bluuebunny/crossref_metadata_2025_split huggingface dataset:
16α‐Hydroxycleroda‐3,13 (14)Z‐dien‐15,16‐olide from Polyalthia longifolia: a safe and orally active antileishmanial agent
Authors: Misra Pragya , Sashidhara Koneni V , Singh Suriya Pratap , Kumar Awanish , Gupta Reema , Chaudhaery Shailendra S , Gupta Souvik Sen , Majumder HK , Saxena Anil K , Dube Anuradha 
Published: February 2010

Background and purpose:  New antileishmanials from natural products are urgently needed due to the emergence of drug resistance complicated by severe cytotoxic effects. 16α‐Hydroxycleroda‐3,13 (14)Z‐dien‐15,16‐olide (Compound 1) from Polyalthia longifolia was found to be a potential antileishmanial and non‐cytotoxic, as evidenced by long‐term survival (>6 months) of treated animals. This prompted us to determine its target and, using molecular modelling, identify the interactions responsible for its specific antileishmanial activity.Experimental approach:  In vitro activity of compound was assessed using intracellular transgenic green fluorescent protein‐stably expressed Leishmania donovani parasites. In vivo activity and survival of animals post‐treatment were evaluated in L. donovani‐infected hamsters. Known property of clerodane diterpenes as potent human DNA topoisomerase inhibitors led us to evaluate the inhibition of recombinant L. donovani topoisomerase I using relaxation assay. Mode of cell death induced by Compound 1 was assessed by phosphotidylserine exposure post‐treatment. Molecular modelling studies were conducted with DNA topoisomerase I to identify the binding interactions responsible for its activity.Key results:  Bioassay‐guided fractionation led to isolation of Compound 1 as a non‐cytotoxic, orally active antileishmanial. Compound 1 inhibited recombinant DNA topoisomerase I which, ultimately, induced apoptosis. Molecular docking studies indicated that five strong hydrogen‐bonding interactions and hydrophobic interactions of Compound 1 with L. donovani DNA‐topoisomerase are responsible for its antileishmanial activity.Conclusions and implications:  The data reveal Compound 1 is a potent and safe antileishmanial. The study further exploited the structural determinants responsible for its non‐cytotoxic and potent activity, to raise the feasibility of specifically targeting the target enzyme responsible for its activity through rational drug design.
Statins suppress interleukin‐6‐induced monocyte chemo‐attractant protein‐1 by inhibiting Janus kinase/signal transducers and activators of transcription pathways in human vascular endothelial cells
Authors: Jougasaki Michihisa , Ichiki Tomoko , Takenoshita Yoko , Setoguchi Manabu 
Published: February 2010

Background and purpose:  The mechanisms of anti‐inflammatory actions of statins, 3‐hydroxy‐3‐methylglutaryl CoA (HMG‐CoA) reductase inhibitors, remain unclear. We investigated the effects of statins on interleukin (IL)‐6‐induced monocyte chemo‐attractant protein (MCP)‐1 expression and monocyte chemotaxis.Experimental approach:  Cultures of human aortic endothelial cells (HAECs) were stimulated with IL‐6 in the absence and presence of statins. Gene expression and protein secretion of MCP‐1, phosphorylation of Janus kinase (JAK) and the signal transducers and activators of transcription (STAT) pathway, and human monocyte migration were examined.Key results:  IL‐6 plus its soluble receptor sIL‐6R (IL‐6/sIL‐6R) promoted THP‐1 monocyte migration, and increased gene expression and protein secretion of MCP‐1, more than IL‐6 alone or sIL‐6R alone. Various statins inhibited IL‐6/sIL‐6R‐promoted monocyte migration and MCP‐1 expression in HAECs. Co‐incubation of mevalonate and geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, reversed the inhibitory effects of statins on MCP‐1 expression. Geranylgeranyl transferase inhibitor, but not farnesyl transferase inhibitor, suppressed IL‐6/sIL‐6R‐stimulated MCP‐1 expression. IL‐6/sIL‐6R rapidly phosphorylated JAK1, JAK2, TYK2, STAT1 and STAT3, which were inhibited by statins. Transfection of STAT3 small interfering RNA (siRNA), but not STAT1 siRNA, attenuated the ability of IL‐6/sIL‐6R to enhance THP‐1 monocyte migration. In addition, statins blocked IL‐6/sIL‐6R‐induced translocation of STAT3 to the nucleus.Conclusions and implications:  Statins suppressed IL‐6/sIL‐6R‐induced monocyte chemotaxis and MCP‐1 expression in HAECs by inhibiting JAK/STAT signalling cascades, explaining why statins have anti‐inflammatory properties beyond cholesterol reduction.
Nicotinic acetylcholine receptors expressed in the ventralposterolateral thalamic nucleus play an important role in anti‐allodynic effects
Authors: Ueda M , Iida Y , Tominaga A , Yoneyama T , Ogawa M , Magata Y , Nishimura H , Kuge Y , Saji H 
Published: February 2010

Background and purpose: Much interest is currently being focused on the anti‐nociceptive effects mediated by nicotinic acetylcholine (nACh) receptors, including their location and mechanism of action. The purpose of this study was to elucidate these issues using 5‐iodo‐3‐(2(S)‐azetidinylmethoxy)pyridine (5IA), a nACh receptor agonist, and [125I]5IA.Experimental approach: We partially ligated the sciatic nerve of Sprague‐Dawley rat to induce neuropathic pain [Seltzer's partial sciatic nerve ligation (PSL) model]. We then examined the changes in nACh receptor density in the CNS using [125I]5IA autoradiography and the involvement of nACh receptors in anti‐nociceptive effects in the region where changes occurred.Key results: Autoradiographic studies showed that the accumulation of [125I]5IA and the number of nACh receptors in the thalamus of PSL rats were increased about twofold compared with those in the sham‐operated rats. No change was observed in other brain regions. Rats injected in the ventral posterolateral thalamic nucleus (VPL) with 5IA demonstrated a significant and dose‐dependent anti‐allodynic effect and this effect was completely antagonized by mecamylamine, injected with 5IA, into the VPL. The blockade of nACh receptors in the VPL by mecamylamine decreased by 70% the anti‐allodynic effect of 5IA, given i.c.v. Moreover, mecamylamine given intra‐VPL by itself, induced significant hyperalgesia.Conclusions and implications: Our findings suggest that the nACh receptors expressed in the VPL play an important role in the anti‐allodynic effects produced by exogenous and endogenous agonists.
Poly(lactic acid‐glycolic acid) nanoparticles markedly improve immunological protection provided by peptide P10 against murine paracoccidioidomycosis
Authors: Amaral André C , Marques Alexandre F , Muñoz Julián E , Bocca Anamélia L , Simioni Andreza R , Tedesco Antonio C , Morais Paulo C , Travassos Luiz R , Taborda Carlos P , Felipe Maria Sueli S 
Published: February 2010

Background and purpose:  The present study reports on the preparation and testing of a sustained delivery system for the immunomodulatory peptide P10 aimed at reducing the in vivo degradation of the peptide and the amount required to elicit a protective immune response against paracoccidioidomycosis.Experimental approach:  BALB/c mice were infected with the yeast Paracoccidioides brasiliensis to mimic the chronic form of paracoccidioidomycosis. The animals were treated daily with sulfamethoxazole/trimethoprim alone or combined with peptide P10, either emulsified in Freund's adjuvant or entrapped in poly(lactic acid‐glycolic acid) (PLGA) nanoparticles at different concentrations (1 µg, 5 µg, 10 µg, 20 µg or 40 µg·50 µL−1). Therapeutic efficacy was assessed as fungal burden in tissues and the immune response by quantitative determination of cytokines.Key results:  Animals given combined chemotherapy and P10 nanotherapy presented a marked reduction of fungal load in the lungs, compared with the non‐treated animals. After 30 days of treatment, P10 entrapped within PLGA (1 µg·50 µL−1) was more effective than ‘free’ P10 emulsified in Freund's adjuvant (20 µg·50 µL−1), as an adjuvant to chemotherapy. After treatment for 90 days, the higher doses of P10 entrapped within PLGA (5 or 10 µg·50 µL−1) were most effective. Treatment with P10 emulsified in Freund's adjuvant (20 µg·50 µL−1) or P10 entrapped within PLGA (1 µg·50 µL−1) were accompanied by high levels of interferon‐gamma in lung.Conclusions and implications:  Combination of sulfamethoxazole/trimethoprim with the P10 peptide entrapped within PLGA demonstrated increased therapeutic efficacy against paracoccidioidomycosis. P10 incorporation into PLGA nanoparticles dramatically reduced the peptide amount necessary to elicit a protective effect.
Differing effects of exogenous and endogenous hydrogen sulphide in carrageenan‐induced knee joint synovitis in the rat
Authors: Ekundi‐Valentim E , Santos KT , Camargo EA , Denadai‐Souza A , Teixeira SA , Zanoni CI , Grant AD , Wallace JL , Muscará MN , Costa SK 
Published: February 2010

Background and purpose:  Recent findings suggest that the noxious gas H2S is produced endogenously, and that physiological concentrations of H2S are able to modulate pain and inflammation in rodents. This study was undertaken to evaluate the ability of endogenous and exogenous H2S to modulate carrageenan‐induced synovitis in the rat knee.Experimental approach:  Synovitis was induced in Wistar rats by intra‐articular injection of carrageenan into the knee joint. Sixty minutes prior to carrageenan injection, the rats were pretreated with indomethacin, an inhibitor of H2S formation (dl‐propargylglycine) or an H2S donor [Lawesson's reagent (LR)].Key results:  Injection of carrageenan evoked knee inflammation, pain as characterized by impaired gait, secondary tactile allodynia of the ipsilateral hindpaw, joint swelling, histological changes, inflammatory cell infiltration, increased synovial myeloperoxidase, protein nitrotyrosine residues, inducible NOS (iNOS) activity and NO production. Pretreatment with LR or indomethacin significantly attenuated the pain responses, and all the inflammatory and biochemical changes, except for the increased iNOS activity, NO production and 3‐NT. Propargylglycine pretreatment potentiated synovial iNOS activity (and NO production), and enhanced macrophage infiltration, but had no effect on other inflammatory parameters.Conclusions and implications:  Whereas exogenous H2S delivered to the knee joint can produce a significant anti‐inflammatory and anti‐nociceptive effect, locally produced H2S exerts little immunomodulatory effect. These data further support the development and use of H2S donors as potential alternatives (or complementary therapies) to the available anti‐inflammatory compounds used for treatment of joint inflammation or relief of its symptoms.
Inhalational anaesthetics andn‐alcohols share a site of action in the neuronal Shaw2 Kvchannel
Authors: Bhattacharji Aditya , Klett Nathan , Go Ramon Christopher V , Covarrubias Manuel 
Published: February 2010

Background and purpose: Neuronal ion channels are key targets of general anaesthetics and alcohol, and binding of these drugs to pre‐existing and relatively specific sites is thought to alter channel gating. However, the underlying molecular mechanisms of this action are still poorly understood. Here, we investigated the neuronal Shaw2 voltage‐gated K+(Kv) channel to ask whether the inhalational anaesthetic halothane andn‐alcohols share a binding site near the activation gate of the channel.Experimental approach: Focusing on activation gate mutations that affect channel modulation byn‐alcohols, we investigatedn‐alcohol‐sensitive andn‐alcohol‐resistant Kvchannels heterologously expressed inXenopusoocytes to probe the functional modulation by externally applied halothane using two‐electrode voltage clamping and a gas‐tight perfusion system.Key results: Shaw2 Kvchannels are reversibly inhibited by halothane in a dose‐dependent and saturable manner (K0.5= 400 µM;nH= 1.2). Also, discrete mutations in the channel's S4S5 linker are sufficient to reduce or confer inhibition by halothane (Shaw2‐T330L and Kv3.4‐G371I/T378A respectively). Furthermore, a point mutation in the S6 segment of Shaw2 (P410A) converted the halothane‐induced inhibition into halothane‐induced potentiation. Lastly, the inhibition resulting from the co‐application ofn‐butanol and halothane is consistent with the presence of overlapping binding sites for these drugs and weak binding cooperativity.Conclusions and implications: These observations strongly support a molecular model of a general anaesthetic binding site in the Shaw2 Kvchannel. This site may involve the amphiphilic interface between the S4S5 linker and the S6 segment, which plays a pivotal role in Kvchannel activation.
Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine
Authors: Van Der Loos M. L. M. , Mulder P. , Hartong E. G. Th. M. , Blom M. B. J. , Vergouwen A. C. , Van Noorden M. S. , Timmermans M. A. , Vieta E. , Nolen W. A. ,   for the LamLit Study Group
Published: February 2010

van der Loos MLM, Mulder P, Hartong EGThM, Blom MBJ, Vergouwen AC, van Noorden MS, Timmermans MA, Vieta E, Nolen WA, for the LamLit Study Group. Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine.Objective:  In a previous paper, we reported about the efficacy of the addition of lamotrigine to lithium in patients with bipolar depression. In the second phase of this study paroxetine was added to ongoing treatment in non‐responders.Method:  Bipolar depressed patients (n = 124) treated with lithium were randomized to addition of lamotrigine or placebo. In non‐responders after 8 weeks, paroxetine 20 mg was added for another 8 weeks to ongoing treatment.Results:  After 8 weeks the improvement in patients treated with lamotrigine vs. patients treated with placebo was significant. After addition of paroxetine this difference disappeared as a result of greater further improvement in the non‐responders to placebo.Conclusion:  Addition of lamotrigine to lithium was found effective in bipolar depressed patients. Further addition of paroxetine in non‐responders to lithium plus lamotrigine did not appear to provide additional benefit, while it appeared to do so in non‐responders to lithium plus placebo.
Cancer risk from diagnostic radiology in a deliberate self‐harm patient
Authors: Norelli L. J. , Coates A. D. , Kovasznay B. M. 
Published: February 2010

Norelli LJ, Coates AD, Kovasznay BM. Cancer risk from diagnostic radiology in a deliberate self‐harm patient.Objective:  Patients who engage in recurrent deliberate self‐harm (DSH) behaviours have increased morbidity and mortality and use emergency services more than others. Unrecognized iatrogenic injury may play a role. Specifically, we call attention to the potential danger of cumulative radiation exposure.Method:  Case presentation and discussion.Results:  A 29‐year‐old woman with multiple episodes of deliberate foreign body ingestion received over 400 diagnostic radiology examinations during a 12 year period. The patient’s calculated total radiation dose reached an average of 20.5 mSv per year, a dose comparable to atomic bomb survivors and nuclear industry workers, populations in which there is a significant excess cancer risk.Conclusion:  Patients with recurrent self‐injurious behaviours, frequent users of healthcare services who often undergo repeated medical assessment and treatment, are likely at higher risk for iatrogenic adverse events. Multiple diagnostic radiology examinations have recently come under scrutiny for causing increased lifetime risk of cancer. Healthcare providers, in particular psychiatrists and emergency department physicians, should consider the cumulative risks of radiological procedures when assessing and treating patients with DSH.
Sedoanalgesia in paediatric intensive care: a survey of 19 Italian units
Authors: Benini F , Farina M , Capretta A , Messeri A , Cogo P 
Published: February 2010

AbstractAim:  To analyse the methods used to manage and monitor sedoanalgesia at Italian paediatric intensive care units (ICUs).Methods:  Data were collected by administering a questionnaire that aimed to investigate whether ICUs adopted a validated protocol to manage sedoanalgesia.Results:  The results revealed that a majority of the ICUs adopt a protocol for dealing with sedation and analgesia, but this protocol is implemented with difficulty or not at all in routine clinical practice. The most often used pharmacological combination, is midazolam and fentanyl. Several weaknesses remain in terms of the methods used to assess sedoanalgesia, which are generally not standardized, but rather based on recording the patient’s physiological parameters.Conclusion:  Sedation and analgesia are priority issues in the management of critically ill children. None of the numerous drugs available is ideal and the protocols currently used in clinical practice involve the combined use of different drugs. There is currently no shared and validated approach as to which is the most effective and safest sedoanalgesic regimen in critically ill children.
Prevalence of Undiagnosed Testosterone Deficiency in Aging Athletes: Does Exercise Training Influence the Symptoms of Male Hypogonadism?
Authors: Di Luigi Luigi , Sgrò Paolo , Fierro Valentina , Bianchini Serena , Battistini Giancarlo , Magini Valter , Jannini Emmanuele A. , Lenzi Andrea 
Published: February 2010

ABSTRACT

Introduction
Worldwide many aging males practice sports. A high prevalence of late-onset male hypogonadism has been observed in general population. Sport-participation influences the neuroendocrine system and may decrease serum testosterone.

Aim
This preliminary study was designed to estimate the prevalence and the symptoms of undiagnosed testosterone deficiency in aging athletes.

Methods
This observational survey was performed in 183 caucasian male athletes &gt;50 years, in the setting of pre-participation screening. Pituitary–gonadal hormones and symptoms of hypogonadism were investigated. Serum total testosterone (TT), sex hormone binding globulin, luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), free-T4, and thyroid stimulation hormone (TSH) were assayed, and free T, bioactive T, and the LH/TT ratio were calculated. The International Index of Erectile Dysfunction (IIEF-15) and the Center for Epidemiological Studies Depression Scale (CES-D) were administered. Hypogonadal athletes were compared with eugonadal athletes as controls.

Main Outcome Measures
Prevalence and clinical symptoms of severe (TT&lt;8 nmol/L) or mild (8 nmol/L ≤ TT&lt;12 nmol/L) testosterone deficiency were investigated.

Results
The mean sample age was 61.9 ± 7.5 years (range 50–75). Severe or mild testosterone deficiency was observed in 12% and 18%, respectively, of overall athletes, with the highest prevalence in athletes &gt;70 years (27.5% and 25.0%, respectively). TT did not correlate with age, training duration, or questionnaire scores. No differences were observed for nonspecific symptoms of hypogonadism, IIEF-15 and CES-D scores between eugonadal and severe hypogonadal athletes.

Conclusions
Independently of its etiology, a significant percentage of aging athletes had undiagnosed testosterone deficiency. In a relevant number of these cases, testosterone deficiency was not overtly symptomatic. Our results suggest that sport-participation per se can influence the symptoms of hypogonadism. The history of clinical symptoms may be inaccurate to diagnose testosterone deficiency in aging athletes. Future research should address the clinical relevance and the specific risks of testosterone deficiency in aging athletes, and the need of a systematic pre-participation serum testosterone evaluation.
The Dopamine Transporter Gene (DAT1) Polymorphism is Associated with Premature Ejaculation
Authors: Santtila Pekka , Jern Patrick , Westberg Lars , Walum Hasse , Pedersen Christin T. , Eriksson Elias , Kenneth Sandnabba Nils 
Published: February 2010

ABSTRACTIntroductionPrevious research has suggested brain dopamine (DA) neurotransmission to be involved in the control of ejaculation. Furthermore, previous studies indicate a partly hereditary background to premature ejaculation.AimTo investigate whether the dopamine transporter gene (DAT1) polymorphism is associated with premature ejaculation.MethodsRetrospective self-reports of four indicators reflecting ejaculatory function—anteportal ejaculation, number of penile thrusts, ejaculation latency time, and feeling of control over ejaculation—and saliva samples for DNA analysis were obtained from 1,290 men (M=26.9, standard deviation=4.7 years; range 18–45) with sexual experience.Main Outcome MeasuresCalculations of allelic effects were computed using the Generalized Estimating Equations module of SPSS 17.ResultsCarriers of the 10R10R genotype had scores indicating a lower threshold to ejaculate on each of the indicators compared to the combined 9R9R/9R10R carrier group. The differences were significant both for the composite score and for anteportal ejaculation, number of thrusts, and feeling of control over ejaculation, but not for ejaculation latency time. The effect of the polymorphism remained significant after controlling for age, homosexual experience, having a regular sexual partner, level of sexual desire, and frequency of sexual activity, hence suggesting that it is not secondary to an association between the studied polymorphism and some other aspect of sexual behavior, but due to a specific influence of DA on ejaculation.ConclusionsThe findings of the present study support results of previous studies indicating involvement of dopaminergic neurotransmission in ejaculation. Santtila P, Jern P, Westberg L, Walum H, Pedersen CT, Eriksson E, and Sandnabba NK. The dopamine transporter gene (DAT1) polymorphism is associated with premature ejaculation.
The Effect of Intracavernous Injection of Adipose Tissue-Derived Stem Cells on Hyperlipidemia-Associated Erectile Dysfunction in a Rat Model
Authors: Huang Yun-Ching , Ning Hongxiu , Shindel Alan W. , Fandel Thomas M. , Lin Guiting , Harraz Ahmed M. , Lue Tom F. , Lin Ching-Shwun 
Published: February 2010

ABSTRACTIntroductionHyperlipidemia has been associated with erectile dysfunction (ED) via damage to the cavernous endothelium and nerves. Adipose tissue-derived stem cells (ADSC) have been shown to differentiate into endothelial cells and secrete vasculotrophic and neurotrophic factors.AimTo assess whether ADSC have therapeutic effects on hyperlipidemia-associated ED.MethodsTwenty-eight male rats were induced to develop hyperlipidemia with a high-fat diet (hyperlipidemic rats, HR). Ten additional male rats were fed a normal diet to serve as controls (normal rats, NR). Five months later, all rats were subjected to ADSC isolation from paragonadal fat. The cells were cultured for 1 week, labeled with 5-ethynyl-2′-deoxyuridine (EdU), and then injected autologously into the corpus cavernosum of 18 HR. The remaining 10 HR rats were injected with phosphate buffered saline (PBS). At 2 and 14 days post-transplantation, four rats in the HR+ADSC group were sacrificed for tracking of the transplanted cells. At 28 days post-transplantation, all remaining rats were analyzed for serum biochemistry, erectile function, and penile histology.Main Outcome MeasuresErectile function was assessed by intracavernous pressure (ICP) measurement during electrostimulation of the cavernous nerve. Cavernous nerves, endothelium, and smooth muscle were assessed by immunohistochemistry.ResultsSerum total cholesterol and low-density lipoprotein levels were significantly higher in HR than in NR. High-density lipoprotein level was significantly lower in HR than in NR. Mean ICP/mean arterial pressure ratio was significantly lower in HR+PBS than in NR+PBS or HR+ADSC. Neuronal nitric oxide synthase (nNOS)-positive nerve fibers and endothelial cells were fewer in HR+PBS than in HR+ADSC. Smooth muscle content was significantly higher in both HR groups than in NR.ConclusionsHyperlipidemia is associated with abnormalities in both the nerves and endothelium. Treatment with ADSC ameliorates these adverse effects and holds promise as a potential new therapy for ED.