bluuebunny/crossref_metadata_2025 huggingface dataset:
The Upper Airway Evaluation of Habitual Snorers and Obstructive Sleep Apnea Patients
Authors: Karakoc Omer , Akcam Timur , Gerek Mustafa , Genc Hakan , Ozgen Fuat
Published: April 2012

Objective: To investigate the relationship between the Apnea Hypopnea Index (AHI) and upper airway examination findings of habitual snorers and obstructive sleep apnea (OSA) patients. Materials and Methods: This study included 264 patients whose tonsils were evaluated in 4 grades. The Mallampati classification was used to determine the relationship between tongue and palate. All patients performed the Müller maneuver in a sitting position. The Fujita classification was used to define the type of obstruction. All patients had polysomnography and were divided into 4 groups according to AHI. Statistical analysis was performed to evaluate the relationship between examination findings and AHI. Results: Of the patients, 133 (50.4%) were habitual snorers, 66 (25%) were mild OSA, 40 (15.2%) were moderate OSA and 25 (9.5%) were severe OSA patients. There was a positive correlation between neck circumference, BMI and AHI in males (p < 0.001). There was a significant difference between patient groups according to Mallampati classification, collapse at the velopharyngeal level and hypopharyngeal level and Fujita classification (all p < 0.001). There were significant relationships between tonsil size, Fujita classification, Mallampati classification, collapse ratios and AHI. Conclusion: We saw that hypopharyngeal area often contributes to obstruction and some examination methods correlate more with AHI. This can aid sleep physicians in the evaluation of OSA patients.
Quercetin Induces Rapid eNOS Phosphorylation and Vasodilation by an Akt-Independent and PKA-Dependent Mechanism
Authors: Li Peng-Gao , Sun Li , Han Xin , Ling Shuang , Gan Wo-ting , Xu Jin-Wen
Published: April 2012

Consumption of the flavonoid quercetin exerts beneficial effects on many chronic diseases. The mechanisms involved in the vasorelaxant effect of quercetin remain uncertain. In the present study, we examined the role of quercetin in vasodilation and rapid endothelial nitric oxide synthase (eNOS) activity in endothelial cells. Quercetin induced a rapid, dose-dependent phosphorylation of eNOS at serine 1179. PKA, Akt and ERK1/2 were all quickly phosphorylated in the process too, but not AMPK and CaMK II. The specific kinase inhibitors for Akt or ERK1/2 could not abolish the quercetin-induced eNOS phosphorylation at Ser1179, which, however, was significantly abolished by H89, an inhibitor of PKA. Concomitantly, intracellular cAMP production was quickly increased by quercetin stimulation and an adenylate cyclase activator, forskolin, also induced eNOS phosphorylation at Ser1179. Quercetin enhanced nitric oxide (NO) production, which was abolished by an eNOS inhibitor, L-NAME or H89. Quercetin exerted a vasodilatory effect on rings with an intact endothelium but not on endothelium-deprived rings, and also inhibited vascular contractility induced by angiotensin II or phenylephrine in rat aortic rings. We conclude that quercetin quickly phosphorylates eNOS at Ser1179 via an Akt-independent, cAMP/PKA-mediated pathway to enhance the production of NO and to promote vasodilation.
Etiologies and Clinical Presentation of Gigantism in Algeria
Authors: Chentli Farida , Azzoug Said , Amani Mohammed El Amine , Haddam Ali El Mahdi , Chaouki Dalal , Meskine Djamila , Chaouki Mohamed Lamine
Published: April 2012

Background/Aims: True gigantism is an exceptional and fascinating pediatric disease. Our aim in this study was to describe the different etiologies of a large group of children with gigantism and the natural history of their growth. Methods: In this multicenter study, we considered as giant children, adolescents and adults whose heights were ≥3 SD compared to their target stature or to our population average lengths. Isolated hypogonadism and Klinefelter syndrome were excluded from this series. All underwent clinical exam, and hormonal and neurological investigations. Results: From 1980 to 2010, we observed 30 giants: 26 males (86.6%) and 4 females (mean age 19.8 ± 11 years). Among the 13 patients (40.3%) who consulted before the age of 16 years, 9 had acromegaly and 6 had mental retardation and body malformations. Based on growth hormone (GH) secretion evaluation, 2 groups were observed: pituitary gigantism (n = 16): GH = 150 ± 252 ng/ml (n ≤ 5), and other causes with normal GH (0.7 ± 0.6 ng/ml): 6 Sotos syndrome and 8 idiopathic cases. Only the first group had neurological, ophthalmological, metabolic and cardiovascular complications and received treatment. The result was not optimal as GH normalization was not observed. Reduction of tumor size and decreased GH plasma values were not observed. Conclusion: Gigantism predominates in males. The main cause is GH excess. The diagnosis was very late except for cerebral gigantism. Complications were observed in pituitary gigantism only.
Optimization of Growth Hormone Dosing in Children Born Small for Gestational Age: An Open-Label, Randomized Study of Children during the Fourth Year of Therapy
Authors: Chatelain P. , Colle M. , Nako J.-P. , Le Luyer B. , Wagner K. , Berlier P. , Tauber M.
Published: April 2012

Background: Optimal dosage for growth hormone (GH) therapy in short, prepubertal children born small for gestational age (SGA) is controversial. Methods: SGA OPTIMIS (NCT00249821) is a multicenter, open-label, parallel-group, pilot study of short children born SGA who had received recombinant human GH (r-hGH) (57 µg/kg/day) for 3 years. Children were randomized 1:1 to receive either 57 or 35 µg/kg/day r-hGH during year 4. The primary endpoint was height gain during year 4. Results: 22 children were randomized (57 µg/kg/day, n = 10; 35 µg/kg/day, n = 12) and 21 completed the fourth year of therapy; 22 were included in efficacy analyses. During year 4, mean [standard deviation (SD)] height velocity was 6.4 (1.4) and 4.4 (1.2) cm/year (p = 0.001) and height velocity SD score (SDS) was 0.3 (0.3) and –0.1 (0.2) (p = 0.002) in the 57 and 35 µg/kg/day groups, respectively. The 57 µg/kg/day group continued with catch-up growth, had a significantly higher mean weight gain (p = 0.015) and significantly higher insulin-like growth factor-I levels at 12 months (p = 0.038). Five treatment-emergent adverse events were reported; none was serious or caused study withdrawal. Conclusions: Children who continued receiving 57 µg/kg/day r-hGH in year 4 had significantly greater height gain than those receiving 35 µg/kg/day r-hGH.
A Phase I Study of Infusional 5-Fluorouracil, Leucovorin, Oxaliplatin and Irinotecan in Japanese Patients with Advanced Colorectal Cancer Who Harbor UGT1A1*1/*1,*1/*6 or *1/*28
Authors: Sunakawa Yu , Fujita Ken-ichi , Ichikawa Wataru , Ishida Hiroo , Yamashita Keishi , Araki Kazuhiro , Miwa Keisuke , Kawara Kaori , Akiyama Yuko , Yamamoto Wataru , Nagashima Fumio , Saji Shigehira , Sasaki Yasutsuna
Published: April 2012

Objective: To evaluate the safety and efficacy of combination chemotherapy with 5-fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin (FOLFOXIRI) in Japanese patients with advanced colorectal cancer. Methods: This phase I dose-finding study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD) or both of FOLFOXIRI. Patients with UDP-glucuronosyltransferase (UGT) 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded, because these UGT1A1 genotypes are linked to severe neutropenia in Japanese. Results: A total of 10 Japanese patients with advanced colorectal cancer were studied. The MTD of FOLFOXIRI in these Japanese patients was 165 mg/m2 irinotecan, 85 mg/m2 oxaliplatin and 2,400 mg/m2 5-FU. Accordingly, the RD of FOLFOXIRI was determined to be 150 mg/m2 irinotecan, 85 mg/m2 oxaliplatin and 2,400 mg/m2 5-FU. Toxic effects, evaluated until the completion of 4 cycles, were manageable. Grade 3–4 neutropenia occurred in 27% of cycles, but there was no febrile neutropenia. Among the 9 assessable patients, the objective response rate was 89%. Conclusions: We thus determined the RD of FOLFOXIRI in Japanese patients with advanced colorectal cancer who do not have UGT1A1*28/*28, *6/*6 or *6/*28 genotypes. Our results indicate that FOLFOXIRI is a well-tolerated regimen for these Japanese patients.
Non-Invasive Cardiac Output Monitoring in Neonates Using Bioreactance: A Comparison with Echocardiography
Authors: Weisz Dany E. , Jain Amish , McNamara Patrick J. , EL-Khuffash Afif
Published: April 2012

Objectives: Non-invasive cardiac output monitoring is a potentially useful clinical tool in the neonatal setting. Our aim was to evaluate a new method of non-invasive continuous cardiac output (CO) measurement (NICOM™) based on the principle of bioreactance in neonates. Methods: In this prospective observational study, 10 neonates underwent 97 paired NICOM and echocardiography (echo) assessments of left ventricular output (LVO). For each neonate, NICOM measurements of left ventricular stroke volume (SV) and LVO over a 2- to 4-hour period were correlated with blinded, simultaneous, discrete echo measurements of SV and LVO. The precision and accuracy of the NICOM monitor relative to echo during periods of steady state were assessed. Results: The infants’ median birth weight was 2.72 kg (IQR 1.56–3.23 kg, range 1.44–4.00) and their median gestation was 37 weeks (IQR 31–40 weeks, range 31–41). Median NICOM SV and LVO readings were consistently lower than echo (2.6 ml [IQR 1.4–3.2, range 0.6–5.3] vs. 3.5 ml [IQR 2.1–4.4, range 1.1–6.8], and 400 ml/min [IQR 233–476] vs. 559 ml/min [IQR 386–652], p < 0.001). The NICOM LVO readings were lower than the echo readings by a mean of 153 ± 56 ml/kg. NICOM consistently under-read LVO by 31 ± 8%, and this systematic difference was constant across the range of LVOs obtained. There was a strong correlation between NICOM and echo measurements of LVO (r = 0.95, p < 0.001). Conclusion: Non-invasive cardiac output monitoring is feasible in neonates. Further validation studies in neonatal animal experimental models and human neonates need to be conducted before routine clinical use.
Osteopontin Plays a Critical Role in Interstitial Fibrosis but Not Glomerular Sclerosis in Diabetic Nephropathy
Authors: Nagao Tomoaki , Okura Takafumi , Irita Jun , Jotoku Masanori , Enomoto Daijiro , Desilva Veena Rasika , Miyoshi Ken-ichi , Kurata Mie , Matsui Yutaka , Uede Toshimitsu , Higaki Jitsuo
Published: April 2012

Background/Aims: Osteopontin (OPN) has been implicated in the pathology of several renal conditions. The aim of this study was to clarify the roles of OPN in diabetic nephropathy. Methods: Diabetes mellitus (DM) was induced in wild-type (WT) and OPN knockout (KO) mice by injecting streptozotocin. The mice were killed 20 weeks after induction of DM and their kidneys removed. Results: Renal mRNA expression of OPN was increased in WT-DM mice compared to WT-sham mice. Immunohistochemistry showed high levels of OPN expression in the proximal tubules of WT-DM mice. Kidney weight and urinary albumin excretion increased to similar levels in the WT-DM and KO-DM mice. Interstitial fibrosis was increased in WT-DM mice compared to KO-DM mice. However, there were no differences in the degree of mesangial expansion or glomerular hypertrophy between the two groups. F4/80-positive cells (macrophages) and FSP-1-positive cells (fibroblasts) showed significantly higher infiltration in WT-DM mice than in KO-DM mice. Renal mRNA expression of NADPH oxidase subunits and urinary 8-isoprostane excretion were also increased in WT-DM mice. Conclusions: These results indicated that OPN is a key molecule that induces interstitial fibrosis in the diabetic kidney, but does not induce glomerular sclerosis.
Is There Any Clinically Relevant Cannabinoid-Induced Analgesia?
Authors: Kraft Birgit
Published: April 2012

Cannabis sativa is one of the oldest crops cultivated for the production of fibers and for medical and recreational purposes. Since the detection of specific cannabinoid receptors and their physiological ligands, the understanding of the cannabinoid signalling system has increased, leading to a recent resurgence of interest in its medicinal properties. In animal studies, cannabinoids exerted significant analgesic and antihyperalgesic effects, suggesting the usefulness of cannabinoids in pain conditions. However, in human experimental or clinical trials, no convincing reduction of acute pain was observed. In contrast, in chronic pain and (painful) spasticity, an increasing number of randomized, double-blind, placebo-controlled studies have shown some efficacy of cannabinoids. Besides pain, cannabinoids consistently improved mood, sleep and coping. Although cannabinoids are not first-line analgesics, they may be useful adjuvants for some special groups of patients.
Proteinase-Activated Receptor-4 Plays a Major Role in the Recruitment of Neutrophils Induced by Trypsin or Carrageenan during Pleurisy in Mice
Authors: Gomides L.F. , Duarte I.D. , Ferreira R.G. , Perez A.C. , Francischi J.N. , Klein A.
Published: April 2012

Background/Aims: The activation of proteinase-activated receptors (PARs) has been implicated in the development of important hallmarks of inflammation, including in vivo leukocyte recruitment. Here, we examined the effects of aprotinin, a potent inhibitor of trypsin proteinase and the kallikrein-kinin system, and the PAR-4 antagonist YPGKF-NH2 (tcY-NH2) on neutrophil recruitment in response to carrageenan and trypsin in the pleural cavity of mice. Methods: BALB/c mice were intrapleurally injected with trypsin or PAR-4-activating peptide AY-NH2, pretreated with aprotinin or tcY-NH2 (1 µg/cavity) prior to an intrapleural injection of trypsin or carrageenan, or pretreated with leukotriene B4 antagonist U-75302 (3 µg/cavity) prior to a trypsin injection. The number of infiltrating neutrophils was evaluated after 4 h. Results: PAR-4-activating peptide AY-NH2 and trypsin-induced neutrophil recruitment was inhibited by aprotinin, tcY-NH2 or U-75302. Aprotinin and tcY-NH2 also inhibited neutrophil recruitment induced by carrageenan. Conclusion: These data suggest a key role for PAR-4 in mediating neutrophil recruitment in a mouse model of pleurisy induced by the activity of trypsin or trypsin-like enzymes.
Allium ursinum L.: Bioassay-Guided Isolation and Identification of a Galactolipid and a Phytosterol Exerting Antiaggregatory Effects
Authors: Sabha Dina , Hiyasat Bahi , Grötzinger Kristina , Hennig Lothar , Schlegel Franziska , Mohr Friedrich-Wilhelm , Rauwald Hans Wilhelm , Dhein Stefan
Published: April 2012

Aims: We wanted to investigate the possible antithrombotic effects and elucidate the chemical identity of the active principles involved in inhibitory effects against adenosine diphosphate (ADP)-induced aggregation of human platelets by wild garlic, Allium ursinum L. Methods: For this purpose, a bioassay-guided isolation procedure was used followed by spectrometric identification of pure active compounds. For the bioassay, blood was taken from healthy human volunteers and platelet-rich plasma was prepared for turbidimetric platelet aggregation tests. Platelet-rich plasma, stimulated with 20 µmol/l of ADP, was treated with extracts of different polarities, fractions and isolated single compounds from A. ursinum. The extracts were investigated by thin-layer chromatography (TLC), HPLC, mass spectroscopy, electrospray ionization mass spectrometry (ESI-MS) and 1/2-dimensional 1H/13C-nuclear magnetic resonance (NMR) spectroscopic techniques. Results: Fresh A. ursinum leaves were extracted with ethanol, which was the potent form that effectively inhibited ADP-induced aggregation of human platelets. This ethanolic extract was subjected to liquid-liquid partition. Whilst the aqueous phase, containing the moiety of cysteine sulphoxide and thiosulphinate derivatives, showed only weak activity on platelet aggregation, the ethyl-acetate and particularly the chloroform partitions showed the highest aggregation-inhibiting potency. Thus, in our bioassay, the effects of alliins/allicins could be neglected. The chloroform phase, possessing the strongest activity, was separated into 28 fractions by gradient-elution open column chromatography on silica gel. The most active fractions 11–17 were separated again, yielding 10 subfractions. This afforded 1,2-di-O-α-linolenoyl-3-O-β-D-galactopyranosyl-sn-glycerol and β-sitosterol-3-O-β-D-glucopyranoside, the structures of which were determined by ESI-MS and 1/2-dimensional 1H/13C NMR spectroscopic techniques. Furthermore, the minute amounts of volatile oil of A. ursinum leaves obtained by steam distillation according to Ph. Eur. could be evaluated as a third aggregation-inhibiting principle. Conclusion: In our study, for the first time, 2 active, non-sulphur-containing constituents of wild garlic, namely a galactolipid and a phytosterol, could be identified exhibiting inhibitory action on ADP-induced aggregation in human blood platelets. As a major constituent, the galactolipid, 1,2-di-O-α-linolenoyl-3-O-β-D-galactopyranosyl-sn-glycerol, not yet found in Allium sp., appears as a new, highly useful marker substance for A. ursinum drugs, or their pharmaceutical or food preparations, as shown by our orientating TLC analyses.
Clonidine-Induced Growth Hormone and Growth-Hormone-Releasing Hormone Release Is Mediated by Tachykinin NK2 Receptors in Sheep
Authors: Lemamy Guy-Joseph , Guillaume Viviane , Ndéboko Bénédicte , Mouecoucou Justine , Renard Mireille , Oliver Charles
Published: April 2012

Clonidine is an α2-adrenergic agonist, historically known to treat high blood pressure. Further studies showed that it could be used in the treatment of neuropsychiatric disorders. Afterwards, it has been reported that clonidine stimulated growth hormone (GH) release in many species including man. Using a transnasal surgery technique in awake sheep that allowed accessing hypothalamopituitary portal vessels, our laboratory previously reported that the injection of clonidine in sheep induced a significant, immediate and short-lasting increase in peripheral GH and portal GH-releasing hormone (GHRH) levels. In this study, we show that the clonidine-induced peripheral GH and portal GHRH increase in sheep appears to be mediated by the tachykinin NK2 receptor.
Botulinum Toxin for Vaginismus Treatment
Authors: Ferreira Juliana Rocha , Souza Renan Pedra
Published: April 2012

Background/Aims: Vaginismus is characterized by recurrent or persistent involuntary contraction of the perineal muscles surrounding the outer third of the vagina when penile, finger, tampon, or speculum penetration is attempted. Recent results have suggested the use of botulinum toxin for the treatment of vaginismus. Here, we assessed previously published data to evaluate the therapeutic effectiveness of botulinum toxin for vaginismus. Methods: We have carried out a systematic review followed by a meta-analysis. Results: Our results indicate that botulinum toxin is an effective therapeutic option for patients with vaginismus (pooled odds ratio of 8.723 with 95% confidence interval limits of 1.942 and 39.162, p = 0.005). This may hold particularly true in treatment-refractory patients because most of the studies included in this meta-analysis have enrolled these subjects in their primary analysis. Conclusion: Botulinum toxin appears to be a reasonable intervention for vaginismus. However, this conclusion should be read carefully because of the deficiency of placebo-controlled randomized clinical trials and the quality issues presented in the existing ones.
Mini-Cog and Mini-Mental State Examination: Agreement in a Cross-Sectional Study with an Elderly Sample
Authors: Costa Diogo , Severo Milton , Fraga Sílvia , Barros Henrique
Published: April 2012

Background/Aims: We aimed to compare the Mini-Mental State Examination (MMSE) with the Mini-Cog, measuring agreement in participants’ classification, using a general population sample. Methods: Cross-sectional evaluation of 609 community dwellers aged ≥60 years was performed by trained interviewers. Cohen’s kappa and 95% confidence intervals (CI) were calculated to assess overall agreement, and Cronbach alphas computed to assess reliability. Two-parameter Item Response Theory models (difficulty and discrimination parameters) were used to assess discrimination. Results: Considering MMSE cut-point for scores <24, 3.1% of the participants would be ‘cognitive impaired’ and 6.2% considering cut-point scores <25. Following Mini-Cog’s cut-point score <3, 11.3% would be impaired. For MMSE cut-point <24 and Mini-Cog <3, we observed a Cohen’s kappa of 0.116 (95% CI: –0.073 to 0.305), and of 0.258 (95% CI: 0.101–0.415) for cut-point <25. The highest kappa was obtained for cut-point <26 on the MMSE and Mini-Cog <3 (kappa = 0.413). MMSE Cronbach alpha was 0.6108 and Mini-Cog’s alpha was 0.2776. Cocalibration according to inherent ability is graphically presented. Conclusions: Agreement between scales seems fragile in our sample. The discriminative and reliability analysis suggests a better performance for subsets of the MMSE compared with the Mini-Cog. Usefulness of calibrated scores is discussed.
Advances in WNK Signaling of Salt and Potassium Metabolism: Clinical Implications
Authors: Arroyo Juan Pablo , Gamba Gerardo
Published: April 2012

Recent evidence due to the discovery of a family of kinases implicated in arterial hypertension now points to the underlying molecular mechanisms that dictate Na+, K+ and water handling in the nephron. These new key players need to be understood in order to fully comprehend the pathophysiology, manifestations, and treatment of common clinical entities such as hypovolemic shock, congestive heart failure, primary hyperaldosteronism, nephrotic syndrome and hypertension. It is through the analysis of the volume status and electrolyte abnormalities that commonly present with these diseases that we can begin to create a link between the abstract concept of a kinase regulation and how a patient will respond to a particular treatment. This review is an attempt to bridge that gap.
Acute Kidney Injury and Mortality in Hospitalized Patients
Authors: Wang Henry E. , Muntner Paul , Chertow Glenn M. , Warnock David G.
Published: April 2012

Background: The objective of this study was to determine the incidence of acute kidney injury (AKI) and its relation with mortality among hospitalized patients. Methods: Analysis of hospital discharge and laboratory data from an urban academic medical center over a 1-year period. We included hospitalized adult patients receiving two or more serum creatinine (sCr) measurements. We excluded prisoners, psychiatry, labor and delivery, and transferred patients, ‘bedded outpatients’ as well as individuals with a history of kidney transplant or chronic dialysis. We defined AKI as (a) an increase in sCr of ≥0.3 mg/dl; (b) an increase in sCr to ≥150% of baseline, or (c) the initiation of dialysis in a patient with no known history of prior dialysis. We identified factors associated with AKI as well as the relationships between AKI and in-hospital mortality. Results: Among the 19,249 hospitalizations included in the analysis, the incidence of AKI was 22.7%. Older persons, Blacks, and patients with reduced baseline kidney function were more likely to develop AKI (all p < 0.001). Among AKI cases, the most common primary admitting diagnosis groups were circulatory diseases (25.4%) and infection (16.4%). After adjustment for age, sex, race, admitting sCr concentration, and the severity of illness index, AKI was independently associated with in-hospital mortality (adjusted odds ratio 4.43, 95% confidence interval 3.68–5.35). Conclusions: AKI occurred in over 1 of 5 hospitalizations and was associated with a more than fourfold increased likelihood of death. These observations highlight the importance of AKI recognition as well as the association of AKI with mortality in hospitalized patients.
Tumor Lysis Syndrome after Propranolol Therapy in Ulcerative Infantile Hemangioma: Rare Complication or Incidental Finding?
Authors: Cavalli R. , Buffon R.B. , de Souza M. , Colli A.M. , Gelmetti C.
Published: April 2012

A 33-day-old female with an ulcerated infantile hemangioma (IH) undergoing oral therapy with propranolol 2 mg/kg per day developed hyperkalemia and hyperphosphatemia 24 h after starting medication. No electrocardiographic or clinical abnormalities secondary to the electrolyte changes were noticed. A laboratory tumor lysis syndrome (TLS) was diagnosed after excluding other causes of electrolyte imbalance in the diagnostic workup. No treatment was required to reverse the TLS condition, and the propranolol therapy was continued as the electrolyte alterations were only mild. One month later, the IH was remarkably reduced in size and no longer ulcerated. Maintenance of propranolol was extended for a total of 6 months. Parallel to the gradual involution of the IH, serum potassium and phosphorus levels returned within normal levels. We suggest that TLS may be a rare complication of ulcerated IH treated with propranolol. Clinicians must be aware and order appropriate screening tests for TLS in patients at risk.
Gender Influences Short-Term Growth Hormone Treatment Response in Children
Authors: Sävendahl Lars , Blankenstein Oliver , Oliver Isabelle , Thybo Christesen Henrik , Lee Peter , Tønnes Pedersen Birgitte , Rakov Viatcheslav , Ross Judith
Published: April 2012

Background: Gender may affect growth hormone (GH) treatment outcome. This study assessed gender-related differences in change from baseline height standard deviation scores (ΔHSDS) after 2 years’ GH treatment. Methods: Data from two observational databases were analyzed – the NordiNet® International Outcome Study (NordiNet® IOS) and the American Norditropin Studies: Web Enabled Research Program (ANSWER Program®). Of all the evaluated patients (n = 5,880; age 0 to <18 years), 4,471 were diagnosed with GH deficiency (GHD), 422 with multiple pituitary hormone deficiency, and 987 were born small for gestational age (SGA). Data were analyzed by indication, gender and pubertal status (total population/prepubertal). Results: In the total population, after correcting for dose, mean baseline age and HSDS, ΔHSDS was significantly greater in boys than in girls born SGA (p = 0.0261). In the prepubertal cohort, ΔHSDS was significantly greater for boys versus girls with GHD (p = 0.0004) and SGA (p = 0.0019). No between-gender difference in ΔIGF-I SDS was found. Conclusions: A significant gender difference was found in the 2-year response to GH treatment in the total population of SGA children as well as in the prepubertal cohorts of SGA and GHD children.
Smoking Prevention and Cessation in the Africa and Middle East Region: A Consensus Draft Guideline for Healthcare Providers – Executive Summary
Authors: Ali Ahmed Yousif M. , Safwat Tarek , Onyemelukwe Geoffrey , Otaibi Moh’d Amin Al , Amir Ashraf A. , Nawas Yousef N. , Aouina Hichem , Afif Moulay Hicham , Bolliger Chris T.
Published: April 2012

Despite the abundance of scientific evidence confirming the health consequences of smoking and other forms of tobacco use, the tobacco epidemic remains an important public health problem and by 2030 it is predicted that more than 80% of tobacco deaths will be in developing countries. In Africa and the Middle East, many local factors contribute to the initiation and maintenance of tobacco use. Although efforts to reduce the mortality and morbidity associated with smoking and tobacco dependence are underway, there is a need for guidance on how to utilize appropriate tobacco control policies and psychology- and pharmacology-based therapies to counter tobacco dependence as recommended by the Framework Convention on Tobacco Control (FCTC). A group of tobacco cessation experts from public health services and/or academic institutions in Africa and the Middle East participated in a series of four meetings held in Cairo, Cape Town, and Dubai between May 2008 and February 2011 to develop a draft guideline tailored to their region. This article provides the background to the development of this draft smoking cessation guideline and discusses how the recommendations can be implemented and progress monitored to promote both primary prevention and cessation of tobacco use within our countries. The draft guideline for Africa and the Middle East provides an important resource in combating the devastating effects of tobacco use in these regions which can be further localized through engagement with local stakeholders in the countries of the region.
Effects of Benzalkonium Chloride and Potassium Sorbate on Airway Ciliary Activity
Authors: Wang Chengshuo , Deng Qiu , Han Demin , Zhang Luo
Published: April 2012

Objectives: Preservatives are indispensable components of aqueous multidose topical formulations. The purpose of our study was to investigate the effects of two representative preservatives, benzalkonium chloride (BKC) and potassium sorbate (PS), on rabbit tracheal ciliary beat frequency (CBF). Methods: Rabbit tracheal ciliated cell culture was established and CBF was determined using high-speed digital imaging methods. The effects of preservatives at different concentrations on CBF were observed over a 10-min exposure period. Results: BKC induced inhibition of CBF in a concentration-dependent manner. Ciliary beating was stopped by 0.01% BKC after 5 min of exposure. A low concentration of PS (0.12%) only resulted in a mild decrease in CBF during a 10-min exposure. The CBF decreased by 13.0% from baseline after 10 min. However, there was no statistically significant difference compared with the corresponding control condition. Application of 0.24, 0.48 and 0.96% of PS to rabbit tracheal cells resulted in an increase in CBF, with an increase of 105 ± 9.8, 107.6 ± 4.0, and 117.1 ± 9.5% relative to baseline CBF after 10 min of exposure, respectively. Conclusions: PS could be considered as a safer and more promising preservative than BKC for use in topical formulations.
Tea Tree Oil as a Novel Antipsoriasis Weapon
Authors: Pazyar Nader , Yaghoobi Reza
Published: April 2012

Psoriasis is a clinical skin disease that is characterized by erythematous scaling plaques and involves the extensor site of the extremities, the scalp and other surfaces of the skin. Tea tree oil (TTO) is considered an essential oil, obtained by steam distillation of the leaves and terminal branchlets of Melaleuca alternifolia. Notably,terpinen-4-ol, the major TTO constituent, has been found to have potent anti-inflammatory properties. It is suggested that terpinen-4-ol may be a novel potential agent against psoriasis. This article draws attention to the antipsoriatic effect of TTO and provides a theoretical molecular approach.
Dietary Phosphate Binding and Loading Alter Kidney Angiotensin-Converting Enzyme mRNA and Protein Content in 5/6 Nephrectomized Rats
Authors: Eräranta Arttu , Riutta Asko , Fan Meng , Koskela Jenni , Tikkanen Ilkka , Lakkisto Päivi , Niemelä Onni , Parkkinen Jyrki , Mustonen Jukka , Pörsti Ilkka
Published: April 2012

Background: Vitamin D receptor activation with paricalcitol can modulate the transcription of renin-angiotensin system components in the surgical 5/6 nephrectomy rat model (5/6 NX) of chronic renal insufficiency. We tested the hypothesis whether dietary modification of phosphate influences kidney renin-angiotensin system gene expression at the mRNA level in 5/6 NX rats. Methods: Fifteen weeks after surgery, rats were given control diet (0.3% calcium, 0.5% phosphate), phosphate-lowering diet (3% calcium as carbonate) or high-phosphate diet (1.5%) for 12 weeks. Sham-operated rats were on control diet. Results: Blood pressure, plasma phosphate, parathyroid hormone, glomerulosclerosis, tubulointerstitial damage, and FGF-23 were increased in remnant kidney rats, whereas creatinine clearance was decreased. Phosphate, parathyroid hormone, glomerulosclerosis, tubulointerstitial damage, and FGF-23 were further elevated by the high-phosphate diet, but were reduced by the phosphate-lowering diet. Plasma calcium was increased with the phosphate-lowering diet and decreased with the high-phosphate diet. Remnant kidney rats on control diet showed upregulated kidney angiotensin-converting enzyme (ACE) and angiotensin (Ang) IV receptor (AT4) transcription, while ACE2, Ang II type 2 receptor and renin receptor transcription were downregulated in comparison with sham rats. Phosphate-lowering diet reduced whereas high-phosphate diet increased kidney ACE, and these effects were observed at both mRNA and protein levels. Dietary phosphate loading also resulted in lower AT1a gene transcription. Conclusion: Dietary phosphate loading was associated with elevated kidney ACE expression, increased tissue damage and lower AT1a transcription in 5/6 NX rats. Phosphate binding with 3% calcium carbonate had opposite effects on ACE and kidney damage.
Intracellular Trafficking and Secretion of VLDL
Authors: Tiwari Samata , Siddiqi Shadab A.
Published: April 2012

Steady increase in the incidence of atherosclerosis is becoming a major concern not only in the United States but also in other countries. One of the major risk factors for the development of atherosclerosis is high concentrations of plasma low-density lipoprotein, which are metabolic products of very low-density lipoprotein (VLDL). VLDLs are synthesized and secreted by the liver. In this review, we discuss various stages through which VLDL particles go from their biogenesis to secretion in the circulatory system. Once VLDLs are synthesized in the lumen of the endoplasmic reticulum, they are transported to the Golgi. The transport of nascent VLDLs from the endoplasmic reticulum to Golgi is a complex multistep process, which is mediated by a specialized transport vesicle, the VLDL transport vesicle. The VLDL transport vesicle delivers VLDLs to the
cis
-Golgi lumen where nascent VLDLs undergo a number of essential modifications. The mature VLDL particles are then transported to the plasma membrane and secreted in the circulatory system. Understanding of molecular mechanisms and identification of factors regulating the complex intracellular VLDL trafficking will provide insight into the pathophysiology of various metabolic disorders associated with abnormal VLDL secretion and identify potential new therapeutic targets.
Formin mDia1 Mediates Vascular Remodeling via Integration of Oxidative and Signal Transduction Pathways
Authors: Touré Fatouma , Fritz Günter , Li Qing , Rai Vivek , Daffu Gurdip , Zou Yu Shan , Rosario Rosa , Ramasamy Ravichandran , Alberts Arthur S. , Yan Shi Fang , Schmidt Ann Marie
Published: April 2012

Rationale:

The mammalian diaphanous-related formin (mDia1), governs microtubule and microfilament dynamics while functioning as an effector for Rho small GTP-binding proteins during key cellular processes such as adhesion, cytokinesis, cell polarity, and morphogenesis. The cytoplasmic domain of the receptor for advanced glycation endproducts binds to the formin homology 1 domain of mDia1; mDia1 is required for receptor for advanced glycation endproducts ligand-induced cellular migration in transformed cells.

Objective:

Because a key mechanism in vascular remodeling is the induction of smooth muscle cell migration, we tested the role of mDia1 in this process.

Methods and Results:

We report that endothelial denudation injury to the murine femoral artery significantly upregulates mDia1 mRNA transcripts and protein in the injured vessel, particularly in vascular smooth muscle cells within the expanding neointima. Loss of mDia1 expression significantly reduces pathological neointimal expansion consequent to injury. In primary murine aortic smooth muscle cells, mDia1 is required for receptor for advanced glycation endproducts ligand-induced membrane translocation of c-Src, which leads to Rac1 activation, redox phosphorylation of AKT/glycogen synthase kinase 3β, and consequent smooth muscle cell migration.

Conclusions:

We conclude that mDia1 integrates oxidative and signal transduction pathways triggered, at least in part, by receptor for advanced glycation endproducts ligands, thereby regulating pathological neointimal expansion.
Role of RyR2 Phosphorylation at S2814 During Heart Failure Progression
Authors: Respress Jonathan L. , van Oort Ralph J. , Li Na , Rolim Natale , Dixit Sayali S. , deAlmeida Angela , Voigt Niels , Lawrence William S. , Skapura Darlene G. , Skårdal Kristine , Wisløff Ulrik , Wieland Thomas , Ai Xun , Pogwizd Steven M. , Dobrev Dobromir , Wehrens Xander H.T.
Published: April 2012

Rationale:

Increased activity of Ca
2+
/calmodulin-dependent protein kinase II (CaMKII) is thought to promote heart failure (HF) progression. However, the importance of CaMKII phosphorylation of ryanodine receptors (RyR2) in HF development and associated diastolic sarcoplasmic reticulum Ca
2+
leak is unclear.

Objective:

Determine the role of CaMKII phosphorylation of RyR2 in patients and mice with nonischemic and ischemic forms of HF.

Methods and Results:

Phosphorylation of the primary CaMKII site S2814 on RyR2 was increased in patients with nonischemic, but not with ischemic, HF. Knock-in mice with an inactivated S2814 phosphorylation site were relatively protected from HF development after transverse aortic constriction compared with wild-type littermates. After transverse aortic constriction, S2814A mice did not exhibit pulmonary congestion and had reduced levels of atrial natriuretic factor. Cardiomyocytes from S2814A mice exhibited significantly lower sarcoplasmic reticulum Ca
2+
leak and improved sarcoplasmic reticulum Ca
2+
loading compared with wild-type mice after transverse aortic constriction. Interestingly, these protective effects on cardiac contractility were not observed in S2814A mice after experimental myocardial infarction.

Conclusions:

Our results suggest that increased CaMKII phosphorylation of RyR2 plays a role in the development of pathological sarcoplasmic reticulum Ca
2+
leak and HF development in nonischemic forms of HF such as transverse aortic constriction in mice.
Apolipoprotein C‐III as a Potential Modulator of the Association Between HDL‐Cholesterol and Incident Coronary Heart Disease
Authors: Jensen Majken K. , Rimm Eric B. , Furtado Jeremy D. , Sacks Frank M.
Published: April 2012

Background

High‐density lipoproteins (HDL) are structurally and metabolically heterogeneous and subclasses with differential effects on coronary heart disease (CHD) might exist. Apolipoprotein (apo) C‐III, a small proinflammatory protein that resides on the surface of lipoproteins, enhances the atherogenicity of VLDL and LDL particles, but little is known about the role apoC‐III on HDL. We investigated whether the presence or absence of apoC‐III differentiates HDL into subtypes with nonprotective or protective associations with risk of future CHD.

Methods and Results

High‐density lipoprotein cholesterol (HDL‐C) levels were measured in plasma separated according to apoC‐III (by immunoaffinity chromatography) in two prospective case‐control studies nested within the Nurses’ Health and the Health Professionals Follow‐Up Studies. Baseline was in 1990 and 1994, and 634 incident CHD cases were documented through 10 to 14 years of follow‐up. The relative risk of CHD per each standard deviation of total HDL‐C was 0.78 (95% confidence intervals, 0.63–0.96). The HDL‐C subtypes were differentially associated with risk of CHD, HDL‐C without apoC‐III inversely and HDL‐C with apoC‐III directly (
P
=0.02 for a difference between the HDL types). The relative risk per standard deviation of HDL‐C without apoC‐III was 0.66 (0.53 to 0.93) and 1.18 (1.03 to 1.34) for HDL‐C with apoC‐III. HDL‐C with apoC‐III comprised ~13% of the total HDL‐C. Adjustment for triglycerides and apoB attenuated the risks; however, the two HDL‐C subgroups remained differentially associated with risk of CHD (
P
=0.05).

Conclusion

Separating HDL‐C according to apoC‐III identified two types of HDL with opposing associations with risk of CHD. The proatherogenic effects of apoC‐III, as a component of VLDL and LDL, may extend to HDL.

(
J Am Heart Assoc
. 2012;1:jah3‐e000232 doi

:
10.1161/JAHA.111.000232
.)
Resource Utilization Reduction for Evaluation of Chest Pain in Pediatrics Using a Novel Standardized Clinical Assessment and Management Plan (SCAMP)
Authors: Verghese George R. , Friedman Kevin G. , Rathod Rahul H. , Meiri Amir , Saleeb Susan F. , Graham Dionne A. , Geggel Robert L. , Fulton David R.
Published: April 2012

Background

Chest pain is a common reason for referral to pediatric cardiologists. Although pediatric chest pain is rarely attributable to serious cardiac pathology, extensive and costly evaluation is often performed. We have implemented a standardized approach to pediatric chest pain in our pediatric cardiology clinics as part of a broader quality improvement initiative termed Standardized Clinical Assessment and Management Plans (SCAMPs). In this study, we evaluate the impact of a SCAMP for chest pain on practice variation and resource utilization.

Methods and Results

We compared demographic variables, clinical characteristics, and cardiac testing in a historical cohort (n=406) of patients presenting to our outpatient division for initial evaluation of chest pain in the most recent pre‐SCAMP calendar year (2009) to patients enrolled in the chest pain SCAMP (n=364). Demographic variables including age at presentation, sex, and clinical characteristics were similar between groups. Adherence to the SCAMP algorithm for echocardiography was 84%. Practice variation decreased significantly after implementation of the SCAMP (
P
<0.001). The number of exercise stress tests obtained was significantly lower in the SCAM
P
‐enrolled patients compared with the historic cohort (~3% of patients versus 29%, respectively;
P
<0.001). Similarly, there was a 66% decrease in utilization of Holter monitors and 75% decrease in the use of long‐term event monitors after implementation of the chest pain SCAMP (
P
=0.003 and
P
<0.001, respectively). The number of echocardiograms obtained was similar between groups.

Conclusions

Implementation of a SCAMP for evaluation of pediatric chest pain has lead to a decrease in practice variation and resource utilization.

(
J Am Heart Assoc
. 2012;1:jah3‐e000349 doi

:
10.1161/JAHA.111.000349
.)
Tafazzin Knockdown in Mice Leads to a Developmental Cardiomyopathy With Early Diastolic Dysfunction Preceding Myocardial Noncompaction
Authors: Phoon Colin K. L. , Acehan Devrim , Schlame Michael , Stokes David L. , Edelman‐Novemsky Irit , Yu Dawen , Xu Yang , Viswanathan Nitya , Ren Mindong
Published: April 2012

Background

Barth syndrome is a rare, multisystem disorder caused by mutations in
tafazzin
that lead to cardiolipin deficiency and mitochondrial abnormalities. Patients most commonly develop an early‐onset cardiomyopathy in infancy or fetal life.

Methods and Results

Knockdown of
tafazzin
(TAZKD) in a mouse model was induced from the start of gestation via a doxycycline‐inducible shRNA transgenic approach. All liveborn TAZKD mice died within the neonatal period, and in vivo echocardiography revealed prenatal loss of TAZKD embryos at E12.5‐14.5. TAZKD E13.5 embryos and newborn mice demonstrated significant
tafazzin
knockdown, and mass spectrometry analysis of hearts revealed abnormal cardiolipin profiles typical of Barth syndrome. Electron microscopy of TAZKD hearts demonstrated ultrastructural abnormalities in mitochondria at both E13.5 and newborn stages. Newborn TAZKD mice exhibited a significant reduction in total mitochondrial area, smaller size of individual mitochondria, reduced cristae density, and disruption of the normal parallel orientation between mitochondria and sarcomeres. Echocardiography of E13.5 and newborn TAZKD mice showed good systolic function, but early diastolic dysfunction was evident from an abnormal flow pattern in the dorsal aorta. Strikingly, histology of E13.5 and newborn TAZKD hearts showed myocardial thinning, hypertrabeculation and noncompaction, and defective ventricular septation. Altered cellular proliferation occurring within a narrow developmental window accompanied the myocardial hypertrabeculation‐noncompaction.

Conclusions

In this murine model, tafazzin deficiency leads to a unique developmental cardiomyopathy characterized by ventricular myocardial hypertrabeculation‐noncompaction and early lethality. A central role of cardiolipin and mitochondrial functioning is strongly implicated in cardiomyocyte differentiation and myocardial patterning required for heart development.

(
J Am Heart Assoc
. 2012;1:e000455 doi: 10.1161/JAHA.111.000455.)
Bordering on bipolar: The overlap between borderline personality and bipolarity
Authors: Coulston Carissa M , Tanious Michelle , Mulder Roger T , Porter Richard J , Malhi Gin S
Published: April 2012

Objective: There is much debate over whether borderline personality disorder (BPD) belongs to the bipolar spectrum. The diagnosis of bipolar disorder (BD) in BPD patients, and conversely, BPD in BD patients is common, indicating prevalent co-morbidity, as well as potential misdiagnosis in either group. BD and BPD are often indistinguishable given the core characteristics of emotional dysregulation and impulsivity that feature in both. However, it may be argued that the manifestation of these characteristics in the two groups is different, and that the symptoms are driven by distinct aetiological factors. The primary objective of this paper was to examine where potential areas of discrimination lie between BD and BPD.

Methods: A literature search was conducted using MEDLINE and PubMed databases to identify studies that have researched BD and BPD across the recognised domains of emotional dysregulation, impulsivity, childhood trauma, and their putative neurobiological substrates.

Results: Research comparing BD and BPD patients on self-report measures is limited, and no studies have examined their neurobiological underpinnings in the same design. One possible differentiating variable is childhood trauma which shapes the circumstances in which emotional dysregulation and impulsivity are triggered, the types of behaviours exhibited, and the frequency and duration of mood states. There is growing evidence that childhood trauma not only predisposes individuals to both disorders, but also modulates the clinical expression and course of bipolar illness, particularly rapid cycling BD, a form of bipolarity that resembles the clinical profile of BPD, yet presents quite distinctly from other BD subtypes.

Conclusions: This paper provides an overview of BD and BPD with respect to emotional dysregulation, impulsivity, childhood factors, and neurobiological substrates. Based on findings predominantly within the independent areas of BD and BPD, it tentatively provides an integrated behavioural, aetiological and neurobiological approach for investigating the question of whether BPD belongs to the bipolar spectrum.
The Use and Tolerability of Crotalidae Polyvalent Immune FAB (Ovine) in Pediatric Envenomations
Authors: Farrar Henry C. , Grayham Taylor , Bolden Branson , Vyas Dileep , Graham James , James Laura P.
Published: April 2012

There are limited data on the use of Crotalidae Polyvalent Immune FAB–Ovine (CroFab) in the management of crotalid envenomations in children. Thus, the primary objective of this retrospective chart review was to evaluate the safety and tolerability of CroFab in a pediatric population. Over an 8-year time period at this institution, there were 204 admissions for snakebite of which 82 received CroFab. Children who received CroFab were more often associated with bites to the hands and fingers and tended to have more significant envenomations as indicated by longer hospital stays, greater tissue injury, and a tendency to require surgery more often. Six (7.3%) of the 82 patients who received CroFab experienced an adverse drug reaction. Reactions consisted of allergic symptoms that were mild, responded to minimal interventions, and did not limit the subsequent use of CroFab. It is concluded that CroFab use is typically well tolerated in pediatric patients.