bluuebunny/crossref_metadata_2025 huggingface dataset:
Continuous Electroencephalogram in Comatose Postcardiac Arrest Syndrome Patients Treated With Therapeutic Hypothermia
Authors: Sadaka Farid , Doerr Danielle , Hindia Jiggar , Lee K. Philip , Logan William
Published: January 2014

Purpose:

Therapeutic Hypothermia (TH) is the only therapeutic intervention proven to significantly improve survival and neurologic outcome in comatose postcardiac arrest patients and is now considered standard of care. When we discuss prognostication with regard to comatose survivors postcardiac arrest, we should look for tools that are both reliable and accurate and that achieve a false-positive rate (FPR) equal to or very closely approaching zero.

Methods:

We retrospectively reviewed data that were prospectively collected on all cardiac arrest patients admitted to our ICU. Continuous electroencephalogram (cEEG) monitoring was performed as part of our protocol for therapeutic hypothermia in comatose postcardiac arrest patients. The primary outcome measure was the best score on hospital discharge on the 5-point Glasgow-Pittsburgh cerebral performance category (CPC) scores.

Results:

A total of 58 patients were included in this study. Twenty five (43%) patients had a good neurologic outcome (CPC score of 1-2). Three (5.2%) patients had nonconvulsive status epilepticus, all of whom had poor outcome (CPC = 5). Seventeen (29%) patients had burst suppression (BS); all had poor outcome. Both nonconvuslsive seizures (NCS) and BS had a specificity of 100% (95% confidence interval [CI], 84%-100%), positive predictive values of 100% (95% CI, 31%-100%), and 100% (95% CI, 77%-100%), respectively. Both NCS and BS had FPRs of zero (95% CI, 0.0-0.69, and 0.0-0.23, respectively).

Conclusions:

In comatose postcardiac arrest patients treated with hypothermia, EEG during the maintenance and rewarming phase of hypothermia can contribute to prediction of neurologic outcome. Pending large multicenter prospective studies evaluating the role of cEEG in prognostication, our study adds to the existing evidence that cEEG can play a potential role in prediction of outcome in postcardiac arrest patients treated with hypothermia.
Long-term water absorption and dimensional stability of composites from recycled polypropylene and rubberwood flour
Authors: Homkhiew Chatree , Ratanawilai Thanate , Thongruang Wiriya
Published: January 2014

The present study aims to investigate the moisture absorption of polypropylene (PP)/rubberwood flour (RWF) composites and its effects on dimensional stability. The compositions included different grades of plastic, and the amounts of wood flour, maleic anhydride-grafted polypropylene (MAPP), and ultraviolet (UV) stabilizer were varied. The composite materials were manufactured into panels by a twin-screw extruder. Long-term water absorption (WA), long-term thickness swelling (TS), and degradation of flexural properties of the composites were studied for a range of water immersion times. The WA and TS of the samples increased with RWF content and immersion time. Recycled PP gave higher WA and TS than virgin PP, for the composites with 45 wt% RWF. Increasing MAPP content from 3 to 5 wt% had no significant effect on WA and TS, whereas the addition of 1 wt% UV stabilizer increased them. A MAPP content of 3 wt% is recommended for moisture resistance, while the amount of UV stabilizer should be kept as low as possible. Flexural strength and modulus of composites also decreased with moisture uptake; however, <3% WA did not significantly affect the flexural strength. In contrast, the maximum strain of composites consistently increased with WA.
Wisdom’s Whimsical Ways
Authors: Bunkers Sandra Schmidt
Published: January 2014

The purpose of this article is to explore the various ways wisdom is manifested in day-to-day living. Selected literature on wisdom is explored from a humanbecoming nurse perspective, perspectives from philosophy, psychiatry, theology, anthropology and the martial arts. A humanbecoming perspective on living wisdom is synthesized from the literature review.
Methotrexate in systemic lupus erythematosus: a systematic review of its efficacy
Authors: Sakthiswary R , Suresh E
Published: January 2014

Objective

The objective of this review is to evaluate the evidence for efficacy of methotrexate (MTX) in systemic lupus erythematosus (SLE).

Methods

A comprehensive, computerized search was performed in MEDLINE (PubMed), EMBASE and the Cochrane Controlled Trials registry to screen for studies that examined the efficacy of MTX in adult SLE patients. The Jadad scoring system was used to assess study quality, and data were pooled using the random effects model.

Results

Of the 53 articles that were identified, 44 were excluded. Nine studies (including three randomized controlled and six observational) were eligible for inclusion. All of the included studies predominantly involved patients with arthritis or mucocutaneous features. There was significant reduction of the SLE Disease Activity Index (SLEDAI) among MTX-treated patients when compared with controls ( p = 0.001, odds ratio (OR) 0.444, 95% confidence interval (CI) 0.279 to 0.707). There was also significant reduction in the average dose of corticosteroids among MTX-treated patients when compared with controls ( p = 0.001, OR 0.335, 95% CI 0.202 to 0.558). The effect of MTX on laboratory and serological markers, including erythrocyte sedimentation rate, anti-dsDNA and complement levels (C3 and C4), could not be determined because of the limited numbers of controlled trials.

Conclusion

The use of MTX is associated with significant reductions in SLEDAI and the average dose of corticosteroids in adult patients with SLE.
DNA and RNA isolation from canine oncologic formalin-fixed, paraffin-embedded tissues for downstream “-omic” analyses
Authors: Granato Anna , Giantin Mery , Ariani Pietro , Carminato Antonio , Baratto Chiara , Zorzan Eleonora , Vascellari Marta , Bozzato Elisa , Dacasto Mauro , Mutinelli Franco
Published: January 2014

Formalin-fixed, paraffin-embedded (FFPE) tissues represent a unique source of archived biological material, but obtaining suitable DNA and RNA for retrospective “-omic” investigations is still challenging. In the current study, canine tumor FFPE blocks were used to 1) compare common commercial DNA and RNA extraction kits; 2) compare target gene expression measured in FFPE blocks and biopsies stored in a commercial storage reagent; 3) assess the impact of fixation time; and 4) perform biomolecular investigations on archival samples chosen according to formalin fixation times. Nucleic acids yield and quality were determined by spectrophotometer and capillary electrophoresis, respectively. Quantitative real-time polymerase chain reaction assays for the following genes: BCL-2–associated X protein, B-cell lymphoma extra large, antigen identified by monoclonal antibody Ki-67, proto-oncogene c-KIT ( c-kit). Two internal control genes ( Golgin A1 and canine transmembrane BAX inhibitor motif containing 4), together with direct sequencing of c-kit exons 8, 9, 11, and 17, were used as end points. Differences in DNA/RNA yield and purity were noticed among the commercial kits. Nucleic acids (particularly RNA) extracted from paraffin blocks were degraded, even at lower fixation times. Compared to samples held in the commercial storage reagent, archived tissues showed a poorer amplification. Therefore, a gold standard protocol for DNA/RNA isolation from canine tumor FFPE blocks for molecular investigations is still troublesome. More standardized storage conditions, including time between sample acquisition and fixation, fixation time, and sample thickness, are needed to guarantee the preservation of nucleic acids and, then, their possible use in retrospective transcriptomic analysis.
Successful Coil Embolization of Circumflex Iliac Artery Pseudoaneurysms Following Paracentesis
Authors: Day Ryan W. , Huettl Eric A. , Naidu Sailendra G. , Eversman William G. , Douglas David D. , O’Donnell Mark E.
Published: January 2014

Abdominal paracentesis complicated by perforation of a penetrating arterial branch is an extremely rare complication. We report 2 patients who presented with abdominal wall pseudoaneurysms following abdominal paracentesis for the evaluation and treatment of their hepatic dysfunction. We subsequently review the treatment modalities and interventions performed in each case.
Metastatic Endometrial Sarcoma With Inferior Vena Caval and Cardiac Involvement
Authors: Nathan Derek , Szeto Wilson , Gutsche Jacob , Min Htun , Kalapatapu Venkat
Published: January 2014

Low-grade endometrial stromal sarcoma with intracaval and intracardiac extension represents a complex and often lethal condition. A case of a 40-year-old woman, who underwent hysterectomy for endometrial stromal sarcoma 4 years previously and developed recurrence with intracaval and intracardiac metastases, is presented. Operative management of resection of the intracaval and intracardiac tumor is described. The literature is reviewed in order to highlight the data on diagnosis and management of recurrent endometrial stromal sarcoma with vascular involvement, including the multimodality approach required in treating this disease.
Is It Possible to Eliminate Sutures in Open (Lichtenstein Technique) and Laparoscopic (Totally Extraperitoneal Endoscopic) Inguinal Hernia Repair? A Randomized Controlled Trial With Tissue Adhesive (n-Hexyl-α-Cyanoacrylate)
Authors: Moreno-Egea Alfredo
Published: January 2014

Background. The morbidity linked to the use of sutures in inguinal hernioplasty is well known. Tissue adhesives may be an alternative, so as to be able to improve levels of postoperative comfort, but clinical experience using them is limited. The aim of this study is to evaluate the efficiency of cyanoacrylate as a substitute for sutures in the treatment of inguinal hernias. Patients. Randomized clinical trial in abdominal wall unit. A total of 208 patients were operated upon for inguinal hernias of which 102 were unilateral hernias via open surgery using the Lichtenstein technique, randomized to receive prolene sutures (n = 52) or n-hexyl-α-cyanoacrylate glue (n = 50) and 106 were patients with bilateral inguinal hernias operated upon via totally extraperitoneal laparoscopy and randomized to receive either tackers (n = 54) or glue (n = 52). Main Outcome Measures. The primary endpoints were pain and recurrence. Secondary endpoints were operating time, postoperative morbidity, pain, and analgesic consumption. Results. No morbidity associated with the use of the glue existed. The use of glue significantly reduced the mean of surgical time (12 minutes in open surgery, 13 minutes in laparoscopic surgery), pain, and analgesics consumption, both via the open and laparoscopic approaches ( P < .001). After 1 year the adhesive did not change the recurrence rate in either of the approaches. The economic analysis shows potential yearly savings of 123 916.3 Euros. Conclusions. Substituting sutures with glue ( n-hexyl-α-cyanoacrylate) in open or laparoscopic inguinal hernioplasty is safe with less postoperative pain and the same possibilities of recurrence.
Novel association of rectal evacuation disorder and rumination syndrome: Diagnosis, comorbidities, and treatment
Authors: Vijayvargiya Priya , Iturrino Johanna , Camilleri Michael , Shin Andrea , Vazquez-Roque Maria , Katzka David A , Snuggerud Jill R , Seime Richard J
Published: January 2014

Background

Patients with disorders of gastrointestinal function may undergo unnecessary treatment if misdiagnosed as motility disorders.

Objective

To report on clinical features, medical, surgical, and psychiatric comorbidities, and prior treatments of a patient cohort diagnosed concurrently with nonpsychogenic rumination syndrome and pelvic floor dysfunction (also termed rectal evacuation disorder).

Methods

From a consecutive series (1994–2013) of 438 outpatients with rectal evacuation disorders in the practice of a single gastroenterologist at a tertiary care centre, 57 adolescents or adults were diagnosed with concomitant rumination syndrome. All underwent formal psychological assessment or completed validated questionnaires.

Results

All 57 patients (95% female) fulfilled Rome III criteria for rumination syndrome; rectal evacuation disorder was confirmed by testing of anal sphincter pressures and rectal balloon evacuation. Prior to diagnosis, most patients underwent multiple medical and surgical treatments (gastrostomy, gastric fundoplication, other gastric surgery, ileostomy, colectomy) for their symptoms. Psychological comorbidity was identified in 93% of patients. Patients were managed predominantly with psychological and behavioural approaches: diaphragmatic breathing for rumination and biofeedback retraining for pelvic floor dysfunction.

Conclusions

Awareness of concomitant rectal evacuation disorder and rumination syndrome and prompt identification of psychological comorbidity are keys to instituting behavioural and psychological methods to avoid unnecessary treatment.
Prevalence and factors associated with low bone mineral density in Saudi women: a community based survey
Authors: AlQuaiz AlJohara M , Kazi Ambreen , Tayel Salwa , Shaikh Shaffi Ahamed , Al-Sharif Abdullah , Othman Saleh , Habib Fawzia , Fouda Mona , Sulaimani Riad
Published: January 2014

Background

Low bone mineral density (BMD) is a public health issue in Saudi Arabia. This study measured the prevalence and factors associated with low BMD in Saudi women in Riyadh, Saudi Arabia.

Methods

A cross sectional study using two stage cluster sampling technique was conducted in Riyadh, 2009. Thirty clusters, each comprising of 300 houses were randomly chosen and from each cluster 38–40 households were selected to identify 1150 women of >40 years. Women were invited to primary health care center for filling of self-administered questionnaire (n = 1069) comprising of sociodemographic, health, diet and physical activity variables. 1008 women underwent screening for low BMD using the quantitative ultrasound technique. 535 (53%) women with positive screening test were referred to King Khalid Hospital for Dual X-ray Energy absorptiometry (DXA).

Results

362 women underwent DXA and 212 (39.6%) were screened low BMD either at lumbar spine or femur neck. Mean age of women was 55.26(±8.84) years. Multivariate logistic analysis found; being aged 61 to 70 years (OR 2.75, 95% CI: 1.32-1.48), no literacy (OR 2.97, 95% CI:1.44 - 6.12) or primary education (OR 4.12, 95% CI:2.05-8.29), history of fractures (OR 2.20, 95% CI:1.03- 4.69) and not drinking laban(diluted yogurt) (OR 2.81, 95% CI:1.47- 5.37) significantly associated with low BMD.

Conclusions

Women with low level of education, who do not drink laban and had history of fractures were at high risk of low BMD.
Initial and Cyclic Recruitment of Ovarian Follicles*
Authors: McGee Elizabeth A. , Hsueh Aaron J. W.
Published: January 2014

Mammalian ovaries consist of follicles as basic functional units. The total number of ovarian follicles is determined early in life, and the depletion of this pool leads to reproductive senescence. Each follicle develops to either ovulate or, more likely, to undergo degeneration. The dynamics of ovarian follicle development have interested endocrinologists and developmental biologists for many years. With the advent of assisted reproductive techniques in humans, the possibility of regulating follicle development in vivo and in vitro has gained clinical relevance. In this review, we focus upon key branching points during the development of ovarian follicles as well as factors involved in determining the eventual destiny of individual follicles. We discuss inconsistencies in the literature regarding the definitions of follicle recruitment and selection and propose to name the two major steps of follicle development as initial and cyclic recruitment, respectively. Because some of these disparities have arisen due to differences in the animal systems studied, we also compare the development of the ovarian follicles of both humans and rats. We also review the status of knowledge of several puzzling clinical issues that may provide important clues toward unlocking the mechanisms of follicle development.
Endocrine Dysfunction in Prader-Willi Syndrome: A Review with Special Reference to GH
Authors: Burman Pia , Ritzén E. Martin , Lindgren Ann Christin
Published: January 2014

Prader-Willi syndrome is a genetic disorder occurring in 1 in 10,000–16,000 live-born infants. In the general population, approximately 60 people in every 1,000,000 are affected. The condition is characterized by short stature, low lean body mass, muscular hypotonia, mental retardation, behavioral abnormalities, dysmorphic features, and excessive appetite with progressive obesity. Furthermore, morbidity and mortality are high, probably as a result of gross obesity. Most patients have reduced GH secretory capacity and hypogonadotropic hypogonadism, suggesting hypothalamic-pituitary dysfunction. Replacement of GH and/or sex hormones may therefore be beneficial in Prader-Willi syndrome, and several clinical trials have now evaluated GH replacement therapy in affected children. Results of GH treatment have been encouraging: improved growth, increased lean body mass, and reduced fat mass. There was also some evidence of improvements in respiratory function and physical activity. The long-term benefits of GH treatment are, however, still to be established. Similarly, the role of sex hormone replacement therapy needs to be clarified as few data exist on its efficacy and potential benefits. In summary, Prader-Willi syndrome is a disabling condition associated with GH deficiency and hypogonadism. More active treatment of these endocrine disorders is likely to benefit affected individuals.
Hypoglycemia from IGF2 Overexpression Associated with Activation of Fetal Promoters and Loss of Imprinting in a Metastatic Hemangiopericytoma
Authors: Lawson Elizabeth A. , Zhang Xun , Crocker Jonathan T. , Wang Wei-Lien , Klibanski Anne
Published: January 2014

Context

The mechanism of IGF2 overexpression in non-islet-cell tumor hypoglycemia is not understood.

Objective

We investigated the imprinting control and promoter usage for IGF2 expression to identify a mechanism for increased IGF-II production in non-islet-cell tumor hypoglycemia.

Patient and Methods

A patient with metastatic hemangiopericytoma was studied. Tissue from the original hemangiopericytoma, metastatic tumor, and uninvolved liver was analyzed for IGF-II immunohistochemistry. IGF2, a paternally imprinted gene, shares a control region with maternally imprinted H19, a putative tumor suppressor. IGF-II and H19 mRNA expression was compared in metastatic tumor and uninvolved liver by quantitative RT-PCR. Imprinting of IGF2/H19 genes and IGF2 promoter usage in metastatic tumor was investigated by RT-PCR and sequence analysis, and the methylation pattern in the IGF2/H19 imprinting control region was analyzed.

Results

IGF-II protein expression was increased in metastatic tumor vs. uninvolved liver and original tumor. In the metastatic tumor, IGF-II mRNA was increased 60-fold, but H19 mRNA was comparable to uninvolved liver; loss of imprinting of IGF2, but not H19, was identified; no major change in methylation of the IGF2/H19 imprinting control regions was observed; and transcripts from four different IGF2 promoters were detected, compared to two in uninvolved liver.

Conclusions

IGF-2 overexpression, newly acquired in the metastatic tumor, was associated with loss of IGF2 gene imprinting and different promoter usage. The imprinting control mechanism governing the IGF2/H19 locus was intact, as evidenced by normal levels of H19, maintenance of H19 imprinting, and no major change in methylation of the imprinting control regions.
Physiological Thyroid Hormone Levels Regulate Numerous Skeletal Muscle Transcripts
Authors: Visser W. Edward , Heemstra Karen A. , Swagemakers Sigrid M. A. , Özgür Zeliha , Corssmit Eleonora P. , Burggraaf Jacobus , van Ijcken Wilfred F. J. , van der Spek Peter J. , Smit Johannes W. A. , Visser Theo J.
Published: January 2014

Context

Skeletal muscle is an important target tissue for thyroid hormone (TH). It is currently unknown which genes are regulated by physiological TH levels.

Objective

We examined the effects of l-thyroxine on human skeletal muscle transcriptome.

Design

Microarray analysis of transcript levels was performed using skeletal muscle biopsies from patients under euthyroid and hypothyroid conditions.

Setting

The study was conducted in a university hospital laboratory.

Patients

We studied skeletal muscle obtained from 10 thyroidectomized patients with differentiated thyroid carcinoma on and after 4 wk off l-thyroxine replacement.

Mean Outcome Measures

Gene expression changes were measured using microarrays. Results were analyzed using dedicated statistical methods.

Results

We detected 607 differentially expressed genes on l-thyroxine treatment, of which approximately 60% were positively and approximately 40% were negatively regulated. Representative genes were validated by quantitative PCR. Genes involved in energy and fuel metabolism were overrepresented among the up-regulated genes, of which a large number were newly associated with thyroid state. l-thyroxine therapy induced a large down-regulation of the primary transcripts of the noncoding microRNA pair miR-206/miR-133b.

Conclusion

We demonstrated that physiological levels of TH regulate a myriad of genes in human skeletal muscle. The identification of novel putatively TH-responsive genes may provide the molecular basis of clinical effects in subjects with different TH status. The observation that TH regulates microRNAs reveals a new layer of complexity by which TH influences cellular processes.
Subcutaneous Injection of Kisspeptin-54 Acutely Stimulates Gonadotropin Secretion in Women with Hypothalamic Amenorrhea, But Chronic Administration Causes Tachyphylaxis
Authors: Jayasena Channa N. , Nijher Gurjinder K. , Chaudhri Owais B. , Murphy Kevin G. , Ranger Amita , Lim Adrian , Patel Daksha , Mehta Amrish , Todd Catriona , Ramachandran Radha , Salem Victoria , Stamp Gordon W. , Donaldson Mandy , Ghatei Mohammad A. , Bloom Stephen R. , Dhillo Waljit S.
Published: January 2014

Background

Kisspeptin is a critical regulator of normal reproductive function. A single injection of kisspeptin in healthy human volunteers potently stimulates gonadotropin release. However, the effects of kisspeptin on gonadotropin release in women with hypothalamic amenorrhea (HA) and the effects of repeated administration of kisspeptin to humans are unknown.

Aim

The aim of this study was to determine the effects of acute and chronic kisspeptin administration on gonadotropin release in women with HA.

Methods

We performed a prospective, randomized, double-blinded, parallel design study. Women with HA received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline (n = 5 per group) for 2 wk. Changes in serum gonadotropin and estradiol levels, LH pulsatility, and ultrasound measurements of reproductive activity were assessed.

Results

On the first injection day, potent increases in serum LH and FSH were observed after sc kisspeptin injection in women with HA (mean maximal increment from baseline within 4 h after injection: LH, 24.0 ± 3.5 IU/liter; FSH, 9.1 ± 2.5 IU/liter). These responses were significantly reduced on the 14th injection day (mean maximal increment from baseline within 4 h postinjection: LH, 2.5 ± 2.2 IU/liter, P < 0.05; FSH, 0.5 ± 0.5 IU/liter, P < 0.05). Subjects remained responsive to GnRH after kisspeptin treatment. No significant changes in LH pulsatility or ultrasound measurements of reproductive activity were observed.

Conclusion

Acute administration of kisspeptin to women with infertility due to HA potently stimulates gonadotropin release, but chronic administration of kisspeptin results in desensitization to its effects on gonadotropin release. These data have important implications for the development of kisspeptin as a novel therapy for reproductive disorders in humans.
Activation of the Aryl-Hydrocarbon Receptor Inhibits Invasive and Metastatic Features of Human Breast Cancer Cells and Promotes Breast Cancer Cell Differentiation
Authors: Hall Julie M. , Barhoover Melissa A. , Kazmin Dmitri , McDonnell Donald P. , Greenlee William F. , Thomas Russell S.
Published: January 2014

The current statistics associated with breast cancer continue to show a relatively high recurrence rate together with a poor survival for aggressive metastatic disease. These findings reflect, in part, the pharmaceutical intractability of processes involved in the metastatic process and highlight the need to identify additional drug targets for the treatment of late-stage disease. In the current study, we report that ligand activation of the aryl-hydrocarbon receptor (AhR) inhibits multiple aspects of the metastatic process in a panel of breast cancer cell lines that represent the major breast cancer subtypes. Specifically, it was observed that treatment with exogenous AhR agonists significantly inhibited cell invasiveness and motility in the Boyden chamber assay and inhibited colony formation in soft agar regardless of estrogen receptor (ER), progesterone receptor, or human epidermal growth factor receptor 2 status. Knockdown of the AhR using small interfering RNA duplexes demonstrated that the inhibition of invasiveness was receptor dependent and that endogenous receptor activity was protective in each cell type examined. The inhibition of invasiveness and anchorage-independent growth correlated with the ability of exogenous AhR agonists to promote differentiation. Finally, exogenous AhR agonists were able to promote differentiation in a putative mammary cancer stem cell line. Cumulatively, these results suggest that the AhR plays an important role in mammary epithelial differentiation and, as such, represent a promising therapeutic target for a range of phenotypically distinct human breast cancers.
Chemerin, A Novel Adipokine in the Regulation of Angiogenesis
Authors: Bozaoglu Kiymet , Curran Joanne E. , Stocker Claire J. , Zaibi Mohamed S. , Segal David , Konstantopoulos Nicky , Morrison Shona , Carless Melanie , Dyer Thomas D. , Cole Shelley A. , Goring Harald H. H. , Moses Eric K. , Walder Ken , Cawthorne Michael A. , Blangero John , Jowett Jeremy B. M.
Published: January 2014

Context

Chemerin is a new adipokine associated with obesity and the metabolic syndrome. Gene expression levels of chemerin were elevated in the adipose depots of obese compared with lean animals and was markedly elevated during differentiation of fibroblasts into mature adipocytes.

Objective

To identify factors that affect the regulation and potential function of chemerin using a genetics approach.

Design, setting, patients and intervention

Plasma chemerin levels were measured in subjects from the San Antonio Family Heart Study (SAFHS), a large family-based genetic epidemiological study including 1354 Mexican American individuals. Individuals were randomly sampled without regard to phenotype or disease status.

Main Outcome Measures

A genome wide association analysis using 542,944 SNPs in a subset of 523 of the same subjects was undertaken. The effect of chemerin on angiogenesis was measured using human endothelial cells and interstitial cells in co-culture in a specially formulated medium.

Results

Serum chemerin levels were found to be highly heritable (h2 = 0.25; P = 1.4 x 10−9). The SNP showing strongest evidence of association (rs347344; P = 1.4 x 10−6) was located within the gene encoding EDIL3, which has a known role in angiogenesis. Functional angiogenesis assays in human endothelial cells confirmed that chemerin significantly mediated the formation of blood vessels to a similar extent as VEGF.

Conclusion

Here we demonstrate for the first time that plasma chemerin levels are significantly heritable and identified a novel role for chemerin as a stimulator of angiogenesis.
Periovulatory Expression of Hyaluronan and Proteoglycan Link Protein 1 (Hapln1) in the Rat Ovary: Hormonal Regulation and Potential Function
Authors: Liu Jing , Park Eun-Sil , Curry Thomas E. , Jo Misung
Published: January 2014

Periovulatory follicular matrix plays an important role in cumulus-oocyte complex (COC) expansion, ovulation, and luteal formation. Hyaluronan and proteoglycan link protein 1 (HAPLN1), a component of follicular matrix, was shown to enhance COC expansion in vitro. However, the regulatory mechanisms of periovulatory expression of Hapln1 and its role in periovulatory granulosa cells have not been elucidated. We first determined the periovulatory expression pattern of Hapln1 using pregnant mare serum gonadotropin/human chorionic gonadotropin (hCG)-primed immature rat ovaries. Hapln1 expression was transiently induced both in intact ovaries and granulosa cells at 8 h and 12 h after hCG injection. This in vivo expression of Hapln1 was recapitulated by culturing preovulatory granulosa cells with hCG. The stimulatory effect of hCG was blocked by inhibition of protein kinase A, phosphatidylinositol dependent kinase, p38 MAPK, epidermal growth factor signaling, and prostaglandin synthesis, revealing key mediators involved in LH-induced Hapln1 expression. In addition, knockdown of Runx1 and Runx2 expression by small interfering RNA or inhibition of RUNX activities by dominant-negative RUNX decreased hCG or agonist-induced Hapln1 expression. Chromatin immunoprecipitation assays verified the in vivo binding of RUNX1 and RUNX2 to the Hapln1 promoter in periovulatory granulosa cells. Luciferase reporter assays revealed that mutation of the RUNX binding sites completely obliterated the agonist-induced activity of the Hapln1 promoter. These data conclusively identified RUNX proteins as the crucial transcription regulators for LH-induced Hapln1 expression. Functionally, treatment with HAPLN1 increased the viability of cultured granulosa cells and decreased the number of the cells undergoing apoptosis, whereas knockdown of Hapln1 expression decreased granulosa cells viability. This novel finding indicates that HAPLN1 may promote periovulatory granulosa cell survival, which would facilitate their differentiation into luteal cells.
Cevoglitazar, a Novel Peroxisome Proliferator-Activated Receptor-α/γ Dual Agonist, Potently Reduces Food Intake and Body Weight in Obese Mice and Cynomolgus Monkeys
Authors: Chen Hong , Dardik Beatriz , Qiu Ling , Ren Xianglin , Caplan Shari L. , Burkey Bryan , Boettcher Brian R. , Gromada Jesper
Published: January 2014

Cevoglitazar is a dual agonist for the peroxisome proliferator-activated receptor (PPAR)-α and -γ subtypes. Dual activation of PPARα and -γ is a therapeutic approach in development for the treatment of type 2 diabetes mellitus and diabetic dyslipidemia. In this report, we show that, in addition to improving insulin sensitivity and lipid metabolism like other dual PPAR agonists, cevoglitazar also elicits beneficial effects on energy homeostasis in two animal models of obesity. In leptin-deficient ob/ob mice, administration of cevoglitazar at 0.5, 1, or 2 mg/kg for 18 d led to acute and sustained, dose-dependent reduction of food intake and body weight. Furthermore, plasma levels of glucose and insulin were normalized after 7 d of cevoglitazar treatment at 0.5 mg/kg. Plasma levels of free fatty acids and triglycerides were dose-dependently reduced. In obese and insulin-resistant cynomolgus monkeys, treatment with cevoglitazar at 50 and 500 μg/kg for 4 wk lowered food intake and body weight in a dose-dependent manner. In these animals, cevoglitazar also reduced fasting plasma insulin and, at the highest dose, reduced hemoglobin A1c levels by 0.4%. These preclinical results demonstrate that cevoglitazar holds promise for the treatment of diabetes and obesity-related disorders because of its unique beneficial effect on energy balance in addition to improving glycemic and metabolic control.
Minireview: A Skeleton in Serotonin’s Closet?
Authors: Kawai Masanobu , Rosen Clifford J.
Published: January 2014

The serotonin molecule plays a multifunctional role in mammalian homeostasis serving as a neurotransmitter in the central nervous system, a gut-derived mediator of peristalsis, and a circulating hormone that regulates appetite, cardiovascular function, and hemostasis. Recent evidence from the clinic and the bench highlight an unexpected target for serotonin action, the skeleton. Clinically, two classes of drugs, the second generation antipsychotic drugs (SGAs) and selective serotonin reuptake inhibitors (SSRIs), which modulate central and peripheral serotonin signaling, have been shown to alter bone remodeling although the mechanism is not clear. In contrast, genetically engineered mouse models have demonstrated a bimodal control system whereby gut-derived serotonin under the control of the Wnt/Lrp/β-catenin system acts systemically to suppress bone formation, whereas CNS serotonin activated by leptin modulates sympathetic outflow to the skeleton. In this brief review, we will summarize recent findings linking serotonin to the skeleton and discuss future directions for this new but challenging aspect of this multidimensional molecule.
Inflammation and Obesity Pathogenesis: The Hypothalamus Heats Up
Authors: Thaler Joshua P. , Schwartz Michael W.
Published: January 2014

Obesity induced by high-fat (HF) feeding is associated with low-grade inflammation in peripheral tissues that predisposes to insulin resistance. Recent evidence suggests the occurrence of a similar process in the hypothalamus, which favors weight gain through impairment of leptin and insulin signaling. In addition to its implications for obesity pathogenesis, this hypothesis suggests that centrally targeted antiinflammatory therapies may prove effective in prevention and treatment of this disorder. This article highlights molecular and cellular mechanisms by which hypothalamic inflammation predisposes to diet-induced obesity.
GH Response to Oral Glucose Tolerance Test: A Comparison between Patients with Acromegaly and Other Pituitary Disorders
Authors: Verrua E. , Filopanti M. , Ronchi C. L. , Olgiati L. , Ferrante E. , Giavoli C. , Sala E. , Mantovani G. , Arosio M. , Beck-Peccoz P. , Lania A. G. , Spada A.
Published: January 2014

Context

The cutoff value of nadir GH after an oral glucose tolerance test (OGTT) used to define disease remission in acromegaly is higher than that observed in healthy subjects. However, it is uncertain whether the impaired GH inhibition might be related to subtle abnormalities of GH secretion or to functional and/or anatomical hypothalamic-pituitary disconnection due to tumor per se or treatments.

Objective

The objective of the study was to evaluate the impact of pituitary disorders other than acromegaly on GH response to OGTT.

Design, Subjects, and Methods

Thirty-three patients (24 females and nine males, aged 50.1 ± 12.3 yr, 13 operated and two irradiated) with various hypothalamic-pituitary disorders (HPDs), 45 healthy subjects (controls), and 42 cured acromegalic patients matched for sex, age. and body mass index were investigated. All subjects were studied for IGF-I levels and GH levels before and during the OGTT.

Results

In HPD patients mean postglucose nadir GH levels were 0.11 ± 0.08 μg/liter without any difference between patients treated with neurosurgery and/or radiotherapy and untreated and between patients with and without pituitary stalk alterations and/or hyperprolactinemia. Mean nadir GH values were similar in HPD patients and controls (0.11 ± 0.08 vs. 0.08 ± 0.08 μg/liter, P = 0.23) and lower than those found in cured acromegalic patients (0.18 ± 0.13 μg/liter, P = 0.02), although there was an overlapping in about half of patients.

Conclusions

Hypothalamic control of glucose-mediated GH suppression is not perturbed in patients with HPD. These data indicate that defective GH suppression to glucose that is found in acromegaly is unlikely to reflect a lack of integrity of hypothalamic function.
Leptin-Independent Programming of Adult Body Weight and Adiposity in Mice
Authors: Cottrell Elizabeth C. , Martin-Gronert Malgorzata S. , Fernandez-Twinn Denise S. , Luan Jian'an , Berends Lindsey M. , Ozanne Susan E.
Published: January 2014

Low birth weight and rapid postnatal weight gain are independent and additive risk factors for the subsequent development of metabolic disease. Despite an abundance of evidence for these associations, mechanistic data are lacking. The hormone leptin has received significant interest as a potential programming factor, because differences in the profile of leptin in early life have been associated with altered susceptibility to obesity. Whether leptin alone is a critical factor for programming obesity has, until now, remained unclear. Using the leptin-deficient ob/ob mouse, we show that low birth weight followed by rapid catch-up growth during lactation (recuperated offspring) leads to a persistent increase in body weight in adult life, both in wild-type and ob/ob animals. Furthermore, recuperated offspring are hyperphagic and epididymal fat pad weights are significantly increased, reflecting greater adiposity. These results show definitively that factors other than leptin are crucial in the programming of energy homeostasis in this model and are powerful enough to alter adiposity in a genetically obese strain.
Effects of Gestation on Enzymes Controlling Aldosterone Synthesis in the Rat Adrenal*
Authors: Brochu Michèle , Lehoux Jean-Guy , Picard Serge
Published: January 2014

In the present study, the effects of gestation on various enzymes implicated in corticosteroid synthesis were evaluated in adrenal zona glomerulosa and zona fasciculata-reticularis of the Sprague-Dawley rat. The activity and expression of cholesterol side-chain cleavage cytochrome P450, 11β-hydroxylase cytochrome P450, and aldosterone synthase cytochrome P450 (P450aldo) were analyzed. Plasma aldosterone levels were increased significantly at 22 days gestation (n = 10) and fell below the nonpregnant levels at 18–36 h postpartum (n = 11). The activity and expression of 11β-hydroxylase cytochrome P450 and cholesterol side-chain cleavage cytochrome P450 were not modified by gestation. P450aldo activity increased at 14 days gestation (n= 4) and returned to the prepregnancy level at 2 weeks postpartum (n = 5). As shown by Northern blot analysis (n = 3), P450aldo messenger RNA increased significantly at 22 days gestation and decreased 18–36 h postpartum. We clearly demonstrated that elevated plasma aldosterone levels during pregnancy are associated with augmented activity and messenger RNA levels of P450aldo in the zona glomerulosa.
Corticotropin-Releasing Hormone Induces Skin Mast Cell Degranulation and Increased Vascular Permeability, A Possible Explanation for Its Proinflammatory Effects*
Authors: Theoharides Theoharis C. , K. Singh Leena , Boucher William , Pang Xinzhu , Letourneau Richard , Webster Elizabeth , Chrousos George
Published: January 2014

Mast cells are involved in atopic disorders, often exacerbated by stress, and are located perivascularly close to sympathetic and sensory nerve endings. Mast cells are activated by electrical nerve stimulation and millimolar concentrations of neuropeptides, such as substance P (SP). Moreover, acute psychological stress induces CRH-dependent mast cell degranulation. Intradermal administration of rat/human CRH (0.1–10 μm) in the rat induced mast cell degranulation and increased capillary permeability in a dose-dependent fashion. The effect of CRH on Evans blue extravasation was stronger than equimolar concentrations of the mast cell secretagogue compound 48/80 or SP. The free acid analog of CRH, which does not interact with its receptors (CRHR), had no biological activity. Moreover, systemic administration of antalarmin, a nonpeptide CRHR1 antagonist, prevented vascular permeability only by CRH and not by compound 48/80 or SP. CRHR1 was also identified in cultured leukemic human mast cells using RT-PCR. The stimulatory effect of CRH, like that of compound 48/80 on skin vasodilation, could not be elicited in the mast cell deficient W/Wv mice but was present in their +/+ controls, as well as in C57BL/6J mice; histamine could still induce vasodilation in the W/Wv mice. Treatment of rats neonatally with capsaicin had no effect on either Evans blue extravasation or mast cell degranulation, indicating that the effect of exogenous CRH in the skin was not secondary to or dependent on the release of neuropeptides from sensory nerve endings. The effect of CRH on Evans blue extravasation and mast cell degranulation was inhibited by the mast cell stabilizer disodium cromoglycate (cromolyn), but not by the antisecretory molecule somatostatin. To investigate which vasodilatory molecules might be involved in the increase in vascular permeability, the CRH injection site was pretreated with the H1-receptor antagonist diphenhydramine, which largely inhibited the CRH effect, suggesting that histamine was involved in the CRH-induced vasodilation. The possibility that nitric oxide might also be involved was tested using pretreatment with a nitric oxide synthase inhibitor that, however, increased the effect of CRH. These findings indicate that CRH activates skin mast cells at least via a CRHR1-dependent mechanism leading to vasodilation and increased vascular permeability. The present results have implications for the pathophysiology and possible therapy of skin disorders, such as atopic dermatitis, eczema, psoriasis, and urticaria, which are exacerbated or precipitated by stress.
Isolation, Primary Structure, and Effects onα -Melanocyte-Stimulating Hormone Release of Frog Neurotensin**This work was supported by the NSF, INSERM, and the Conseil Régional de Haute-Normandie.
Authors: Desrues Laurence , Tonon Marie-Christine , Leprince Jerome , Vaudry Hubert , Conlon J. Michael
Published: January 2014

Neurotensin (NT) was isolated in pure form from the small intestine of the European green frog, Rana ridibunda, and its primary structure was established as pGlu-Ala-His-Ile-Ser-Lys-Ala-Arg-Arg-Pro-Tyr-Ile-Leu. This sequence contains five amino acid substitutions (Leu2→Ala, Tyr3→His, Glu4→Ile, Asn5→Ser, and Pro7→Ala) compared with human NT. A peptide with identical chromatographic properties was identified in an extract of frog brain. Synthetic frog NT produced a concentration-dependent increase in αMSH release from perifused frog pars intermedia cells, with an ED50 of 5 × 10−9m. A maximum response (276.3 ± 45.5% above basal release) was produced by a 10−8-m concentration. Repeated administration of NT to melanotrope cells revealed the occurrence of a rapid and pronounced desensitization mechanism. The data are consistent with a possible role for the peptide as a hypophysiotropic factor in amphibians.
Effects of CP-336,156, a New, Nonsteroidal Estrogen Agonist/Antagonist, on Bone, Serum Cholesterol, Uterus, and Body Composition in Rat Models
Authors: Ke Hua Zhu , Paralkar Vishwas M. , Grasser William A. , Crawford D. Todd , Qi Hong , Simmons Hollis A. , Pirie Christine M. , Chidsey-Frink Kristin L. , Owen Thomas A. , Smock Steven L. , Chen Hong Ka , Jee Webster S. S. , Cameron Kimberly O. , Rosati Robert L. , Brown Thomas A. , Dasilva-Jardine Paul , Thompson David D.
Published: January 2014

We have discovered a new, nonsteroidal, potent estrogen agonist/antagonist, CP-336,156. CP-336,156 binds selectively and with high affinity to the human estrogen receptor-α with a half-inhibition concentration of 1.5 nm, which is similar to that seen with estradiol (4.8 nm). When given orally to immature (3-week-old) female Sprague-Dawley rats for 3 days at doses of 0.1, 1.0, 10, or 100 μg/kg·day, unlike 17α-ethynyl estradiol, CP-336,156 had no effect on uterine wet or dry weight. Similarly, no uterine hypertrophy was observed in aged (17-month-old) female rats treated (po) with CP-336,156 at 10 or 100 μg/kg·day for 28 days. We also found that CP-336,156 decreased total serum cholesterol and fat body mass and had no effect on lean body mass in these aged female rats. In 5-month-old ovariectomized (OVX) Sprague-Dawley female rats, CP-336,156 completely prevented OVX-induced increases in body weight gain, total serum cholesterol, and serum osteocalcin at doses between 10 and 1000 μg/kg·day after 4 weeks. At these doses, CP-336,156 completely prevented OVX-induced bone loss and inhibited the increased bone turnover associated with estrogen deficiency in lumbar vertebrae, proximal tibiae, and distal femora. Similar to estrogen, CP-336,156 induced apoptosis and p53 expression with a concomitant decrease in the number of tartrate-resistant acid phosphatase-positive multinuclear cells in rat bone marrow cell cultures in vitro, suggesting that the induction of apoptosis may be a mechanism for the estrogenic activities of CP-336,156 in bone. In summary, CP-336,156 is a new, orally active, nonsteroidal, potent estrogen agonist/antagonist that has similar effects in bone as estradiol but without the uterine-stimulating effects associated with estradiol in rats.
Phosphate Transport in Pig Proximal Small Intestines during Postnatal Development: Lack of Modulation by Calcitriol*
Authors: Schröder Bernd , Hattenhauer Olaf , Breves Gerhard
Published: January 2014

The role of calcitriol in the intestinal absorption of inorganic phosphate (Pi) during postnatal development was studied in newborn [<1 week postpartum (pp)], suckling (3–4 weeks pp), and weaned (>6 weeks pp) control piglets (con) and piglets suffering from inherited calcitriol deficiency (def). In addition, a number of def piglets were treated with vitamin D3 (def-D3).

Regardless of age, plasma calcitriol concentrations in def piglets were unphysiologically low (16–21 pg/ml) and differed significantly from those in respective con animals (60–69 pg/ml) and vitamin D3-treated def piglets (50–56 pg/ml). However, newborn and suckling def piglets had normal Ca (∼3.0 mmol/liter) and Pi (∼2.8 mmol/liter) plasma levels. Def piglets became hypocalcemic (1.9 mmol/liter) and hypophosphatemic (1.9 mmol/liter) between 4–6 weeks pp. Treatment with vitamin D3 significantly increased plasma Ca (3.2 mmol/liter) and Pi (2.7 mmol/liter) levels in weaned def animals.

Regardless of calcitriol status, net Pi flux rates (active Pi absorption, as determined with the in vitro Ussing-chamber technique) from the upper small intestines was maximal at birth [170–224 nmol/(cm2·h)] and decreased by approximately 80% during the first week of life before remaining constant [30–50 nmol/(cm2·h)] during the following development. In weaned def piglets, net Pi flux rates were significantly lower by about 80% compared with those in con animals. Treatment of def piglets with vitamin D3 had no effect in newborn and suckling animals but reconstituted net Pi flux rates to normal values at weaning age. Age-dependent and calcitriol-mediated changes in net Pi flux rates were paralleled by respective maximum velocity values of Na+-dependent Pi uptake across the brush border membrane of the enterocytes (newborn piglets, 1.9–2.2 nmol/(mg protein·10 sec); suckling piglets, 0.4–0.6 nmol/(mg protein·10 sec); weaned piglets, 0.7, 0.3, and 0.7 nmol/(mg protein·10 sec) in con, def, and def-D3 animals, respectively). These findings suggest that the apical Pi uptake represents the major rate-limiting step of the overall transepithelial Pi transport. At weaning, Na+/Pi transport across the intestinal brush-border membrane is clearly stimulated by calcitriol, but no significant effects of age or calcitriol on the Km values (0.5–0.7 mmol/liter) were observed.

In conclusion, our findings reveal calcitriol-independent mechanisms for active intestinal Pi absorption during the neonatal and suckling periods. The onset of the classical calcitriol-dependent mechanism for active intestinal Pi absorption does not occur until weaning.