bluuebunny/crossref_metadata_2025_split huggingface dataset:
Burst generation mediated by cholinergic input in terminal nerve‐gonadotrophin releasing hormone neurones of the goldfish
Authors: Kawai Takafumi , Abe Hideki , Oka Yoshitaka 
Published: August 2013

Key points
Burst firing activities are effective for the release of neuropeptides from peptidergic neurones.
A peptidergic neurone, the terminal nerve (TN)‐gonadotrophin releasing hormone (GnRH) neurone, shows spontaneous burst firing activities only infrequently.
Only a single pulse electrical stimulation of the neuropil surrounding the TN‐GnRH neurones induces transient burst activities in TN‐GnRH neurones via cholinergic mechanisms.
The activation of muscarinic acetylcholine receptors results in a long‐lasting hyperpolarisation, inducing rebound burst activities in TN‐GnRH neurones.
These new findings suggest a novel type of cholinergic regulation of burst activities in peptidergic neurones, which should contribute to the release of neuropeptides.
Abstract  Peptidergic neurones play a pivotal role in the neuromodulation of widespread areas in the nervous system. Generally, it has been accepted that the peptide release from these neurones is regulated by their firing activities. The terminal nerve (TN)‐gonadotrophin releasing hormone (GnRH) neurones, which are one of the well‐studied peptidergic neurones in vertebrate brains, are characterised by their spontaneous regular pacemaker activities, and GnRH has been suggested to modulate the sensory responsiveness of animals. Although many peptidergic neurones are known to exhibit burst firing activities when they release the peptides, TN‐GnRH neurones show spontaneous burst firing activities only infrequently. Thus, it remains to be elucidated whether the TN‐GnRH neurones show burst activities and, if so, how the mode switching between the regular pacemaking and bursting modes is regulated in these neurones. In this study, we found that only a single pulse electrical stimulation of the neuropil surrounding the TN‐GnRH neurones reproducibly induces transient burst activities in TN‐GnRH neurones. Our combined physiological and morphological data suggest that this phenomenon occurs following slow inhibitory postsynaptic potentials mediated by cholinergic terminals surrounding the TN‐GnRH neurones. We also found that the activation of muscarinic acetylcholine receptors induces persistent opening of potassium channels, resulting in a long‐lasting hyperpolarisation. This long hyperpolarisation induces sustained rebound depolarisation that has been suggested to be generated by a combination of persistent voltage‐gated Na+ channels and low‐voltage‐activated Ca2+ channels. These new findings suggest a novel type of cholinergic regulation of burst activities in peptidergic neurones, which should contribute to the release of neuropeptides.
Orexin neurons are indispensable for prostaglandin E2‐induced fever and defence against environmental cooling in mice
Authors: Takahashi Yoshiko , Zhang Wei , Sameshima Kohei , Kuroki Chiharu , Matsumoto Ami , Sunanaga Jinko , Kono Yu , Sakurai Takeshi , Kanmura Yuichi , Kuwaki Tomoyuki 
Published: August 2013

Key points
We recently showed that orexin neurons in the hypothalamus are indispensable for stress‐induced thermogenesis.
In this study we examined whether the orexin neurons are also important for other forms of thermogenic processes, including brain prostaglandin E2 (PGE2) injection that mimics inflammatory fever and environmental cold exposure.
As was the case with stress‐induced thermogenesis, orexin neuron‐ablated (ORX‐AB) mice exhibited a blunted PGE2‐induced fever and intolerance to cold (5°C) exposure.
Injection of retrograde tracer into the medullary raphe nucleus, where sympathetic premotor neurons regulating thermogenesis by the brown adipose tissue are located, revealed direct and indirect projection from the orexin neurons, of which the latter seemed to be preserved in the ORX‐AB mice.
These results suggest that orexin neurons are important in general thermogenic processes, and their importance is not restricted to stress‐induced thermogenesis.
Abstract  We recently showed using prepro‐orexin knockout (ORX‐KO) mice and orexin neuron‐ablated (ORX‐AB) mice that orexin neurons in the hypothalamus, but not orexin peptides per se, are indispensable for stress‐induced thermogenesis. To examine whether orexin neurons are more generally involved in central thermoregulatory mechanisms, we applied other forms of thermogenic perturbations, including brain prostaglandin E2 (PGE2) injections which mimic inflammatory fever and environmental cold exposure, to ORX‐KO mice, ORX‐AB mice and their wild‐type (WT) litter mates. ORX‐AB mice, but not ORX‐KO mice, exhibited a blunted PGE2‐induced fever and intolerance to cold (5°C) exposure, and these findings were similar to the results previously obtained with stress‐induced thermogenesis. PGE2‐induced shivering was also attenuated in ORX‐AB mice. Both mutants responded similarly to environmental heating (39°C). In WT and ORX‐KO mice, the administration of PGE2 and cold exposure activated orexin neurons, as revealed by increased levels of expression of c‐fos. Injection of retrograde tracer into the medullary raphe nucleus revealed direct and indirect projection from the orexin neurons, of which the latter seemed to be preserved in the ORX‐AB mice. In addition, we found that glutamate receptor antagonists (d‐(–)‐2‐amino‐5‐phosphonopentanoic acid and 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione) but not orexin receptor antagonists (SB334867 and OX2 29) successfully inhibited PGE2‐induced fever in WT mice. These results suggest that orexin neurons are important in general thermogenic processes, and their importance is not restricted to stress‐induced thermogenesis. In addition, these results indicate the possible involvement of glutamate in orexin neurons implicated in PGE2‐induced fever.
Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis
Authors: Wenzler Tanja , Yang Sihyung , Braissant Olivier , Boykin David W. , Brun Reto , Wang Michael Zhuo 
Published: August 2013

ABSTRACT

Human African trypanosomiasis (HAT, also called sleeping sickness), a neglected tropical disease endemic to sub-Saharan Africa, is caused by the parasites
Trypanosoma brucei gambiense
and
T. brucei rhodesiense
. Current drugs against this disease have significant limitations, including toxicity, increasing resistance, and/or a complicated parenteral treatment regimen. DB829 is a novel aza-diamidine that demonstrated excellent efficacy in mice infected with
T. b. rhodesiense
or
T. b. brucei
parasites. The current study examined the pharmacokinetics,
in vitro
and
in vivo
activity against
T. b. gambiense
, and time of drug action of DB829 in comparison to pentamidine. DB829 showed outstanding
in vivo
efficacy in mice infected with parasites of
T. b. gambiense
strains, despite having higher
in vitro
50% inhibitory concentrations (IC
50
s) than against
T. b. rhodesiense
strain STIB900. A single dose of DB829 administered intraperitoneally (5 mg/kg of body weight) cured all mice infected with different
T. b. gambiense
strains. No cross-resistance was observed between DB829 and pentamidine in
T. b. gambiense
strains isolated from melarsoprol-refractory patients. Compared to pentamidine, DB829 showed a greater systemic exposure when administered intraperitoneally, partially contributing to its improved efficacy. Isothermal microcalorimetry and
in vivo
time-to-kill studies revealed that DB829 is a slower-acting trypanocidal compound than pentamidine. A single dose of DB829 (20 mg/kg) administered intraperitoneally clears parasites from mouse blood within 2 to 5 days. In summary, DB829 is a promising preclinical candidate for the treatment of first- and second-stage HAT caused by both
Trypanosoma brucei
subspecies.
Risk Factors for Treatment Failure of Polymyxin B Monotherapy for Carbapenem-Resistant Klebsiella pneumoniae Infections
Authors: Dubrovskaya Yanina , Chen Ting-Yi , Scipione Marco R. , Esaian Diana , Phillips Michael S. , Papadopoulos John , Mehta Sapna A. 
Published: August 2013

ABSTRACT

Polymyxins are reserved for salvage therapy of infections caused by carbapenem-resistant
Klebsiella pneumoniae
(CRKP). Though synergy has been demonstrated for the combination of polymyxins with carbapenems or tigecycline,
in vitro
synergy tests are nonstandardized, and the clinical effect of synergy remains unclear. This study describes outcomes for patients with CRKP infections who were treated with polymyxin B monotherapy. We retrospectively reviewed the medical records of patients with CRKP infections who received polymyxin B monotherapy from 2007 to 2011. Clinical, microbiology, and antimicrobial treatment data were collected. Risk factors for treatment failure were identified by logistic regression. Forty patients were included in the analysis. Twenty-nine of 40 (73%) patients achieved clinical cure as defined by clinician-documented improvement in signs and symptoms of infections, and 17/32 (53%) patients with follow-up culture data achieved microbiological cure. End-of-treatment mortality was 10%, and 30-day mortality was 28%. In a multivariate analysis, baseline renal insufficiency was associated with a 6.0-fold increase in clinical failure after adjusting for septic shock (odds ratio [OR] = 6.0; 95% confidence interval [CI] = 1.22 to 29.59). Breakthrough infections with organisms intrinsically resistant to polymyxins occurred in 3 patients during the treatment. Eighteen of 40 (45%) patients developed a new CRKP infection a median of 23 days after initial polymyxin B treatment, and 3 of these 18 infections were polymyxin resistant. The clinical cure rate achieved in this retrospective study was 73% of patients with CRKP infections treated with polymyxin B monotherapy. Baseline renal insufficiency was a risk factor for treatment failure after adjusting for septic shock. Breakthrough infections with organisms intrinsically resistant to polymyxin B and development of resistance to polymyxin B in subsequent CRKP isolates are of concern.
CYP2J2 and CYP2C19 Are the Major Enzymes Responsible for Metabolism of Albendazole and Fenbendazole in Human Liver Microsomes and Recombinant P450 Assay Systems
Authors: Wu Zhexue , Lee Doohyun , Joo Jeongmin , Shin Jung-Hoon , Kang Wonku , Oh Sangtaek , Lee Do Yup , Lee Su-Jun , Yea Sung Su , Lee Hye Suk , Lee Taeho , Liu Kwang-Hyeon 
Published: August 2013

ABSTRACTAlbendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 was the predominant enzyme catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is primarily mediated by CYP2J2 (0.34 μl/min/pmol P450, which is a rate 3.9- and 8.1-fold higher than the rates for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 μl/min/pmol P450 for CYP2C19 and CYP2J2, respectively, which are rates 11.7- and 8.4-fold higher than the rate for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is primarily catalyzed by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazolein vivo.
Preclinical Characterization of GLS4, an Inhibitor of Hepatitis B Virus Core Particle Assembly
Authors: Wu Guoyi , Liu Bo , Zhang Yingjun , Li Jing , Arzumanyan Alla , Clayton Marcia M. , Schinazi Raymond F. , Wang Zhaohe , Goldmann Siegfried , Ren Qingyun , Zhang Faxhou , Feitelson Mark A. 
Published: August 2013

ABSTRACT

Hepatitis B virus (HBV)-associated chronic liver diseases are treated with nucleoside analogs that target the virus polymerase. While these analogs are potent, drugs are needed to target other virus-encoded gene products to better block the virus replication cycle and chronic liver disease. This work further characterized GLS4 and compared it to the related BAY 41-4109, both of which trigger aberrant HBV core particle assembly, where the virus replication cycle occurs. This was done in HepAD38 cells, which replicate HBV to high levels.
In vitro
, GLS4 was significantly less toxic for primary human hepatocytes (
P
< 0.01 up to 100 μM), inhibited virus accumulation in the supernantant of HepAD38 cells (
P
< 0.02 up to 100 nM), inhibited HBV replicative forms in the liver with a significantly lower 50% effective concentration (EC
50
) (
P
< 0.02), and more strongly inhibited core gene expression (
P
< 0.001 at 100 to 200 nM) compared to BAY 41-4109.
In vivo
characterization was performed in nude mice inoculated with HepAD38 cells, which grew out as tumors, resulting in viremia. Treatment of mice with GLS4 and BAY 41-4109 showed strong and sustained suppression of virus DNA to about the same extents both during and after treatment. Both drugs reduced the levels of intracellular core antigen in the tumors. Alanine aminotransferase levels were normal. Tumor and total body weights were not affected by treatment. Thus, GLS4 was as potent as the prototype, BAY 41-4109, and was superior to lamivudine, in that there was little virus relapse after the end of treatment and no indication of toxicity.
In VitroandIn VivoActivities of AIC292, a Novel HIV-1 Nonnucleoside Reverse Transcriptase Inhibitor
Authors: Wildum Steffen , Paulsen Daniela , Thede Kai , Ruebsamen-Schaeff Helga , Zimmermann Holger 
Published: August 2013

ABSTRACTNonnucleoside reverse transcriptase inhibitors (NNRTIs) are important and frequently used elements of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. However, the development of drug resistance, as well as the side effects of existing drugs, defines a medical need for novel NNRTIs with excellent tolerability, improved activity against NNRTI-resistant viruses, and a low barrier to resistance. Within the chemical class of diarylpyrazole-[imidazolidinone]-carboxamides, AIC292 was identified as a promising novel HIV-1 NNRTI and has successfully completed single-dose clinical phase I studies. Here, we report on the antiviral activity of AIC292, evaluatedin vitroagainst wild-type and NNRTI-resistant HIV-1 isolates andin vivousing an engineered mouse xenograft model. AIC292 inhibited wild-type HIV-1 laboratory strains at low nanomolar concentrations, was well tolerated in different cell lines, and showed excellent selectivity in a lead profiling screen. In addition, activity of AIC292 could be demonstrated against a broad panel of wild-type HIV-1 group M and group O clinical isolates. AIC292 also retained activity against viruses harboring NNRTI resistance-associated mutations (RAMs), including the most prevalent variants, K103N, Y181C, and G190A. Interestingly, viruses bearing the L100I RAM were hypersusceptible to AIC292. Two-drug combination assays showed no antagonistic interactions between AIC292 and representative marketed HIV drugs with regard to antiviral activity. Furthermore, AIC292 displayed potent antiviralin vivoefficacy in a mouse xenograft model when applied once daily. Taken together, these data show that AIC292 represents a molecule with the antiviral properties of a novel NNRTI for the treatment of HIV-1 infection.
Associations of metabolic factors and adipokines with pain in incipient upper extremity soft tissue disorders: a cross-sectional study
Authors: Rechardt Martti , Shiri Rahman , Lindholm Harri , Karppinen Jaro , Viikari-Juntura Eira 
Published: August 2013

ObjectivesEarlier studies have suggested associations between metabolic factors and musculoskeletal pain or disorders. We studied the associations of obesity, lipids, other features of the metabolic syndrome and adipokines (adiponectin, leptin, resistin, visfatin) with upper extremity pain in a clinical population with incipient upper extremity soft tissue disorders (UESTDs).DesignA cross-sectional study.SettingPrimary healthcare (occupational health service) with further examinations at a research institute.ParticipantsPatients (N=163, 86% were women) seeking medical advice in the occupational health service due to incipient upper extremity symptoms with symptom duration of <1 month were referred for consultation to the Finnish Institute of Occupational Health from Spring 2006 to Fall 2008. We included all actively working subjects meeting diagnostic criteria based on physical examination. We excluded subjects meeting predetermined conditions.Outcome measurePain intensity was assessed with visual analogue scale and dichotomised at the highest tertile (cut-point 60).ResultsObesity (adjusted OR for high waist circumference 2.9, 95% CI 1.1 to 7.3), high-density lipoprotein cholesterol (OR 3.9, 95% CI 1.4 to 10.1 for low level) and triglycerides (OR 2.6, 95% CI 1.0 to 6.8 for high level) were associated with pain intensity. Of four adipokines studied, only visfatin was associated with upper extremity pain (adjusted OR 1.4, 95% CI 1.0 to 2.1 for 1SD increase in level).ConclusionsAbdominal obesity and lipids may have an impact on pain intensity in UESTDs. They may intensify pain through proinflammatory pain-modifying molecular pathways or by causing soft tissue pathology and dysfunction of their supplying arteries. Of four adipokines studied only one (visfatin) was associated with pain intensity. In the future, further studies are required to better understand the relationship between metabolic factors and UESTDs.
Is teenage pregnancy an obstetric risk in a welfare society? A population-based study in Finland, from 2006 to 2011
Authors: Leppälahti Suvi , Gissler Mika , Mentula Maarit , Heikinheimo Oskari 
Published: August 2013

ObjectiveTo assess obstetric outcomes in teenage pregnancies in a country with a low teenage delivery rate and comprehensive high-quality prenatal care.DesignRetrospective population-based register study.SettingFinland.ParticipantsAll nulliparous teenagers (13–15 years (n=84), 16–17 years (n=1234), 18–19 years (n=5987)) and controls (25-year-old to 29-year-old women (n=51 142)) with singleton deliveries in 2006–2011.Main outcome measuresRisk of adverse obstetric outcomes adjusted for demographic factors and clinically relevant pregnancy complications, with main focus on maternal pregnancy complications.ResultsTeenage mothers were more likely than controls to live in rural areas (16% (n=1168) vs 11.8% (n=6035)), smoke (36.4% (n=2661) vs 7% (n=3580)) and misuse alcohol or drugs (1.1% (n=82) vs 0.2% (n=96); p<0.001 for all). Teenagers made a good mean number of antenatal clinic visits (16.4 vs 16.5), but were more likely to have attended fewer than half of the recommended visits (3% (n=210) vs 1.4% (n=716)). Teenagers faced increased risks of several obstetric complications, for example, anaemia (adjusted OR 1.8, 95% CI 1.6 to 2.1), proteinuria (1.8, 1.2 to 2.6), urinary tract infection (UTI; 2.9, 1.8 to 4.8), pyelonephritis (6.3, 3.8 to 10.4) and eclampsia (3.2, 1.4 to 7.3), the risks increasing with descending age for most outcomes. Elevated risks of pre-eclampsia (3.7, 1.5 to 9.0) and preterm delivery (2.5, 1.2 to 5.3) were also found among 13-year-olds to 15-year-olds. However, teenage mothers were more likely to have vaginal delivery (1.9, 1.7 to 2.0) without complications. Inadequate prenatal care among teenagers was a risk factor of eclampsia (12.6, 2.6 to 62.6), UTI (5.8, 1.7 to 19.7) and adverse neonatal outcomes.ConclusionsPregnant teenagers tended to be socioeconomically disadvantaged versus controls and faced higher risks of various pregnancy complications. Special attention should be paid to enrolling teenagers into adequate prenatal care in early pregnancy.
Molecular Pathways: Adipose Inflammation as a Mediator of Obesity-Associated Cancer
Authors: Howe Louise R. , Subbaramaiah Kotha , Hudis Clifford A. , Dannenberg Andrew J. 
Published: August 2013

Abstract
The increasing rate of obesity worldwide is predicted to be associated with a surge in diseases. Notably, obesity has been linked to approximately 20% of cancer cases in the United States; obesity is associated with both increased risk and worse outcomes after diagnosis. Altered levels of circulating factors are strongly implicated, including insulin, insulin-like growth factor 1, leptin, adiponectin, and interleukin-6 (IL-6). In addition, increasing attention has focused on the consequences of local adipose inflammation. Inflammatory foci characterized by crown-like structures consisting of dead adipocytes encircled by macrophages occur in white adipose depots, including the breast tissue, of most overweight and obese women. Saturated fatty acids, released as a consequence of obesity-associated lipolysis, induce macrophage activation via Toll-like receptor 4, thereby stimulating NF-κB signaling. This, in turn, activates transcription of proinflammatory genes including COX-2, IL-6, IL-1β, and TNFα. Elevated levels of proinflammatory mediators cause both local and systemic effects. Of particular relevance with regard to breast cancer is increased transcription of the CYP19 gene encoding aromatase, the rate-limiting enzyme for estrogen synthesis. Notably, this obesity–inflammation–aromatase axis provides a plausible explanation for increased rates of postmenopausal, hormone receptor–positive breast cancer associated with obesity and hence may offer targets for interventions to attenuate risk or improve prognosis. Potential approaches include weight reduction, exercise, and suppression of obesity-driven signaling pathways using pharmaceutical or dietary agents. A key future goal is to identify biomarkers that accurately report adipose inflammation, both for identification of at-risk individuals and to assess the efficacy of interventions. Clin Cancer Res; 19(22); 6074–83. ©2013 AACR.