utility of organotypic cultures for modeling the epidermis, studies in this system may bridge the gap between the rodent assays and clinical studies of human epidermal responses to PPs.
Impact of Disease and Treatments on Growth and Puberty of Pediatric Patients with Inflammatory Bowel Disease
Authors: Ezri Jessica , Marques-Vidal Pedro , Nydegger Andreas
Published: June 2012

Growth retardation, associated with delayed puberty, is a frequent feature in pediatric patients with inflammatory bowel disease (IBD), especially with Crohn’s disease. It is mainly induced by malnutrition and the effects of the inflammatory process on the growth hormone/insulin-like growth factor-1 axis or on the growth plate. Therefore, control of disease activity and mucosal healing are paramount to promote growth and adequate pubertal onset. Current therapeutic strategies for maintenance in IBD include anti-inflammatory drugs, immunosuppressives, and, more recently, biologic agents. Although these treatments are efficient in minimizing inflammation and inducing prolonged remission, their long-term effects on growth and final height remain controversial. Furthermore, glucocorticoid therapy, even though very efficient in inducing remission, clearly shows deleterious effects on growth, which is not the case for exclusive enteral nutrition showing comparable results regarding induction of remission. Thus regular assessment of weight, height and pubertal stage is essential in children and adolescents with chronic disease, namely IBD.
Interleukin-6 -634G>C Genetic Polymorphism Is Associated with Prognosis following Surgery for Advanced Thoracic Esophageal Squamous Cell Carcinoma
Authors: Motoyama Satoru , Nakatsu Toshinobu , Miura Masatomo , Hinai Yudai , Minamiya Yoshihiro , Ogawa Jun-ichi
Published: June 2012

Objective: Systemic and/or local interleukin-6 (IL-6) reportedly plays an active role in the progression and prognosis of thoracic esophageal squamous cell carcinoma (TESCC). We assessed the associations between IL-6 and IL-6 receptor (IL-6R) genetic polymorphisms, tumoral IL-6 expression and survival rates following surgery. Methods: The study participants were 63 Japanese patients treated between 2003 and 2008 for T2–T4 advanced TESCC using curative esophagectomy without neoadjuvant treatment. We investigated IL-6 -634G>C (rs1800796) and IL-6R 48892A>C (rs8192284, Asp358Ala) genetic polymorphisms using DNA from peripheral blood samples. In addition, tumoral IL-6 expression was investigated immunohistochemically in resected specimens, and serum IL-6 was measured using a human IL-6 immunoassay. Results: There was a significant difference in survival between patients with the IL-6 -634G/G+G/C genotype and those with the C/C genotype, such that their 5-year overall survival rates were 42 and 72%, respectively. By contrast, the IL-6R 48892A /C genotype and tumoral IL-6 expression had no significant effect on survival among patients. Univariate and multivariate analyses revealed that IL-6 -634G>C polymorphism was an independent prognostic factor with a hazard ratio of 3. Conclusions: IL-6 -634G>C genetic polymorphism may be a predictive prognostic factor in patients receiving esophagectomy for TESCC.
Xanthogranulomatous Cholecystitis: Catching the Culprit – Clinical and Imaging Analysis
Authors: Jain Sarika , Saluja Sundeep Singh , Sharma Ashok Kumar , Sant Hridesh , Mishra Pramod Kumar
Published: June 2012

Background: Radiological and intraoperative findings of xanthogranulomatous cholecystitis (XGC) mimic carcinoma gallbladder (CaGB) leading to extended surgical resections and increased morbidity. We reviewed the clinical and CECT findings of histopathologically proven XGC and compared them with those of CaGB. Methods: The clinical and CECT findings from 22 patients with XGC were compared with 15 patients with CaGB manifesting as diffuse wall thickening. Results: GB wall thickness was similar in both groups (XGC 12.4 ± 3 mm, CaGB 13.9 ± 6.5 mm; p = 0.61). Intramural hypoattenuating nodules occupying >60% of the GB wall were suggestive of XGC, while the absence of nodules suggested CaGB (p = 0.017). The mucosal lining was intact and enhancing in XGC (20/22) and disrupted in CaGB (10/15; p = 0.001). Among adjacent organ infiltration, bile duct invasion resulting in obstruction was a significant finding in patients with CaGB (p = 0.04). Among XGC patients, 11 patients underwent radical cholecystectomy, 10 had open cholecystectomy and frozen section and 1 underwent bypass. Conclusions: Though there is an overlap between XGC and CaGB, the presence of intramural hypoattenuating nodules occupying >60% of the diffusely thickened GB wall with intact mucosal line and the absence of obstructive features suggest XGC. In the presence of such imaging features, frozen biopsy should be done before proceeding with mutilating radical surgery.
Measuring Impact in Stereotactic and Functional Neurosurgery: An Analysis of the Top 100 Most Highly Cited Works and the Citation Classics in the Field
Authors: Lipsman Nir , Lozano Andres M.
Published: June 2012

Background: Functional neurosurgery is a rapidly expanding field, with an exponentially growing literature. However, as with other fields, it can sometimes be difficult to distinguish between what is incremental and what is transformational. One way of measuring durable impact is examining the number of times a specific piece of scholarship is cited by others in the field. For example, papers that have been cited at least 400 times are designated ‘citation classics’ or works that, by virtue of very high citations, have been deemed of particular importance by researchers working in related disciplines. Methods: We queried a large, web-based scholarly database using 49 pre-selected search terms. The results for each individual query was manually examined for relevance to the functional neurosurgery field in order to arrive at the top 100 most highly cited papers as well as the citation classics. Results: The top 100 most cited papers, including 61 citation classics, in the stereotactic and functional neurosurgery field can be divided into 7 categories: functional/anatomic studies, technological innovations, and papers relevant to movement disorders, pain, psychiatry, radiosurgery and epilepsy. Conclusions: We have attempted to ascertain which papers have had, and continue to have, significant impact in our rapidly advancing field. At a minimum, the citation classics in functional neurosurgery provide both trainees and seasoned surgeons with a reading list of the ‘must-know’ works in the field – works whose influence have helped shape the direction of functional neurosurgery well into the future.
Methylation and Expression Analyses of the 7q Autism Susceptibility Locus Genes MEST, COPG2, and TSGA14 in Human and Anthropoid Primate Cortices
Authors: Schneider E. , Mayer S. , El Hajj N. , Jensen L.R. , Kuss A.W. , Zischler H. , Kondova I. , Bontrop R.E. , Navarro B. , Fuchs E. , Zechner U. , Haaf T.
Published: June 2012

The autism susceptibility locus on human chromosome 7q32 contains the maternally imprinted MEST and the non-imprinted COPG2 and TSGA14 genes. Autism is a disorder of the ‘social brain’ that has been proposed to be due to an overbalance of paternally expressed genes. To study regulation of the 7q32 locus during anthropoid primate evolution, we analyzed the methylation and expression patterns of MEST, COPG2, and TSGA14 in human, chimpanzee, Old World monkey (baboon and rhesus macaque), and New World monkey (marmoset) cortices. In all human and anthropoid primate cortices, the MEST promoter was hemimethylated, as expected for a differentially methylated imprinting control region, whereas the COPG2 and TSGA14 promoters were completely demethylated, typical for transcriptionally active non-imprinted genes. The MEST gene also showed comparable mRNA expression levels in all analyzed species. In contrast, COPG2 expression was downregulated in the human cortex compared to chimpanzee, Old and New World monkeys. TSGA14 either showed no differential regulation in the human brain compared to chimpanzee and marmoset or a slight upregulation compared to baboon. The human-specific downregulation supports a role for COPG2 in the development of a ‘social brain’. Promoter methylation patterns appear to be more stable during evolution than gene expression patterns, suggesting that other mechanisms may be more important for inter-primate differences in gene expression.
Two-Stage Extreme Phenotype Sequencing Design for Discovering and Testing Common and Rare Genetic Variants: Efficiency and Power
Authors: Kang Guolian , Lin Dongyu , Hakonarson Hakon , Chen Jinbo
Published: June 2012

Next-generation sequencing technology provides an unprecedented opportunity to identify rare susceptibility variants. It is not yet financially feasible to perform whole-genome sequencing on a large number of subjects, and a two-stage design has been advocated to be a practical option. In stage I, variants are discovered by sequencing the whole genomes of a small number of carefully selected individuals. In stage II, the discovered variants of a large number of individuals are genotyped to assess associations. Individuals with extreme phenotypes are typically selected in stage I. Using simulated data for unrelated individuals, we explore two important aspects of this two-stage design: the efficiency of discovering common and rare single-nucleotide polymorphisms (SNPs) in stage I and the impact of incomplete SNP discovery in stage I on the power of testing associations in stage II. We applied a sum test and a sum of squared score test for gene-based association analyses evaluating the power of the two-stage design. We obtained the following results from extensive simulation studies and analysis of the GAW17 dataset. When individuals with trait values more extreme than the 99.7–99th quantile were included in stage I, the two-stage design could achieve the same power as or even higher than the one-stage design if the rare causal variants had large effect sizes. In such design, fewer than half of the total SNPs including more than half of the causal SNPs were discovered, which included nearly all SNPs with minor allele frequencies (MAFs) ≥5%, more than half of the SNPs with MAFs between 1% and 5%, and fewer than half of the SNPs with MAFs <1%. Although a one-stage design may be preferable to identify multiple rare variants having small to moderate effect sizes, our observations support using the two-stage design as a cost-effective option for next-generation sequencing studies.
Hypogonadism in Patients with Sickle Cell Disease: Central or Peripheral?
Authors: Taddesse A. , Woldie I.L. , Khana P. , Swerdlow P.S. , Chu J.-W. , Abrams J. , Abou-Samra A.-B.
Published: June 2012

There is conflicting evidence in the literature on the etiology of hypogonadism in patients with sickle cell disease (SCD). A cross-sectional study was done to determine whether hypogonadism in male patients with SCD is due to primary testicular failure or secondary pituitary/hypothalamic dysfunction and assess the association between hypogonadism and serum ferritin levels. Hormonal assessment for serum concentrations of testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) was done for 34 men with SCD and their charts were reviewed for relevant clinical variables. Eight men (24%) were classified hypogonadal based on their serum testosterone levels. These men have significantly lower LH (p = 0.001) and FSH (p = 0.01) levels than normogonadal men, indicating a central etiology. There was no significant difference between hypogonadal and normogonadal men with respect to ferritin levels (p = 0.71). Our study indicates a central etiology of hypogonadism in patients with SCD. In this small study ferritin level was not significantly related to hypogonadism.
Biochemical, Virological, Immunological and Histopathological Features of 702 Incidentally Detected Chronic Hepatitis B Virus Carriers in Bangladesh
Authors: Al-Mahtab Mamun , Akbar Sheikh Mohammad Fazle , Rahman Salimur , Kamal Mohammad , Khan Mohammad Sakirul Islam
Published: June 2012

Background/Aims: Simultaneous assessment of biochemical, virological, and histological parameters of incidentally detected chronic hepatitis B virus (HBV)-infected subjects in Bangladesh were done to develop strategies for containment of HBV and management of liver diseases of these patients. Methods: A total of 702 chronic HBV carriers detected incidentally were enrolled in the study. Levels of HBV DNA and alanine aminotransferase (ALT) in sera were measured. The extent of hepatic inflammation and liver fibrosis was evaluated in all patients by examining liver biopsy specimens. Results: Of the 702 patients, 358 (50.7%) exhibited HBV DNA levels >105 copies/ml. ALT levels were above the upper limit of normal (ULN; >42 U/l) in more than 50% of the patients. High levels of HBV DNA (>105 copies/ml), increased ALT (>1.0 × ULN), moderate hepatic inflammation (HAI-NI ≥7) and severe hepatic fibrosis (HAI-F ≥3) were detected in 60 patients. Conclusion: As considerable numbers of apparently healthy subjects are unaware of the fact that they are chronically infected by HBV, many of whom have already developed progressive liver damage, emergency strategies would be needed for the containment and management of HBV infection in developing countries.
Prevalence, Patterns of Treatment, and Control of Hypertension in Predialysis Patients with Chronic Kidney Disease
Authors: Sarafidis Pantelis A. , Sharpe Claire C. , Wood Eleri , Blacklock Rochelle , Rumjon Adam , Al-Yassin Aziza , Ariyanayagam Rachel , Simmonds Shanique , Fletcher-Rogers Jessica , Vinen Katie
Published: June 2012

Background/Aims: Data on the prevalence, treatment and control of hypertension in patients with advanced chronic kidney disease (CKD) are limited. This study aimed to examine the above factors in a cohort of predialysis patients. Methods: During a period of 4 months, we recorded information on blood pressure (BP), comorbidities, medications and related parameters of patients followed up in the Low-Clearance Clinic of our Department. Control rates of hypertension were calculated at two thresholds: <130/80 and <140/90 mm Hg. Univariate and multiple linear regression analyses were employed to assess factors associated with BP control. Results: In the population studied [n = 238, males 58.4%, age 66.21 ± 4.2 years (mean ± SD), estimated glomerular filtration rate 14.5 ± 4.8 ml/min/1.73 m2], the prevalence of hypertension was 95.0%. Treatment rate among hypertensives was at 99.1%. On average, 3.04 ± 1.32 antihypertensive drugs were used, ranging from 1 to 7 agents. BP control rates at the <130/80 and <140/90 mm Hg thresholds were 26.5% and 48.2%, respectively. The systolic goal was achieved in 31.0% and 50.4%, whereas the diastolic goal was achieved in 67.7% and 91.2% of patients, respectively. In multivariate analysis, only black race was independently and inversely related with hypertension control (β = –0.187, p = 0.030). No specific antihypertensive class showed independent associations with control. Conclusions: Hypertension is highly prevalent in predialysis CKD patients. An almost universal treatment, employing a multi-agent regime, can help towards improved rates of control. Systolic BP is the main barrier to successful control and black race is associated with poorer control rates.
Effect of High-Dose Intravenous Methyl-prednisolone Treatment on Intraocular Pressure in Multiple Sclerosis Patients with Relapse
Authors: Acar Memed , Gedizlioglu Muhtesem , Koskderelioglu Asli , Ozturk Feriste , Kilinc Serkan , Talay Nurdan
Published: June 2012

Aim: The aim of the study was to determine the intraocular pressure (IOP) changes with high-dose intravenous methylprednisolone (HIVMP) treatment given for the treatment of acute relapses in relapsing multiple sclerosis (MS). Methods: Forty patients with clinically definite MS admitted for a new demyelinating event were included in the study. All patients were treated with HIVMP (1 g) once daily for 5 consecutive days. IOPs of 40 patients were recorded before treatment, during the course of systemic methylprednisolone administration and at the end of each month for 3 successive months, four times a day. The average IOP of each day was statistically compared to the pretreatment value. Results: The initial IOP was 13.5 ± 2.4 mm Hg before steroid administration. The IOP values tended to rise significantly during intravenous corticosteroid administration and in the first month of follow-up (p < 0.05). However, the increase remained within normal ranges and IOP values never exceeded 20 mm Hg during the follow-ups. Conclusion: Our study demonstrated that MS patients treated with HIVMP have increased IOP which does not lead to conditions at risk for developing glaucoma.
Postoperative Adhesion Prevention with a New Barrier: An Experimental Study
Authors: Ditzel M. , Deerenberg E.B. , Komen N. , Mulder I.M. , Jeekel H. , Lange J.F.
Published: June 2012

Introduction: Postoperative adhesion formation remains a major clinical problem. The aim of this study was to test the effect of a new hydrogel on adhesion formation in a rat model. Materials and Methods: A reproducible rat model was used to induce standardized adhesion formation in three experiments. In experiment 1, a cross-linked polyvinyl alcohol (PVA) and carboxymethylcellulose (CMC) hydrogel (PVA/CMC, A-Part®; B. Braun Aesculap, Germany) was tested in different dosages. In experiment 2, PVA/CMC gel was compared to icodextrin 4% (Adept®; Baxter USA). In both groups, animals were sacrificed after 2 weeks. In experiment 3, histological examination after 4 and 6 weeks was performed. The percentage of adhesions to the defect was measured and the density was determined according to the Zühlke scale. During histological examination of the abdominal wall, the formation of neoperitoneum and potential residues of the agents were assessed. Results: In experiment 1, a significant reduction in amount as well as density of the adhesions was visible with all dosages of PVA/CMC gel. In experiment 2, again quantity and density of the adhesions were diminished by PVA/CMC hydrogel compared to the control group. Icodextrin 4% showed no significant reduction in adhesion formation. In experiment 3, no residues of PVA/CMC gel or icodextrin 4% were found during histological examination after 4 and 6 weeks and neoperitoneum was present in all cases. Conclusion: PVA/CMC hydrogel appears to be a novel effective adhesion prevention agent. Together with an upcoming safety study, these data encourage to start clinical efficacy studies.
Intravitreal Expansile Gas in the Treatment of Early Macular Hole: Reappraisal
Authors: Chen Ta-Ching , Yang Chang-Hao , Yang Chung-May
Published: June 2012

Purpose: To study the effects of intravitreal injection (IVI) of expansile gas for early macular holes (EMH). Methods: Prospective interventional case series. Twelve eyes of 12 patients with EMH (stage 2) underwent IVI of perfluoropropane 0.2 ml followed by 5 days’ facedown positioning. Results: Six cases (50%) achieved vitreous-macula separation. Three cases (25%) had hole closure with vision improvement; one of them developed rhegmatogenous retinal detachment (RRD) and hole re-opening. Another case with persistent hole also developed RRD. Seven of the 9 cases without hole closure and the one where the hole re-opened had vitrectomy, all resulting in hole closure and vision improvement. Duration of symptoms had borderline significance for hole closure (p = 0.11) and subsequent visual improvement (p = 0.03). Conclusion: With its low success rate, IVI of gas may not be a good option for EMH. Complications include retinal detachment. The procedure seems to not affect hole closure with subsequent vitrectomy.
Exenatide Reduces Urinary Transforming Growth Factor-β1 and Type IV Collagen Excretion in Patients with Type 2 Diabetes and Microalbuminuria
Authors: Zhang Hong , Zhang Xiangcheng , Hu Changjun , Lu Weiping
Published: June 2012

Aims: It was reported that exenatide ameliorated renal injury in diabetic rats. The present study was carried out to evaluate the effect of exenatide on 24-hour urinary albumin, urinary transforming growth factor-β1 (TGF-β1) and type IV collagen excretion in patients with type 2 diabetes and microalbuminuria. Methods: 31 type 2 diabetic patients with microalbuminuria were randomly allocated to receive exenatide (group Exe, n = 13) or glimepiride treatment (group Glm, n = 18) for 16 weeks. Body mass index (BMI), fasting plasma glucose, 2-hour postprandial plasma glucose, glycated hemoglobin A1c, systolic blood pressure, diastolic blood pressure, 24-hour urinary albumin, urinary TGF-β1 and type IV collagen concentration were analyzed between the two treatment groups. 20 age- and BMI-matched healthy subjects were chosen as the normal control group (group NC, n = 20). Results: After 16 weeks of treatment, 24-hour urinary albumin, urinary TGF-β1 and type IV collagen in group Exe were significantly lower than those of group Glm (p < 0.01), while glycemic control had no statistical difference between the two groups. Conclusions: Our results indicate that exenatide reduces urinary TGF-β1 and type IV collagen excretion in patients with type 2 diabetes and microalbuminuria, which may be partly contributory to its directly renoprotective role.
Busulfan-Mediated Germ Cell Depletion Does Not Alter Gonad Differentiation in the Urodele Amphibian Pleurodeles waltl
Authors: Al-Asaad I. , Dumond H. , Chardard D. , Chesnel A. , Flament S.
Published: June 2012

It is not known in urodele amphibians whether germ cells (GCs) are indispensable for gonadal differentiation. In order to address this question in the newt Pleurodeles waltl, we first cloned the ortholog of VASA which is known as a GC marker in many species. Male (ZZ) and female (ZW) larvae were then exposed to the alkylating agent busulfan (25 µg/ml for 3 days) just after hatching (stage 36). In the main body of busulfan-treated larvae, PwVASA mRNA expression decreased before gonad differentiation in both sexes (at stage 50). This suggested GC depletion which was confirmed by histology, with a complete absence of GCs observed slightly earlier in females (stage 54) than in males (stage 54 + 60 days). In busulfan-treated ZW larvae, the presence of the typical central cavity and expression of a high level of aromatase mRNA confirmed the ovarian phenotype. In busulfan-treated ZZ larvae, the presence of a medulla surrounded by a thin cortex and a low level of aromatase mRNA confirmed the testis phenotype. At the juvenile stage, efferent ducts and lobules were present in the first testis lobe. Taken together, these data suggest that GC depletion does not alter gonad differentiation in P. waltl.
A Pooled Analysis of Sequential Therapies with Sorafenib and Sunitinib in Metastatic Renal Cell Carcinoma
Authors: Stenner Frank , Chastonay Rahel , Liewen Heike , Haile Sarah R. , Cathomas Richard , Rothermundt Christian , Siciliano Raffaele D. , Stoll Susanna , Knuth Alexander , Buchler Tomas , Porta Camillo , Renner Christoph , Samaras Panagiotis
Published: June 2012

Objective: To evaluate the optimal sequence for the receptor tyrosine kinase inhibitors (rTKIs) sorafenib and sunitinib in metastatic renal cell cancer. Methods: We performed a retrospective analysis of patients who had received sequential therapy with both rTKIs and integrated these results into a pooled analysis of available data from other publications. Differences in median progression-free survival (PFS) for first- (PFS1) and second-line treatment (PFS2), and for the combined PFS (PFS1 plus PFS2) were examined using weighted linear regression. Results: In the pooled analysis encompassing 853 patients, the median combined PFS for first-line sunitinib and 2nd-line sorafenib (SuSo) was 12.1 months compared with 15.4 months for the reverse sequence (SoSu; 95% CI for difference 1.45–5.12, p = 0.0013). Regarding first-line treatment, no significant difference in PFS1 was noted regardless of which drug was initially used (0.62 months average increase on sorafenib, 95% CI for difference –1.01 to 2.26, p = 0.43). In second-line treatment, sunitinib showed a significantly longer PFS2 than sorafenib (average increase 2.66 months, 95% CI 1.02–4.3, p = 0.003). Conclusion: The SoSu sequence translates into a longer combined PFS compared to the SuSo sequence. Predominantly the superiority of sunitinib regarding PFS2 contributed to the longer combined PFS in sequential use.