bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic Regulation of Infant Neurobehavioral Outcomes
Authors: Lesseur Corina , Paquette Alison G. , Marsit Carmen J.
Published: June 2014

During fetal development and early infancy, environmental signals can induce epigenetic changes that alter neurobehavioral development and later-life mental health. Several neurodevelopmental genetic diseases influence epigenetic regulatory genes and genomic imprinting. Recently, brain epigenetic marks have been involved in idiopathic neurodevelopmental disorders, including autism spectrum disorders. The placenta is an important regulator of the intrauterine environment that links maternal and fetal nervous systems. Placental epigenetic signatures have been associated with the neurodevelopment of healthy newborns quantified through the Neonatal Intensive Care Unit Network Neurobehavioral Scales (NNNS). Associations have been observed for DNA methylation of genes involved in cortisol (NR3C1, HSD11B), serotonin (HTR2A), and metabolic (LEP) pathways. Dysregulation of imprinted genes and microRNAs has also been associated with neurobehavior assessed by NNNS. Further analysis is needed to characterize the mechanisms by which the epigenome influences neurodevelopment and the connection between this dysregulation and mental health disorders. In the future, epigenetic marks could serve as functional biomarkers of mental health and cognitive function.
Is Brain Natriuretic Peptide a Reliable Biomarker of Hydration Status in All Peritoneal Dialysis Patients?
Authors: Crepaldi Carlo , Rosner Mitchel , Teixeira Catarina , Martos Lourdes Blanca , Martino Francesca Katiana , Rodighiero Maria Pia , Ronco Claudio
Published: June 2014

Background: Achievement of euvolemia is a fundamental challenge in the peritoneal dialysis (PD) population. Bioimpedance spectroscopy (BIS) is one of the best techniques for routine assessment of hydration status (HS) in PD, but in recent years, the role of brain natriuretic peptides (BNP) in the assessment of volume status has gained interest. The aim of this study was to investigate the relation between BNP and volume status as measured by BIS in PD patients and to assess how these variables correlate according to the time that a patient has been on PD. Methods: We prospectively studied 68 PD patients from whom measurements of BNP and assessments of HS by BIS were performed every 3 months. Three groups were defined based on HS: group A, measurements of HS <-1.1 liters (underhydrated); group B, measurements of HS between -1.1 and +1.1 liters (normohydrated), and group C, measurements of HS >+1.1 liters (overhydrated). Measurements were also separated according to the time on PD (<6 vs. ≥6 months). Correlation between HS and BNP was performed using Spearman's correlation. Results: We performed a total of 478 measurements of HS and BNP. There was a statistically significant difference in BNP (p < 0.001) among three HS groups, with higher levels of BNP detected in overhydrated patients. We found a positive correlation between HS and BNP (rs = 0.28; p <0.001) that seemed stronger in the first 6 months on PD (rs = 0.42; p = 0.006). Conclusions: BNP correlated positively with fluid overload measured by HS, and this correlation was stronger in the first 6 months on PD.
An Alternative Transcription Start Site Yields Estrogen-Unresponsive Kiss1 mRNA Transcripts in the Hypothalamus of Prepubertal Female Rats
Authors: Castellano Juan Manuel , Wright Hollis , Ojeda Sergio R. , Lomniczi Alejandro
Published: June 2014

The importance of the Kiss1 gene in the control of reproductive development is well documented. However, much less is known about the transcriptional regulation of Kiss1 expression in the hypothalamus. Critical for these studies is an accurate identification of the site(s) where Kiss1 transcription is initiated. Employing 5′-RACE PCR, we detected a transcription start site (TSS1) used by the hypothalamus of rats, mice, nonhuman primates and humans to initiate Kiss1 transcription. In rodents, an exon 1 encoding 5′-untranslated sequences is followed by an alternatively spliced second exon, which encodes 5′-untranslated regions of two different lengths and contains the translation initiation codon (ATG). In nonhuman primates and humans, exon 2 is not alternatively spliced. Surprisingly, in rat mediobasal hypothalamus (MBH), but not preoptic area (POA), an additional TSS (TSS2) located upstream from TSS1 generates an exon 1 longer (377 bp) than the TSS1-derived exon 1 (98 bp). The content of TSS1-derived transcripts increased at puberty in the POA and MBH of female rats. It also increased in the MBH after ovariectomy, and this change was prevented by estrogen. In contrast, no such changes in TSS2-derived transcript abundance were detected. Promoter assays showed that the proximal TSS1 promoter is much more active than the putative TSS2 promoter, and that only the TSS1 promoter is regulated by estrogen. These differences appear to be related to the presence of a TATA box and binding sites for transcription factors activating transcription and interacting with estrogen receptor-α in the TSS1, but not TSS2, promoter.
A Comparison of the Effects of Nifedipine, Verapamil, and Low-Molecular-Weight Heparin on SLIGRL-NH2-Induced Calcium Influx through Proteinase-Activated Receptor 2 Activation
Authors: Sun Jun , Dou Wei , Shen Hong , Hu Jinhong
Published: June 2014

Background: Proteinase-activated receptor 2 (PAR2) may be implicated in skin disorders. Intracellular calcium mobilization is a key step in PAR2-induced signaling. Aims: In this study, we investigated the effects of nifedipine, verapamil, and low-molecular-weight heparin (LMWH) on SLIGRL-NH2-induced PAR2-mediated calcium mobilization within cells. Methods: The intracellular calcium concentration was measured with fluo-8, a fluorescence indicator for free Ca2+. Results: Our results showed that SLIGRL-NH2 induced a dose-dependent calcium influx. This calcium influx was completely blocked in HaCaT cells and significantly blocked by LMWH in HEK293/PAR2 cells. However, both nifedipine and verapamil failed to inhibit the SLIGRL-NH2-induced calcium influx in either cell line. Conclusion: These results indicate that the PAR2 activation-induced calcium mobilization was mediated by intracellular calcium stores but not by extracellular calcium present in the media.
Hemodialysis Patient Outcomes: Provider Characteristics
Authors: Slinin Yelena , Guo Haifeng , Li Suying , Liu Jiannong , Ensrud Kristine , Gilbertson David T. , Collins Allan J. , Ishani Areef
Published: June 2014

Background/Aims: Physician characteristics are associated with differential performance on quality measures and patient outcomes in several medical fields. We aimed to determine whether characteristics of physicians who provide care to dialysis patients were associated with patient outcomes. Methods: This cohort study used United States Renal Data System data for patients who initiated in-center hemodialysis between October 1, 2003, and September 30, 2006 (n = 91,276). Patient characteristics were defined and physicians identified from Part B Medicare claims for outpatient dialysis services submitted during months 4-6 of hemodialysis. Physician characteristics were obtained from the American Medical Association Physician Master File. Associations of physician characteristics with 1-year patient mortality and first hospitalization were determined using Cox proportional hazards analysis; associations with quality of care (defined by influenza vaccination and waitlisting for kidney transplant) were determined using logistic regression. Results: Physician characteristics were not associated with patient mortality. After adjustment for patient and other provider characteristics, patients whose physicians had practiced longer or were in administrative, research, or teaching practices were more likely to be hospitalized; patients whose providers practiced in smaller metropolitan statistical areas (MSAs) were less likely. More years since training was associated with greater chance of waitlisting, and practicing in smaller MSAs with less chance. Graduation from a foreign medical school, practicing in smaller MSAs, and travelling farther from office to dialysis unit were associated with greater odds of influenza vaccination. Conclusions: Several characteristics of physicians seeing incident outpatient hemodialysis patients were associated with hospitalization and quality of care, but none with mortality.
New Insights into the Role of Chronic Inflammation and Cytokines in the Etiopathogenesis of Gastroenteropancreatic Neuroendocrine Tumors
Authors: Cigrovski Berkovic Maja , Cacev Tamara , Catela Ivkovic Tina , Zjacic-Rotkvic Vanja , Kapitanovic Sanja
Published: June 2014

Although previously considered rare, recent epidemiological studies have revealed that the incidence (3.6/100,000) and prevalence (35/100,000) of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has increased over the past few decades. Despite the progress in the understanding of GEP-NET molecular biology, there is still little advance in the early diagnosis due to lack of specific tumor markers. As the tumors are mostly detected in their late stage, they are not well controlled by either biotherapy or conventional chemotherapy, and thus represent a significant clinical issue. Chronic inflammation has been implicated in the development of GEP-NETs. This review presents recent findings that link pro-inflammatory cytokines to the molecular basis of GEP-NET tumorigenesis, leading to a more personalized approach to disease management and therapy.
Importance of Vascular Calcification in Kidney Transplant Recipients
Authors: Cianciolo Giuseppe , Capelli Irene , Angelini Maria Laura , Valentini Chiara , Baraldi Olga , Scolari Maria P. , Stefoni Sergio
Published: June 2014

Background: Kidney transplantation is the treatment of choice for chronic kidney disease (CKD), but in kidney transplant recipients (KTRs) cardiovascular events are the first cause of death with a functioning graft, ranging from 36 to 55%. The impact of vascular calcification (VC) on morbidity and mortality of KTRs is not appreciated enough nowadays. Summary: This review summarizes 13 important studies on VC in KTRs, comparing the results with CKD and dialysis populations. We focused on VC evaluation and use of coronary artery calcification (CAC) and aorta calcification (AoC) scores. We also evaluated the influence of traditional and non-traditional progression risk factors. Key Messages: VC strongly predicts cardiovascular events and all-cause mortality in KTRs. VC assessment is important in KTRs and based essentially on multislice computed tomography or electron beam computed tomography recognition of lesions. Quantitative measurement of CAC and AoC scores is essential for a correct definition of the calcium burden before and after kidney transplant. Progression of CAC slows down but does not halt after kidney transplant. A variable association of both traditional and non-traditional risk factors is shown. There is a strong association between baseline CAC score and CAC progression. A significant improvement in secondary hyperparathyroidism after transplantation favorably affects the progression of CAC. Low 25(OH)D3 levels are an independent determinant of CAC progression. Diabetes is a risk factor for the presence of CAC in KTRs, but has not been independently associated with CAC progression. The data published on the use of immunosuppressive drugs as progression factors are few and inconclusive.
Neoadjuvant Therapy of Gastric Cancer: A Decisive Step Forward
Authors: Menges Markus , Hoehler Thomas
Published: June 2014

Background: Although its incidence has been steadily decreasing in Western countries, gastric cancer remains a leading cause of cancer deaths worldwide. The detection rate of early-stage cancers is improving; nevertheless, the majority of cases is still diagnosed at later stages with a poor prognosis. Furthermore, the results that can be achieved with surgery have reached a plateau of effectiveness. Summary: Neoadjuvant chemotherapy was successfully introduced first in patients with non-curatively resectable disease. In the last decade, neoadjuvant chemotherapy has also been established in potentially curatively resectable cases and has become the state-of-the-art treatment. Esophagogastric junction (EGJ) tumors are not optimally treated with chemotherapy alone, and combined radiochemotherapy (RCT) seems to yield superior outcomes. Key Message: The use of neoadjuvant therapy has been successfully established in patients with curatively resectable disease. Neoadjuvant chemotherapy is now a cornerstone in the treatment of gastric cancer and cancer of the EGJ, although further work is needed in order to define the optimal combination regimen. Practical Implications: Neoadjuvant chemotherapy is currently the gold standard for the treatment of gastric cancer and cancer of the EGJ. Several independent studies have shown the benefits of using combination regimens that included cisplatin and 5-fluorouracil, though recently the use of the EOX (epirubicin, oxaliplatin and capecitabine) regimen has been widely accepted in this setting. Tumors of the EGJ benefit from neoadjuvant treatment with combined RCT. It should be noted that the optimal neoadjuvant regimen in EGJ tumors has not yet been defined, and the survival advantage of neoadjuvant RCT over neoadjuvant chemotherapy remains to be established in this patient population.
Hepatocellular Carcinoma: Basic and Transitional Research
Authors: Yin Chuan , Xie Wei-Fen
Published: June 2014

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. The outcome of HCC therapy depends on the stage of HCC. Early-stage HCC patients can be cured with radical treatment approaches, whereas no standard treatment regimens can be recommended for patients with advanced disease. Summary: In-depth basic research into the molecular mechanisms of HCC has contributed to the development of novel therapeutic agents. This article reviews several key classes of novel therapeutic agents that are under development, including molecular-targeted therapies, cancer stem cell (CSC)-based therapy and differentiation therapy. Key Message: A greater understanding of the molecular pathogenesis of HCC has contributed to the development of novel therapeutic agents. This article reviews several key classes of novel therapeutic agents that are under development, including molecular-targeted therapies, CSC-based therapy and differentiation therapy. Practical Implications: Molecular-targeted therapies based on signaling pathways involved in hepatocarcinogenesis and progression are being evaluated in several clinical trials. There are three main categories of targeted agents: tyrosine kinase inhibitors (TKIs), monoclonal antibodies and enzyme inhibitors. The best-established agent is sorafenib, a non-specific TKI that is accepted as first-line therapy for specific patients. Other similar agents under investigation include erlotinib, linifanib and brivanib. CSC-based therapies are still in the earlier stages of development and include a neutralizing anti-CD44 antibody, small interfering RNA to suppress epithelial cell adhesion molecular levels, a neutralizing anti-CD13 antibody and a CD13 inhibitor. An important point is that CSC-targeted therapy should be combined with conventional therapies to achieve complete tumor regression. Differentiation therapy is defined as a strategy that induces malignant reversion of tumor cells. Hepatocyte nuclear factor 4α or 1α, important transcriptional factors for hepatocyte differentiation and phenotype maintenance, have shown significant antitumor effects by inducing differentiation of both non-CSCs and CSCs in HCC towards a hepatocyte-like phenotype.
Intrauterine Blood Transfusion: Current Indications and Associated Risks
Authors: Lindenburg Irene T.M. , van Kamp Inge L. , Oepkes Dick
Published: June 2014

Fetal anemia is a serious complication in pregnancy and associated with perinatal mortality and morbidity. During 25 years of worldwide experience with intravascular intrauterine blood transfusion, a variety of indications have been described. Intrauterine transfusion (IUT) treatment is considered most successful for fetal anemia due to red cell alloimmunization. Moreover, the use of this procedure has also been reported in pregnancies with parvovirus B19 infection, fetomaternal hemorrhage and placental chorioangiomas, for example. This review focuses on the current indications of intrauterine blood transfusions. In addition, we describe the potential complications of IUT treatment.
Novel, Selective Vitamin D Analog Suppresses Parathyroid Hormone in Uremic Animals and Postmenopausal Women
Authors: Zella Julia B. , Plum Lori A. , Plowchalk David R. , Potochoiba Michael , Clagett-Dame Margaret , DeLuca Hector F.
Published: June 2014

Background: The use of 1α-hydroxylated vitamin D therapy to control secondary hyperparathyroidism in renal failure patients has been a success story, culminating with the demonstration of increased life expectancy in patients treated with these compounds. However, hypercalcemic episodes have been a recurrent problem with these therapies and have resulted in the added use of calcium mimetics. Clearly there is good reason to search for improved vitamin D therapy. In our inventory of vitamin D compounds, 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) surfaced as a potential candidate. This was based on its preferential localization in the parathyroid gland and a clear suppression of serum parathyroid hormone (PTH) levels without a change in serum calcium in a clinical trial in postmenopausal women. Methods: 2MD has now been tested in the rat 5/6-nephrectomy model of renal failure, and in postmenopausal women to determine if it can suppress serum PTH at doses that do not elevate serum calcium and serum phosphorus concentrations. Results: Daily oral treatment of uremic rats on 2.5 ng/bw/day of 2MD dramatically suppressed PTH without a change in serum calcium or serum phosphorus. Further, PTH was suppressed in postmenopausal women after only 3 daily oral doses of 2MD that continued for 4 weeks with no change in serum calcium or serum phosphorus. Conclusion: These results coupled with a pharmacokinetic half-life of ~24 h suggest that 2MD given either daily or at the time of dialysis may be a superior therapy for secondary hyperparathyroidism in chronic renal failure patients.
Predictive Value of Gastrin Levels for the Diagnosis of Gastric Enterochromaffin-Like Cell Hyperplasia in Patients with Hashimoto's Thyroiditis
Authors: Nicolaou Argyro , Thomas Dimitrios , Alexandraki Krystallenia I. , Sougioultzis Stavros , Tsolakis Apostolos V. , Kaltsas Gregory
Published: June 2014

Aim: Gastrin and chromogranin A (CgA) levels have been tested for the diagnosis of enterochromaffin-like cell hyperplasia (ECLH) in patients with type 1 diabetes and autoimmune atrophic gastritis but not for patients with Hashimoto's thyroiditis (HT). The aim of the study was to develop receiver operating characteristic (ROC) curves for gastrin and CgA levels and other clinical and biochemical parameters, as means for pretest probability of gastric ECLH in patients with HT. Methods: A total of 115 patients with HT were prospectively studied for a median period of 4 (2-7) years. Gastrin, CgA, vitamin B12, anti-parietal cell antibodies, free thyroxine, thyrotropin, and neuron-specific enolase levels were measured. Their predictive values were calculated according to the histological findings for ECLH diagnosis from esophagogastroduodenoscopy-obtained biopsies. Results: Thirteen patients (11.3%) had ECLH. The areas under the curve for gastrin and CgA level were 0.898 (p < 0.001) and 0.853 (p < 0.001), respectively. The product sensitivity × specificity was 0.803 and 0.653 for gastrin and CgA levels >89.5 and >89.1 ng/ml, respectively. Two and 4 patients with ECLH had normal gastrin and CgA levels, respectively. The most specific combined parameters predicting ECLH were gastrin >89.5 ng/ml with concomitant low B12 levels (96.1% specificity). Conclusion: Gastrin levels have high diagnostic accuracy for ECLH identification in patients with HT, and are highly specific when combined with low B12 levels. However, they should be interpreted with caution, as some patients may harbor gastric ECLH even if gastrin levels are not increased, necessitating further follow-up.
Mechanisms Contributing to Adverse Cardiovascular Events in Patients with Type 2 Diabetes Mellitus and Stage 4 Chronic Kidney Disease Treated with Bardoxolone Methyl
Authors: Chin Melanie P. , Reisman Scott A. , Bakris George L. , O'Grady Megan , Linde Peter G. , McCullough Peter A. , Packham David , Vaziri Nosratola D. , Ward Keith W. , Warnock David G. , Meyer Colin J.
Published: June 2014

Background: Bardoxolone methyl, an Nrf2-activating and nuclear factor-κB-inhibiting semisynthetic oleanane triterpenoid compound, was evaluated in a phase 3 trial (BEACON) in patients with type 2 diabetes mellitus (T2DM) and stage 4 chronic kidney disease (CKD). The trial was terminated because of an increase in heart failure events in the bardoxolone methyl group, many of which appeared related to fluid retention. Thus, additional analyses were conducted to explain these serious adverse events. Methods: Patients (n = 2,185) were randomized to receive once-daily bardoxolone methyl (20 mg) or placebo. Twenty-four-hour urine collections were analyzed in a subset of the BEACON population and from a separate, open-label pharmacology study in patients with stage 3b/4 CKD and T2DM administered 20 mg bardoxolone methyl once daily for 56 consecutive days. Results: Bardoxolone-methyl-treated patients in the BEACON substudy had a clinically meaningful reduction in urine volume and sodium excretion at week 4 relative to baseline (p < 0.05), and a separate study revealed that decreased sodium excretion and urine output occurred in some patients with stage 4 CKD but not those with stage 3b CKD. The clinical phenotype of fluid overload and heart failure in BEACON was similar to that observed with endothelin receptor antagonists in advanced CKD patients, and preclinical data demonstrate that bardoxolone methyl modifies endothelin signaling. Conclusions: The totality of the evidence suggests that through modulation of the endothelin pathway, bardoxolone methyl may pharmacologically promote acute sodium and volume retention and increase blood pressure in patients with more advanced CKD.
Practical Use of Home Blood Pressure Monitoring in Chronic Kidney Disease
Authors: Sanghavi Sarah , Vassalotti Joseph A.
Published: June 2014

Despite the availability of blood pressure (BP)-lowering medications and dietary education, hypertension is still poorly controlled in the chronic kidney disease (CKD) population. As glomerular filtration rate declines, the number of medications required to achieve BP targets increases, which may lead to reduced patient adherence and therapeutic inertia by the clinician. Home BP monitoring (HBPM) has emerged as a means of improving diagnostic accuracy, risk stratification, patient adherence, and therapeutic intervention. The definition of hypertension by HBPM is an average BP >135/85 mm Hg. Twelve readings over the course of 3-5 days are sufficient for clinical decision making. Diagnostic accuracy is especially important in the CKD population as approximately half of these patients have either white coat hypertension or masked hypertension. Preliminary data suggest that HBPM outperforms office BP monitoring in predicting progression to end-stage renal disease or death. When combined with additional support such as telemonitoring, medication titration, or behavioral therapy, HBPM results in a sustained improvement in BP control. HBPM must be adapted to provide information on the phenomena of nondipping (absence of nocturnal fall in BP) and reverse dipping (paradoxical increase in BP at night). These diurnal patterns are more prevalent in the CKD population and are important cardiovascular risk factors. Ambulatory BP monitoring provides nocturnal BP readings and unlike HBPM may be reimbursed by Medicare when certain criteria are met. Further studies are needed to determine whether HBPM is cost-effective in the current US healthcare system.
Heat-Shock Proteins and Acute Ischaemic Kidney Injury
Authors: O'Neill Stephen , Harrison Ewen M. , Ross James A. , Wigmore Stephen J. , Hughes Jeremy
Published: June 2014

The incidence of acute kidney injury due to ischaemia-reperfusion injury (IRI) is rising but effective treatments and preventative approaches are currently lacking. IRI is also an inevitable consequence of kidney transplantation and significantly contributes to delayed graft function. Heat-shock proteins (Hsps) are highly conserved and ubiquitously expressed molecular chaperones that help maintain and restore normal cellular function in the kidney following IRI. Hsp70 is one of the most frequently studied Hsps because of potential cytoprotective properties and attractiveness as a therapeutic target. However, the protective properties of Hsp70 in renal IRI are not fully understood and putative modes of protection include correction of protein conformation, cytoskeletal stabilisation, anti-inflammatory effects, requirement in autophagy, anti-apoptotic properties, influence over macrophage phenotype and stimulation of regulatory T cells. Significant clinical interest has been generated about the possibility of applying pharmacological agents to induce Hsp70 and prevent renal IRI, but prior to this, an increased mechanistic understanding of the protective nature of Hsp70 is needed. In particular, further investigation of Hsp expression on inflammatory cell behaviour is required as this could lead to the development of new therapeutic strategies for enhancing recovery following renal IRI and broaden the range of these therapies to a wider group of patients.
Estradiol Upregulates Progesterone Receptor and Orphanin FQ Colocalization in Arcuate Nucleus Neurons and Opioid Receptor-Like Receptor-1 Expression in Proopiomelanocortin Neurons That Project to the Medial Preoptic Nucleus in the Female Rat
Authors: Sanathara Nayna M. , Moreas Justine , Mahavongtrakul Matthew , Sinchak Kevin
Published: June 2014

Background: Ovarian steroids regulate sexual receptivity in the female rat by acting on neurons that converge on proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) that project to the medial preoptic nucleus (MPN). Estradiol rapidly activates these neurons to release β-endorphin that activates MPN μ-opioid receptors (MOP) to inhibit lordosis. Lordosis is facilitated by the subsequent action of progesterone that deactivates the estradiol-induced MPN MOP activation. Orphanin FQ (OFQ/N; also known as nociceptin) infusions into the ARH, like progesterone, deactivate MPN MOP and facilitate lordosis in estradiol-primed rats. OFQ/N reduces the activity of ARH β-endorphin neurons through post- and presynaptic mechanisms via its cognate receptor, ORL-1. Methods: We tested the hypotheses that progesterone receptors (PR) are expressed in ARH OFQ/N neurons by immunohistochemistry and ORL-1 is expressed in POMC neurons that project to the MPN by combining Fluoro-Gold injection into the MPN and double-label fluorescent in situ hybridization (FISH). We also hypothesized that estradiol increases coexpression of PR-OFQ/N and ORL-1-POMC in ARH neurons of ovariectomized rats. Results: The number of PR- and OFQ/N-immunopositive ARH neurons was increased as was their colocalization by estradiol treatment. FISH for ORL-1 and POMC mRNA revealed a subpopulation of ARH neurons that was triple labeled, indicating these neurons project to the MPN and coexpress ORL-1 and POMC mRNA. Estradiol was shown to upregulate ORL-1 and POMC expression in MPN-projecting ARH neurons. Conclusion: Estradiol upregulates the ARH OFQ/N-ORL-1 system projecting to the MPN that regulates lordosis.
Puberty-Related Changes in Cortisol, Dehydroepiandrosterone, and Estradiol-17β Secretions within the First Hour after Waking in Premenarcheal Girls
Authors: Kang Jung Y. , Park Jai Y. , Chun Sae I. , Suh Ho S. , Lee Keesook , Ahn Ryun S.
Published: June 2014

Objective: The onset of menstruation is the hallmark of female pubertal development. The present study determined whether pubertal girls experience adrenocortical and ovarian steroid secretions within their first waking hour before getting their period, similar to those observed in adult females with regular cycles. Methods: Cortisol, dehydroepiandrosterone (DHEA), and estradiol-17β concentrations were measured in saliva samples collected after awakening (0, 30, and 60 min after awakening) from 158 normal premenarcheal pubertal girls and 69 adult females with regular menstrual cycles. The girls were subgrouped according to self-reported Tanner breast (B) and pubic hair (PH) stages (B1PH1, B2PH1, B2PH2, B3PH1, and B3PH2). Results: All the subgroups showed a similar pattern of cortisol secretion. However, cortisol levels were higher in girls at B3PH1 and at B3PH2 than other subgroups. DHEA secretion showed a similar pattern across the groups examined. The largest increase in DHEA levels occurred between B1PH1 and B2PH1 stages, and further increased with pubertal progression. DHEA levels in girls at B3PH2 were approximately one half of the adult value. Estradiol-17β profiles in girls at B3PH1 and B3PH2 differed from those of other subgroups of girl. A sharp increase in estradiol-17β levels after awakening which observed in adult females emerged in girls at B3PH1 and B3PH2. However, the estradiol-17β levels did not reach adult values until B3PH2 stage. Conclusions: The progression of female puberty includes an increase in the levels of adrenocortical and ovarian steroid secretions and a gain of adult female-like patterns of estradiol-17β secretion within their first waking hour.
Identification of a Novel Kisspeptin with High Gonadotrophin Stimulatory Activity in the Dog
Authors: Albers-Wolthers Karin H.J. , de Gier Jeffrey , Kooistra Hans S. , Rutten Victor P.M.G. , van Kooten Peter J.S. , de Graaf Janneke J. , Leegwater Peter A.J. , Millar Robert P. , Schaefers-Okkens Auke C.
Published: June 2014

Kisspeptin (KISS1) and its receptor (KISS1r) are essential for normal reproductive function in many species, but the role of kiss1/kiss1r signalling in the dog has not yet been elucidated. The aims of this study were to identify the canine kiss1 and kiss1r genes and to determine gonadotrophin and oestradiol stimulatory activity of KP-10, the shortest biologically active form of KISS1. Canine kiss1 and kiss1r genes were localized by comparing the reference dog genome with relevant human cDNA sequences, using BLASTn software. The amino acid sequence of canine KP-10 (YNWNVFGLRY) differs at two positions from human KP-10 (YNWNSFGLRF). A single bolus of canine KP-10 was administered intravenously to anoestrous Beagle bitches in dosages of 0, 0.1, 0.2, 0.3, 0.5, 1, 5, 10, and 30 μg/kg. Blood samples were collected before and after canine KP-10 administration for the measurement of plasma luteinizing hormone (LH, all doses), follicle-stimulating hormone (FSH) and oestradiol (1-30 μg/kg). From 0.2 μg/kg onwards, canine KP-10 resulted in a rapid and robust rise in plasma LH concentration (max. at 10 min). KP-10 also resulted in a rapid and robust rise in plasma FSH concentration (max. at 10-20 min). Plasma oestradiol concentration increased significantly after dosages of 1, 5, and 10 μg/kg and reached a maximum at 60-90 min. In conclusion, canine KP-10 is a potent kisspeptin which elicits robust gonadotrophin and oestradiol responses in anoestrous bitches, suggesting that canine kiss1/kiss1r are cogent targets for modulating reproduction in dogs.
Editorial N. 12. Eu voltei!
Authors: Pino Claudia Consuelo Amigo , Messias Carolina Augusto , Gama Mônica , Bergonzoni Gisela Anauate
Published: June 2014

Sem resumo
“Posso roubar as suas frases?": Modernistas brasileiros debatem o tema da autoria
Authors: Machado Marcia Regina Jaschke
Published: June 2014

O tema da autoria foi exaustivamente debatido por intelectuais modernistas brasileiros, principalmente ao longo dos anos de 1920. O que podemos chamar de busca por personalidade autoral de estilos modernos era frequentemente associada às noções de influência e plágio. Este artigo tem por objetivo, portanto, apresentar esse debate em textos publicados na época e em cartas trocadas entre Mário de Andrade e alguns de seus interlocutores.
Tangenciando o gesto autobiográfico em Michel Leiris e Herberto Helder
Authors: Rezende Carolina Anglada de
Published: June 2014

Diante da extensa discussão sobre a autobiografia e seu questionado estatuto de gênero literário, o presente artigo tem como objetivo discutir comparativamente o gesto autobiográfico e seus rastros nas obras de dois escritores, os quais, a seus modos, quebram o protocolo associado às escritas do eu. Trata-se da obra A idade viril de Michel Leiris, em que escritura, confissão, memórias e sonhos se fundem, e Photomaton & Vox, reunião de ensaios, comentários, poemas e relatos do poeta português Herberto Helder.
Novel Calmodulin Mutations Associated With Congenital Arrhythmia Susceptibility
Authors: Makita Naomasa , Yagihara Nobue , Crotti Lia , Johnson Christopher N. , Beckmann Britt-Maria , Roh Michelle S. , Shigemizu Daichi , Lichtner Peter , Ishikawa Taisuke , Aiba Takeshi , Homfray Tessa , Behr Elijah R. , Klug Didier , Denjoy Isabelle , Mastantuono Elisa , Theisen Daniel , Tsunoda Tatsuhiko , Satake Wataru , Toda Tatsushi , Nakagawa Hidewaki , Tsuji Yukiomi , Tsuchiya Takeshi , Yamamoto Hirokazu , Miyamoto Yoshihiro , Endo Naoto , Kimura Akinori , Ozaki Kouichi , Motomura Hideki , Suda Kenji , Tanaka Toshihiro , Schwartz Peter J. , Meitinger Thomas , Kääb Stefan , Guicheney Pascale , Shimizu Wataru , Bhuiyan Zahurul A. , Watanabe Hiroshi , Chazin Walter J. , George Alfred L.
Published: June 2014

Background—

Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (
CALM1
,
CALM2
) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype–phenotype correlations associated with calmodulin mutations.

Methods and Results—

We used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in
CALM2
in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for
CALM1
and
CALM2
associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca
2+
-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca
2+
-binding affinity.

Conclusions—

CALM2
mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.
Metabolic Dysfunction Consistent With Premature Aging Results From Deletion of Pim Kinases
Authors: Din Shabana , Konstandin Mathias H. , Johnson Bevan , Emathinger Jacqueline , Völkers Mirko , Toko Haruhiro , Collins Brett , Ormachea Lucy , Samse Kaitlen , Kubli Dieter A. , De La Torre Andrea , Kraft Andrew S. , Gustafsson Asa B. , Kelly Daniel P. , Sussman Mark A.
Published: June 2014

Rationale
:

The senescent cardiac phenotype is accompanied by changes in mitochondrial function and biogenesis causing impairment in energy provision. The relationship between myocardial senescence and Pim kinases deserves attention because Pim-1 kinase is cardioprotective, in part, by preservation of mitochondrial integrity. Study of the pathological effects resulting from genetic deletion of all Pim kinase family members could provide important insight about cardiac mitochondrial biology and the aging phenotype.

Objective
:

To demonstrate that myocardial senescence is promoted by loss of Pim leading to premature aging and aberrant mitochondrial function.

Methods and Results
:

Cardiac myocyte senescence was evident at 3 months in Pim triple knockout mice, where all 3 isoforms of Pim kinase family members are genetically deleted. Cellular hypertrophic remodeling and fetal gene program activation were followed by heart failure at 6 months in Pim triple knockout mice. Metabolic dysfunction is an underlying cause of cardiac senescence and instigates a decline in cardiac function. Altered mitochondrial morphology is evident consequential to Pim deletion together with decreased ATP levels and increased phosphorylated AMP-activated protein kinase, exposing an energy deficiency in Pim triple knockout mice. Expression of the genes encoding master regulators of mitochondrial biogenesis, PPARγ (peroxisome proliferator-activated receptor gamma) coactivator-1 α and β, was diminished in Pim triple knockout hearts, as were downstream targets included in mitochondrial energy transduction, including fatty acid oxidation. Reversal of the dysregulated metabolic phenotype was observed by overexpressing c-Myc (Myc proto-oncogene protein), a downstream target of Pim kinases.

Conclusions
:

Pim kinases prevent premature cardiac aging and maintain a healthy pool of functional mitochondria leading to efficient cellular energetics.
Effect of Bilateral Internal Mammary Artery Grafts on Long-Term Survival
Authors: Yi Gijong , Shine Brian , Rehman Syed M. , Altman Douglas G. , Taggart David P.
Published: June 2014

Background—

Although the potential survival benefit of bilateral internal mammary artery (BIMA) grafting in comparison with single internal mammary artery (SIMA) grafting has been emphasized by many investigators, the use of BIMA is still low in clinical practice in the absence of randomized trials and long-term results. In the current study, we aimed to assess if there is a long-term survival benefit of BIMA up to 10 years after coronary bypass surgery.

Methods and Results—

We selected published articles comparing survival between SIMA and BIMA patients with follow-up duration of more than a mean of 9 years. We evaluated the log hazard ratio with 95% confidence interval for included studies by using a random-effects meta-analysis. Nine eligible observational studies provided 15 583 patients (8270 SIMA and 7313 BIMA) for meta-analysis. Five studies used propensity score methods for statistical adjustment, 2 with a propensity score–based patient-matching method and 3 with quintile-based stratification. A significant reduction in mortality by using BIMA was observed (hazard ratio, 0.79; 95% confidence interval, 0.75–0.84); no study showed any significantly harmful effect of BIMA on survival. Subgroups of studies using different statistical approaches—unmatched, quintile-based propensity score analysis, and propensity score–based exact patient matching—all showed the survival benefit of BIMA grafting.

Conclusions—

BIMA grafting appears to have better survival with up to 10 years follow-up in comparison with SIMA grafting. Long-term survival benefit of BIMA seems to continue in the second decade after surgery. An ongoing randomized trial comparing SIMA and BIMA groups will add evidence on this issue.
Cardiac CD47 Drives Left Ventricular Heart Failure Through Ca
2+
‐CaMKII‐Regulated Induction of HDAC3
Authors: Sharifi‐Sanjani Maryam , Shoushtari Ali Hakim , Quiroz Marisol , Baust Jeffrey , Sestito Samuel F. , Mosher Mackenzie , Ross Mark , McTiernan Charles F. , St. Croix Claudette M. , Bilonick Richard A. , Champion Hunter C. , Isenberg Jeffrey S.
Published: June 2014

Background

Left ventricular heart failure (
LVHF
) remains progressive and fatal and is a formidable health problem because ever‐larger numbers of people are diagnosed with this disease. Therapeutics, while relieving symptoms and extending life in some cases, cannot resolve this process and transplant remains the option of last resort for many. Our team has described a widely expressed cell surface receptor (
CD
47) that is activated by its high‐affinity secreted ligand, thrombospondin 1 (
TSP
1), in acute injury and chronic disease; however, a role for activated
CD
47 in
LVHF
has not previously been proposed.

Methods and Results

In experimental
LVHF TSP
1‐
CD
47 signaling is increased concurrent with up‐regulation of cardiac histone deacetylase 3 (
HDAC
3). Mice mutated to lack
CD
47 displayed protection from transverse aortic constriction (
TAC
)‐driven
LVHF
with enhanced cardiac function, decreased cellular hypertrophy and fibrosis, decreased maladaptive autophagy, and decreased expression of
HDAC
3. In cell culture, treatment of cardiac myocyte
CD
47 with a
TSP
1‐derived peptide, which binds and activates
CD
47, increased
HDAC
3 expression and myocyte hypertrophy in a Ca
2+
/calmodulin protein kinase
II
(Ca
MKII
)‐dependent manner. Conversely, antibody blocking of
CD
47 activation, or pharmacologic inhibition of Ca
MKII
, suppressed
HDAC
3 expression, decreased myocyte hypertrophy, and mitigated established
LVHF
. Downstream gene suppression of
HDAC
3 mimicked the protective effects of
CD
47 blockade and decreased hypertrophy in myocytes and mitigated
LVHF
in animals.

Conclusions

These data identify a proximate role for the
TSP
1‐
CD
47 axis in promoting
LVHF
by Ca
KMII
‐mediated up‐regulation of
HDAC
3 and suggest novel therapeutic opportunities.
Hospital Variation in Survival Trends for In‐hospital Cardiac Arrest
Authors: Girotra Saket , Cram Peter , Spertus John A. , Nallamothu Brahmajee K. , Li Yan , Jones Philip G. , Chan Paul S. ,   The American Heart Association's Get With the Guidelines‐Resuscitation Investigators
Published: June 2014

Background

During the past decade, survival after in‐hospital cardiac arrest has improved markedly. It remains unknown whether the improvement in survival has occurred uniformly at all hospitals or was driven by large improvements at only a few hospitals.

Methods and Results

We identified 93 342 adults with an in‐hospital cardiac arrest at 231 hospitals in the Get With The Guidelines
®
‐Resuscitation registry during 2000–2010. Using hierarchical regression models, we evaluated hospital‐level trends in survival to discharge. Mean age was 66 years, 59% were men, and 21% were black. Between 2000 and 2010, there was a significant
decrease
in age, prevalence of heart failure and myocardial infarction, and cardiac arrests due to shockable rhythms (
P
<0.001 for all) and an
increase
in prevalence of sepsis, respiratory insufficiency, renal insufficiency, intensive care unit location, and mechanical ventilation before arrest
(P
<0.001 for all). After adjustment for temporal trends in baseline characteristics, hospital rates of in‐hospital cardiac arrest survival improved by 7% per year (
odds ratio [OR]
1.07, 95%
CI
1.06 to 1.08,
P
<0.001). Improvement in survival varied markedly and ranged from 3% in the bottom hospital quartile to 11% in the top hospital quartile. Compared with minor teaching hospitals (
OR
1.04, 95%
CI
1.02 to 1.06), hospital rate of survival improvement was greater at major teaching (
OR
1.08, 95%
CI
1.06 to 1.10) and nonteaching hospitals (
OR
1.07, 95%
CI
1.05 to 1.09,
P
value for interaction=0.03).

Conclusion

Although in‐hospital cardiac arrest survival has improved during the past decade, the magnitude of improvement varied across hospitals. Future studies are needed to identify hospital processes that have led to the largest improvement in survival.
Six-Minute Magnetic Resonance Imaging Protocol for Evaluation of Acute Ischemic Stroke
Authors: Nael Kambiz , Khan Rihan , Choudhary Gagandeep , Meshksar Arash , Villablanca Pablo , Tay Jennifer , Drake Kendra , Coull Bruce M. , Kidwell Chelsea S.
Published: June 2014

Background and Purpose—

If magnetic resonance imaging (MRI) is to compete with computed tomography for evaluation of patients with acute ischemic stroke, there is a need for further improvements in acquisition speed.

Methods—

Inclusion criteria for this prospective, single institutional study were symptoms of acute ischemic stroke within 24 hours onset, National Institutes of Health Stroke Scale ≥3, and absence of MRI contraindications. A combination of echo-planar imaging (EPI) and a parallel acquisition technique were used on a 3T magnetic resonance (MR) scanner to accelerate the acquisition time. Image analysis was performed independently by 2 neuroradiologists.

Results—

A total of 62 patients met inclusion criteria. A repeat MRI scan was performed in 22 patients resulting in a total of 84 MRIs available for analysis. Diagnostic image quality was achieved in 100% of diffusion-weighted imaging, 100% EPI-fluid attenuation inversion recovery imaging, 98% EPI-gradient recalled echo, 90% neck MR angiography and 96% of brain MR angiography, and 94% of dynamic susceptibility contrast perfusion scans with interobserver agreements (
k
) ranging from 0.64 to 0.84. Fifty-nine patients (95%) had acute infarction. There was good interobserver agreement for EPI-fluid attenuation inversion recovery imaging findings (
k
=0.78; 95% confidence interval, 0.66–0.87) and for detection of mismatch classification using dynamic susceptibility contrast-Tmax (
k
=0.92; 95% confidence interval, 0.87–0.94). Thirteen acute intracranial hemorrhages were detected on EPI-gradient recalled echo by both observers. A total of 68 and 72 segmental arterial stenoses were detected on contrast-enhanced MR angiography of the neck and brain with
k
=0.93, 95% confidence interval, 0.84 to 0.96 and 0.87, 95% confidence interval, 0.80 to 0.90, respectively.

Conclusions—

A 6-minute multimodal MR protocol with good diagnostic quality is feasible for the evaluation of patients with acute ischemic stroke and can result in significant reduction in scan time rivaling that of the multimodal computed tomographic protocol.
Neuronal Production of Lipocalin-2 as a Help-Me Signal for Glial Activation
Authors: Xing Changhong , Wang Xiaoshu , Cheng Chongjie , Montaner Joan , Mandeville Emiri , Leung Wendy , van Leyen Klaus , Lok Josephine , Wang Xiaoying , Lo Eng H.
Published: June 2014

Background and Purpose—

We explored the hypothesis that injured neurons release lipocalin-2 as a help me signal.

Methods—

In vivo lipocalin-2 responses were assessed in rat focal cerebral ischemia and human stroke brain samples using a combination of ELISA and immunostaining. In vitro, microglia and astrocytes were exposed to lipocalin-2, and various markers and assays of glial activation were quantified. Functional relevance of neuron-to-glia lipocalin-2 signaling was examined by transferring conditioned media from lipocalin-2–activated microglia and astrocytes onto neurons to see whether activated glia could protect neurons against oxygen–glucose deprivation and promote neuroplasticity.

Results—

In human stroke samples and rat cerebral ischemia, neuronal expression of lipocalin-2 was significantly increased. In primary cell cultures, exposing microglia and astrocytes to lipocalin-2 resulted in glial activation. In microglia, lipocalin-2 converted resting ramified shapes into a long-rod morphology with reduced branching, increased interleukin-10 release, and enhanced phagocytosis. In astrocytes, lipocalin-2 upregulated glial fibrillary acid protein, brain-derived neurotropic factor, and thrombospondin-1. Conditioned media from lipocalin-2–treated astrocytes upregulated synaptotagmin, and conditioned media from lipocalin-2–treated microglia upregulated synaptophysin and post-synaptic density 95 (PSD95) and protected neurons against oxygen–glucose deprivation.

Conclusions—

These findings provide proof of concept that lipocalin-2 is released by injured neurons as a help me distress signal that activates microglia and astrocytes into potentially prorecovery phenotypes.