bluuebunny/crossref_metadata_2025 huggingface dataset:
Genotypic detection of rifampicin and isoniazid resistant Mycobacterium tuberculosis strains by DNA sequencing: a randomized trial
Authors: Abdelaal Amina , El-Ghaffar Hassan Abd , Zaghloul Mohammad Hosam Eldeen , El mashad Noha , Badran Ehab , Fathy Amal
Published: January 2009

Background

Tuberculosis is a growing international health concern. It is the biggest killer among the infectious diseases in the world today. Early detection of drug resistance allows starting of an appropriate treatment. Resistance to drugs is due to particular genomic mutations in specific genes of Mycobacterium tuberculosis(MTB). The aim of this study was to identify the presence of Isoniazid (INH) and Rifampicin(RIF) drug resistance in new and previously treated tuberculosis (TB) cases using DNA sequencing.

Methods

This study was carried out on 153 tuberculous patients with positive Bactec 460 culture for acid fast bacilli.

Results

Of the 153 patients, 105 (68.6%) were new cases and 48 (31.4%) were previously treated cases. Drug susceptibility testing on Bactec revealed 50 resistant cases for one or more of the first line antituberculous. Genotypic analysis was done only for rifampicin resistant specimens (23 cases) and INH resistant specimens (26 cases) to detect mutations responsible for drug resistance by PCR amplification of rpoB gene for rifampicin resistant cases and KatG gene for isoniazid resistant cases. Finally, DNA sequencing was done for detection of mutation within rpoB and KatG genes. Genotypic analysis of RIF resistant cases revealed that 20/23 cases (86.9%) of RIF resistance were having rpoB gene mutation versus 3 cases (13.1%) having no mutation with a high statistical significant difference between them (P < 0.001). Direct sequencing of Kat G gene revealed point mutation in 24/26 (92.3%) and the remaining 2/26 (7.7%) had wild type KatG i.e. no evidence of mutation with a high statistical significant difference between them (P < 0.001).

Conclusion

We can conclude that rifampicin resistance could be used as a useful surrogate marker for estimation of multidrug resistance. In addition, Genotypic method was superior to that of the traditional phenotypic method which is time-consuming taking several weeks or longer.
Pore Dilation Occurs in TRPA1 but Not in TRPM8 Channels
Authors: Chen Jun , Kim Donghee , Bianchi Bruce R , Cavanaugh Eric J , Faltynek Connie R , Kym Philip R , Reilly Regina M
Published: January 2009

Abundantly expressed in pain-sensing neurons, TRPV1, TRPA1 and TRPM8 are major cellular sensors of thermal, chemical and mechanical stimuli. The function of these ion channels has been attributed to their selective permeation of small cations (e.g., Ca2+, Na+ and K+), and the ion selectivity has been assumed to be an invariant fingerprint to a given channel. However, for TRPV1, the notion of invariant ion selectivity has been revised recently. When activated, TRPV1 undergoes time and agonist-dependent pore dilation, allowing permeation of large organic cations such as Yo-Pro and NMDG+. The pore dilation is of physiological importance, and has been exploited to specifically silence TRPV1-positive sensory neurons. It is unknown whether TRPA1 and TRPM8 undergo pore dilation. Here we show that TRPA1 activation by reactive or non-reactive agonists induces Yo-Pro uptake, which can be blocked by TRPA1 antagonists. In outside-out patch recordings using NMDG+ as the sole external cation and Na+ as the internal cation, TRPA1 activation results in dynamic changes in permeability to NMDG+. In contrast, TRPM8 activation does not produce either Yo-Pro uptake or significant change in ion selectivity. Hence, pore dilation occurs in TRPA1, but not in TRPM8 channels.
Hook worm caused chronic anemia found during the procedure of acute gastrointestinal bleeding: a case report
Authors: Zhao Yuan , Wang Liangjing , Si Jianmin
Published: January 2009

Background

Upper gastrointestinal bleeding with complicated factors is always difficult to find the primary origin.

Case presentation

Here we present a case of a 74-year-old male farmer suffered from acute upper gastrointestinal bleeding caused by gastric ulcer and Mallory-Weiss syndrome and chronic anemia which was at last found caused by hook worm infection.

Conclusion

It tells us that considering multi-possibility when can not explain the symptom with monophyletism is very important for clinicians.
Increased expression of FcγRI/CD64 on circulating monocytes parallels ongoing inflammation and nephritis in lupus
Authors: Li Yi , Lee Pui Y , Sobel Eric S , Narain Sonali , Satoh Minoru , Segal Mark S , Reeves Westley H , Richards Hanno B
Published: January 2009

Introduction

The high-affinity receptor for IgG Fcγ/CD64 is critical for the development of lupus nephritis (LN). Cross-linking Fc receptor on recruited monocytes by IgG-containing immune complexes is a key step in immune-complex-mediated nephritis in systemic lupus erythematosus (SLE). The goal of this study was to determine whether expression of Fc receptor (FcγR) I on circulating monocytes is associated with systemic inflammation and renal disease in SLE patients.

Methods

We studied 205 SLE patients (132 with LN and 73 without LN) along with 74 healthy control individuals. Surface expression of CD14 (monocytes), FcγRI/CD64, FcγRII/CD32, and FcγRIII/CD16 was evaluated by flow cytometry. Monocyte function was assessed by determining the migratory capacity and the ability to produce CCL2 (monocyte chemotractic protein 1). High-sensitivity C-reactive protein, C3 and C4 were measured by nephelometry.

Results

There was little difference in the expression of FcγRIII/CD16 or FcγRIII/CD32 on circulating monocytes between patients with SLE and control individuals. In contrast, FcγRI/CD64 expression was significantly higher in SLE patients and even higher in patients with LN. FcγRI/CD64 expression was positively associated with serum creatinine and indicators of systemic inflammation. Monocytes from patients with high FcγRI/CD64 expression also exhibited increased chemotaxis and capacity to produce monocyte chemotractic protein 1.

Conclusions

Increased FcγRI/CD64 expression on circulating monocytes parallels systemic inflammation and renal disease in SLE patients. We propose that circulating monocytes activated by immune complexes and/or proinflammatory mediators upregulate surface expression of FcγRI/CD64 in SLE. The enhanced chemotactic and inflammatory potential of the activated monocytes may participate in a vicious cycle of immune cell recruitment and renal injury in SLE.
Pumpless extracorporeal interventional lung assist in patients with acute respiratory distress syndrome: a prospective pilot study
Authors: Zimmermann Markus , Bein Thomas , Arlt Matthias , Philipp Alois , Rupprecht Leopold , Mueller Thomas , Lubnow Matthias , Graf Bernhard M , Schlitt Hans J
Published: January 2009

Introduction

Pumpless interventional lung assist (iLA) is used in patients with acute respiratory distress syndrome (ARDS) aimed at improving extracorporeal gas exchange with a membrane integrated in a passive arteriovenous shunt. In previous studies, feasibility and safety of the iLA system was demonstrated, but no survival benefit was observed. In the present pilot study we tested the hypothesis that timely initiation of iLA using clear algorithms and an improved cannulation technique will positively influence complication rates and management of lung protective ventilation.

Methods

iLA was implemented in 51 patients from multiple aetiologies meeting ARDS-criteria (American-European Consensus) for more than 12 hours. Initiation of iLA followed an algorithm for screening, careful evaluation and insertion technique. Patients with cardiac insufficiency or severe peripheral vascular disease were not considered suitable for iLA. Arterial and venous cannulae were inserted using a new strategy (ultrasound evaluation of vessels by an experienced team, using cannulae of reduced diameter). The incidence of complications and the effects on tidal volumes and inspiratory plateau pressures were primary outcome parameters, while oxygenation improvement and carbon dioxide removal capabilities were secondary study parameters.

Results

Initiation of iLA resulted in a marked removal in arterial carbon dioxide allowing a rapid reduction in tidal volume (≤ 6 ml/kg) and inspiratory plateau pressure. Adverse events occurred in 6 patients (11.9%). The hospital mortality rate was 49%.

Conclusions

The use of an indication algorithm for iLA in early ARDS, combined with a refined application technique was associated with efficient carbon dioxide removal and a reduced incidence of adverse events. iLA could serve as an extracorporeal assist to support mechanical ventilation by enabling low tidal volume and a reduced inspiratory plateau pressure.
MIF homologues from a filarial nematode parasite synergize with IL-4 to induce alternative activation of host macrophages
Authors: Prieto-Lafuente Lidia , Gregory William F , Allen Judith E , Maizels Rick M
Published: January 2009

Macrophage migration inhibitory factor (MIF) is a highly conserved cytokine considered to exert wide-ranging, proinflammatory effects on the immune system. Recently, members of this gene family have been discovered in a number of invertebrate species, including parasitic helminths. However, chronic helminth infections are typically associated with a Th2-dominated, counter-inflammatory phenotype, in which alternatively activated macrophages (AAMs) are prominent. To resolve this apparent paradox, we have analyzed the activity of two helminth MIF homologues from the filarial nematode Brugia malayi, in comparison with the canonical MIF from the mouse. We report that murine MIF (mMIF) and Brugia MIF proteins induce broadly similar effects on bone marrow-derived mouse macrophages, eliciting a measured release of proinflammatory cytokines. In parallel, MIF was found to induce up-regulation of IL-4R on macrophages, which when treated in vitro with MIF in combination with IL-4, expressed markers of alternative activation [arginase, resistin-like molecule α (RELM-α) or found in inflammatory zone 1, Ym-1, murine macrophage mannose receptor] and differentiated into functional AAMs with in vitro-suppressive ability. Consistent with this finding, repeated in vivo administration of Brugia MIF induced expression of alternative macrophage activation markers. As mMIF did not induce RELM-α or Ym-1 in vivo, alternative activation may require components of the adaptive immune response to Brugia MIF, such as the production of IL-4. Hence, MIF may accentuate macrophage activation according to the polarity of the environment, thus promoting AAM differentiation in the presence of IL-4-inducing parasitic helminths.
Inductive and suppressive networks regulate TLR9-dependent gene expression in vivo
Authors: Klaschik Sven , Tross Debra , Klinman Dennis M
Published: January 2009

Bacterial DNA expressing unmethylated CpG motifs binds to TLR9, thereby stimulating a broadly protective, innate immune response. Although CpG-mediated signal transduction has been studied, the scope of TLR9-dependent gene expression is incompletely understood. To resolve these issues, mice were treated with immunostimulatory CpG oligonucleotides (ODN) and splenic mRNA levels monitored from 30 min through 3 days by microarray. Through the unique application of bioinformatic analysis to these experimental data, this study is the first to describe the complex regulatory networks responsible for TLR9-mediated gene expression. Current results are the first to establish that CpG-induced stimulation of the innate immune system proceeds in multiple waves over time, and gene up-regulation is mediated by a small number of temporally activated “major inducers” and “minor inducers”. An additional study of TNF knockout mice supports the conclusion that the regulatory networks identified by our bioinformatic analysis accurately identified CpG ODN-driven gene–gene interactions in vivo. Equally important, this work identifies the counter-regulatory mechanisms embedded within the signaling cascade that suppresses the proinflammatory response triggered in vivo by CpG DNA stimulation. Identifying these network interactions provides novel and global insights into the regulation of TLR9-mediated gene activation, improves our understanding of TLR-mediated host defense, and facilitates the development of interventions designed to optimize the nature and duration of the ensuing response.
Structural and metabolic changes in language areas linked to formal thought disorder
Authors: Horn Helge , Federspiel Andrea , Wirth Miranka , Müller Thomas J. , Wiest Roland , Wang Jiong-Jiong , Strik Werner
Published: January 2009

Background

The role of the language network in the pathophysiology of formal thought disorder has yet to be elucidated.

Aims

To investigate whether specific grey-matter deficits in schizophrenic formal thought disorder correlate with resting perfusion in the left-sided language network.

Method

We investigated 13 right-handed patients with schizophrenia and formal thought disorder of varying severity and 13 matched healthy controls, using voxel-based morphometry and magnetic resonance imaging perfusion measurement (arterial spin labelling).

Results

We found positive correlations between perfusion and the severity of formal thought disorder in the left frontal and left temporoparietal language areas. We also observed bilateral deficits in grey-matter volume, positively correlated with the severity of thought disorder in temporoparietal areas and other brain regions. The results of the voxel-based morphometry and the arterial spin labelling measurements overlapped in the left posterior superior temporal gyrus and left angular gyrus.

Conclusions

Specific grey-matter deficits may be a risk factor for state-related dysfunctions of the left-sided language system, leading to local hyperperfusion and formal thought disorder.
Efficacy, safety and tolerability of two risperidone dosing regimens in adolescent schizophrenia: double-blind study
Authors: Haas Magali , Eerdekens Mariëlle , Kushner Stuart , Singer Julia , Augustyns Ilse , Quiroz Jorge , Pandina Gahan , Kusumakar Vivek
Published: January 2009

Background

Effective treatments for adolescent schizophrenia are needed.

Aims

To compare efficacy and safety of two dosing regimens of risperidone.

Method

Double-blind, 8-week study. Patients, 13–17 years, with an acute episode of schizophrenia, randomised 1:1 to risperidone 1.5–6.0 mg/day (regimen A;n=125) or 0.15–0.6 mg/day (regimen B;n=132). Trial registration number: NCT00034749.

Results

Mean total Positive and Negative Syndrome Scale (PANSS) score improved significantly (P<0.001; effect size=0.49) from baseline to end-point for regimen A (mean=96.4 (s.d.=15.39) to mean=72.8 (s.d.=22.52)) compared with regimen B (mean=93.3 (s.d.=14.14) to mean=80.8 (s.d.=24.33)). Treatment-emergent adverse events occurred in 74% (regimen A) and 65% (regimen B) of patients; 4% of patients overall discontinued for adverse events. Mean change in body weight was 3.2 kg (s.d.=3.49) for regimen A and 1.7 kg (s.d.=3.29) for regimen B.

Conclusions

Adolescent patients in the regimen A group showed greater improvement in total PANSS compared with the regimen B group. Treatment was well tolerated.
Attitudes towards clinical services among people who self-harm: systematic review
Authors: Taylor Tatiana L. , Hawton Keith , Fortune Sarah , Kapur Navneet
Published: January 2009

Background

Self-harm is increasingly common in many countries, is often repeated and may have other negative outcomes.

Aims

To systematically review people's attitudes towards clinical services following self-harm in order to inform service design and improvement.

Method

A search of electronic databases was conducted and experts in the field were contacted in order to identify relevant worldwide qualitative or quantitative studies. Data were extracted independently by two reviewers with more weight given to studies of greater quality and relevance.

Results

Thirty-one studies met the inclusion criteria. Despite variations in healthcare systems and setting, participants' experiences were remarkably similar. Poor communication between patients and staff and a perceived lack of staff knowledge with regard to self-harm were common themes. Many participants suggested that psychosocial assessments and access to after-care needed to be improved.

Conclusions

Specific aspects of care that might increase service user satisfaction and treatment adherence include staff knowledge, communication and better after-care arrangements. A standard protocol could aid regular audits of users' experiences of services.
Psychological processes in bipolar affective disorder: negative cognitive style and reward processing
Authors: Van der Gucht Emma , Morriss Richard , Lancaster Gill , Kinderman Peter , Bentall Richard P.
Published: January 2009

Background

Psychological processes in bipolar disorder are of both clinical and theoretical importance.

Aims

To examine depressogenic psychological processes and reward responsivity in relation to different mood episodes (mania, depression, remission) and bipolar symptomatology.

Method

One hundred and seven individuals with bipolar disorder (34 in a manic/hypomanic or mixed affective state; 30 in a depressed state and 43 who were euthymic) and 41 healthy controls were interviewed with Structured Clinical Interview for DSM–IV and completed a battery of self-rated and experimental measures assessing negative cognitive styles, coping response to negative affect, self-esteem stability and reward responsiveness.

Results

Individuals in all episodes differed from controls on most depression-related and reward responsivity measures. However, correlational analyses revealed clear relationships between negative cognitive styles and depressive symptoms, and reward responsivity and manic symptoms.

Conclusions

Separate psychological processes are implicated in depression and mania, but cognitive vulnerability to depression is evident even in patients who are euthymic.
Age-related grey matter volume correlates of response inhibition and shifting in attention-deficit hyperactivity disorder
Authors: McAlonan Grainne M. , Cheung Vinci , Chua Siew E. , Oosterlaan Jaap , Hung Se-fong , Tang Chun-pan , Lee Chi-chiu , Kwong Shi-leung , Ho Ting-pong , Cheung Charlton , Suckling John , Leung Patrick W. L.
Published: January 2009

Background

Children with attention-deficit hyperactivity disorder (ADHD) have difficulties with executive function and impulse control which may improve with age.

Aims

To map the brain correlates of executive function in ADHD and determine age-related changes in reaction times and brain volumes.

Method

Attention-deficit hyperactivity disorder and control groups were compared on the change task measures of response inhibition (stop signal reaction time, SSRT) and shifting (change response reaction time, CRRT). Voxel-wise magnetic resonance imaging (MRI) correlations of reaction times and grey matter volume were determined, along with bivariate correlations of reaction times, brain volumes and age.

Results

Individuals in the ADHD group had longer SSRTs and CRRTs. Anterior cingulate, striatal and medial temporal volumes highly correlated with SSRT. Striatal and cerebellar volumes strongly correlated with CRRT. Older children had faster reaction times and larger regional brain volumes. In controls, orbitofrontal, medial temporal and cerebellar volumes correlated with CRRT but not SSRT. Neither reaction times nor regional brain volumes were strongly age-dependent.

Conclusions

Our evidence supports delayed brain maturation in ADHD and implies that some features of ADHD improve with age.
Reasons for discontinuing clozapine: matched, case–control comparison with risperidone long-acting injection
Authors: Taylor David M. , Douglas-Hall Petrina , Olofinjana Banke , Whiskey Eromona , Thomas Arwel
Published: January 2009

Background

Clozapine has a range of serious adverse effects that may give rise to an increased risk of death.

Aims

To compare reasons for discontinuation of clozapine with reasons for discontinuation of risperidone long-acting injection in age-matched individuals treated in the same clinical environment.

Method

Comparison of patients receiving clozapine and an age-matched control group receiving risperidone injection.

Results

We established outcome for 529 consecutive patients receiving clozapine and 250 receiving risperidone (161 discontinuers from each group were compared). Adverse effects (odds ratio OR=2.19, 95% CI 1.31–3.67) and death (OR=7.0, 95% CI 2.09–23.5) were more commonly observed as reasons for discontinuation of clozapine than of risperidone. Clozapine was less likely to be withdrawn because of ineffectiveness than was risperidone (OR=0.034, 95% CI 0.01–0.14). Standardised mortality ratio (SMR) was significantly raised for patients receiving clozapine (SMR=4.17, 95% CI 2.78–6.26). Pneumonia was the most common single cause of death.

Conclusions

Clozapine use in patients with severe mental illness was associated with a significantly increased risk of death compared with that for the general population. Causation could not be established. Adverse effects and death are common causes of clozapine discontinuation.
A salience dysregulation syndrome
Authors: van Os Jim
Published: January 2009

Revisions of DSM and ICD are forthcoming. Should the old categories of psychotic disorder, in particular the construct of schizophrenia, be retained or is a new system of representation of psychosis in order? It is argued that both scientific and societal developments point to a system of classification combining categorical and dimensional representations of psychosis in DSM and ICD. Furthermore, it is proposed to introduce, analogous to the functional descriptive term ‘metabolic syndrome’, the diagnosis of salience dysregulation syndrome. Within this syndrome, three sub-categories may be identified, based on scientific evidence of relatively valid and specific contrasts: with affective expression; with developmental expression; and not otherwise specified.
Mentoring scheme for child and adolescent psychiatry consultants in Scotland
Authors: van Beinum Michael , Davies Sandra , David Myra
Published: January 2009

Aims and Method

To describe the mentoring scheme for consultant child psychiatrists in Scotland and discuss findings of a qualitative questionnaire survey of all eligible consultants' use and satisfaction with the scheme.

Results

All 21 respondents who had used the mentoring scheme thought it had been of great help. A third of respondents appointed since the start of the scheme had not used it. This could be because the consultants were not aware of the scheme, there were not enough mentors or mentoring was not included in consultants' job plans.

Clinical Implications

Formal mentoring is strongly recommended for all newly appointed consultants. Written recognition within job plans for both mentoring and being mentored would support mentoring arrangements.
Roofless in a steel city: learning from the homeless mentally ill
Authors: Spence Sean A.
Published: January 2009

A small, city-wide clinical outreach service for the homeless mentally ill in Sheffield, UK, attained its present configuration 6 years ago. This paper discusses the lessons learnt in the course of the service's existence.

The homeless mentally ill identified by the service have disengaged from the ‘mainstream’ services and society. Most are from disturbed homes, nearly all have had prior contact with psychiatric services and as many as half have served prison terms. As service users, they must be actively sought out and engaged, which places specific demands upon a mental health team: flexibility of approach, patience and a willingness not to judge others' values.

Though largely anecdotal, the inferences drawn in Sheffield may have parallels elsewhere, not least since individual lives can turn upon pivotal (‘anecdotal’) encounters and those evinced by the homeless tell us much about society, psychiatry and the values of contemporary healthcare providers. Also, most of the time, the proposed model has been successful.
Supporting children of forensic in-patients: whose role is it?
Authors: Chao Oriana , Kuti Gori
Published: January 2009

Aims and Method

To investigate whether children are in contact with their forensic in-patient parents and whether they are offered support regarding their parent's mental health and offending issues. A questionnaire was completed on in-patients in two medium secure units.

Results

Only 69 of the in-patients surveyed had children aged 18 or under, but only 25 had contact with their children. Support was offered in 14 cases and accepted in 10. Many patients had lost contact with their children.

Clinical Implications

Children of forensic in-patients appear to be a neglected group, with limited attempts made to support them. In the absence of specific difficulties of their own, the onus may be on forensic mental health services to initiate contact.
Are specialised affective disorder services useful?
Authors: Shepherd Debra J. , Insole Lisa M. , McAllister-Williams R. Hamish , Ferrier I. Nicol
Published: January 2009

Across the UK there are a number of tertiary level affective disorder services, usually based in academic centres, that provide support for the management of patients with complex and treatment-resistant conditions. Such services play a potentially important role in instilling hope into patients, carers and healthcare teams in situations where therapeutic nihilism has often developed. They also provide a valuable reservoir of expertise on the use of medications outside of licensed usage, and new and emerging treatments. To date there is relatively little data regarding patient outcomes after referral to such services; however, what there is does suggest important benefits for both patients and healthcare economies. As ever, more research is needed.
Mental Health (Care and Treatment) (Scotland) Act 2003: impact on child and adolescent in-patient services
Authors: Latimer Kate
Published: January 2009

This article examines the recommendations in the Mental Health (Care and Treatment) (Scotland) Act 2003 that are related to child and adolescent psychiatric services. Statistics relating to the first 6 months of the Act are included to indicate how it is being implemented and enable conclusions to be reached on how the Act is working in practice at this early stage.
Coingestion of Acylglycerols Differentially Affects Glucose-Induced Insulin Secretion via Glucose-Dependent Insulinotropic Polypeptide in C57BL/6J Mice
Authors: Shimotoyodome Akira , Fukuoka Daisuke , Suzuki Junko , Fujii Yoshie , Mizuno Tomohito , Meguro Shinichi , Tokimitsu Ichiro , Hase Tadashi
Published: January 2009

The precise role of fat in postprandial glycemia and insulinemia has not been thoroughly researched because postprandial blood glucose and concurrent insulin secretion are largely assumed to be proportional to carbohydrate intake. Recent studies have suggested that dietary fat differentially regulates the postprandial insulin response. To explore this, we examined the effects of coadministered fat on glucose-induced glycemia and insulinemia in C57BL/6J mice. The insulin response to glucose was augmented by the addition of glycerol trioleate (TO) in a dose-dependent manner, which was associated with enhanced glucose transport from the circulation to muscle and adipose tissues. To investigate the mechanism underlying fat-induced hyperinsulinemia, we examined the release of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1. TO increased GIP secretion, whereas glucagon-like peptide-1 secretion was unaffected. TO-induced hyperinsulinemia was significantly attenuated by the pretreatment of mice with a specific GIP antagonist. Diacylglycerol (DAG) promoted lower postprandial GIP and triglyceride responses and, when ingested with glucose, a lower insulin response compared with triacylglycerol of a similar fatty acid composition. Pluronic L-81, an inhibitor of chylomicron formation, reduced not only the triglyceride response but also TO-induced GIP secretion, indicating that the lower GIP response after DAG ingestion may be associated with retarded chylomicron formation in the small intestine. We conclude that dietary fat augments glucose-induced insulinemia via gut-derived GIP and, thereby, influences postprandial nutrient metabolism in mice. DAG promotes a lower GIP and thereby reduced insulin responses compared with triacylglycerol, which may differentially influence postprandial energy homeostasis.
Brain-Derived Neurotrophic Factor/Tropomyosin-Related Kinase Receptor Type B Signaling Is a Downstream Effector of the Brainstem Melanocortin System in Food Intake Control
Authors: Bariohay Bruno , Roux Julien , Tardivel Catherine , Trouslard Jérôme , Jean Andre , Lebrun Bruno
Published: January 2009

It has been shown that the neurotropin brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin-related kinase receptor type B (TrkB), contribute to the central control of food intake. BDNF has previously been implicated as a probable downstream effector of melanocortinergic signaling within the ventromedial hypothalamus, and we have shown its implication as an anorexigenic factor within the brainstem autonomic integrator of food intake control, namely the dorsal vagal complex (DVC). In the brainstem, the melanocortinergic signaling pathway is known to integrate phasic responses to satiety signals, such as cholecystokinin. In this study, we explored the interactions between melanocortin and BDNF/TrkB signaling within the DVC. First, we tested the effect of a local pharmacological activation or inhibition of melanocortin receptors type 3/4 (MC3/4R) on BDNF protein content in the DVC of adult rats. We showed that fourth intracerebroventricular delivery of MC3/4R agonist and antagonist increased and decreased the BDNF protein content within the DVC, respectively. Second, we showed that the orexigenic effect of a selective MC4R antagonist delivered fourth-icv can be blocked by a coadministration of BDNF. We also tested the causal role of BDNF/TrkB signaling in the anorexigenic effect of melanocortinergic signaling by using a recently developed analog-sensitive kinase allele murine model (TrkBF616A mice) and showed that the pharmacological blockade of TrkB abolished the anorexigenic effect of a selective MC4R agonist and of cholecystokinin. Our results provide strong evidence for a role of BDNF as a downstream effector of melanocortinergic signaling pathway within the DVC.
Molecular Determinants of Oocyte Competence: Potential Functional Role for Maternal (Oocyte-Derived) Follistatin in Promoting Bovine Early Embryogenesis
Authors: Lee Kyung-Bon , Bettegowda Anilkumar , Wee Gabbine , Ireland James J. , Smith George W.
Published: January 2009

Previous studies established a positive relationship between oocyte competence and follistatin mRNA abundance. Herein, we used the bovine model to test the hypothesis that follistatin plays a functional role in regulation of early embryogenesis. Treatment of early embryos with follistatin during in vitro culture (before embryonic genome activation) resulted in a dose-dependent decrease in time to first cleavage, increased numbers of blastocysts, and increased blastocyst total and trophectoderm cell numbers. To determine the requirement of endogenous follistatin for early embryogenesis, follistatin ablation/replacement studies were performed. Microinjection of follistatin small interfering RNA into zygotes reduced follistatin mRNA and protein and was accompanied by a reduction in number of embryos developing to eight- to 16-cell and blastocyst stages and reduced blastocyst total and trophectoderm cell numbers. Effects of follistatin ablation were rescued by culture of follistatin small interfering RNA-injected embryos in the presence of exogenous follistatin. To investigate whether follistatin regulation of early embryogenesis is potentially mediated via inhibition of endogenous activin activity, the effects of treatment of embryos with exogenous activin, SB-431542 (inhibitor of activin, TGF-β, and nodal type I receptor signaling) and follistatin plus SB-431542 were investigated. Activin treatment mimicked positive effects of follistatin on time to first cleavage and blastocyst development, whereas negative effects of SB-431542 treatment were observed. Stimulatory effects of follistatin on embryogenesis were not blocked by SB-431542 treatment. Results support a functional role for oocyte-derived follistatin in bovine early embryogenesis and suggest that observed effects of follistatin are likely not mediated by classical inhibition of activin activity.
Defining the Roles of the Iodothyronine Deiodinases: Current Concepts and Challenges
Authors: St. Germain Donald L. , Galton Valerie Anne , Hernandez Arturo
Published: January 2009

As is typical of other hormone systems, the actions of the thyroid hormones (TH) differ from tissue to tissue depending upon a number of variables. In addition to varying expression levels of TH receptors and transporters, differing patterns of TH metabolism provide a critical mechanism whereby TH action can be individualized in cells depending on the needs of the organism. The iodothyronine deiodinases constitute a family of selenoenzymes that selectively remove iodide from thyroxine and its derivatives, thus activating or inactivating these hormones. Three deiodinases have been identified, and much has been learned regarding the differing structures, catalytic activities, and expression patterns of these proteins. Because of their differing properties, the deiodinases appear to serve varying functions that are important in regulating metabolic processes, TH action during development, and feedback control of the thyroid axis. This review will briefly assess these functional roles and others proposed for the deiodinases and examine some of the current challenges in expanding our knowledge of these important components of the thyroid homeostatic system.

This review assesses the functional roles of TH action and others proposed for the deiodinases and examines current challenges in expanding knowledge of these components of the thyroid homeostatic system.
Elevated Glucocorticoid Levels Are Responsible for Induction of Tyrosine Hydroxylase mRNA Expression, Phosphorylation, and Enzyme Activity in the Nucleus of the Solitary Tract during Morphine Withdrawal
Authors: Núñez Cristina , Földes Anna , Pérez-Flores Domingo , García-Borrón J. Carlos , Laorden M. Luisa , Kovács Krisztina J. , Milanés M. Victoria
Published: January 2009

Chronic opiate exposure induces neurochemical adaptations in the noradrenergic system. Enhanced responsiveness of the hypothalamo-pituitary-adrenal axis after morphine withdrawal has been associated with hyperactivity of ascending noradrenergic input from the nucleus of the solitary tract (NTS-A2) cell group to the hypothalamic paraventricular nucleus (PVN). This study addressed the role of morphine withdrawal-induced corticosterone (CORT) release in regulation of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis in adrenalectomized (ADX) rats supplemented with low CORT pellet (ADX plus CORT). Present results show that in sham-ADX rats, noradrenergic neurons in the NTS-A2 became activated during morphine withdrawal, as indicated by increased TH mRNA expression. However, this induction of TH expression is not detected in ADX plus CORT rats that are unable to mount CORT secretory response to morphine withdrawal. Total TH protein levels were elevated in the NTS-A2 from sham-operated rats during morphine dependence and withdrawal, whereas we did not find any alteration in ADX plus CORT animals. Furthermore, high levels of TH phosphorylated (activated) at Ser31 (but not at Ser40) were found in the A2 area from sham-morphine withdrawn rats. Consistent with these effects, we observed an increase in the enzyme activity of TH in the PVN. However, induction of morphine withdrawal to ADX plus CORT animals did not alter the phosphorylation (activation) of TH in NTS-A2 and decreased TH activity in the PVN. These results suggest the existence of a positive reverberating circle in which elevated glucocorticoids during morphine abstinence play a permissive role in morphine withdrawal-induced activation of noradrenergic pathway innervating the PVN.
Thyrotropin-Releasing Hormone and the Thyroid Hormone Feedback Mechanism
Authors: Chiamolera Maria Izabel , Wondisford Fredric E.
Published: January 2009

Thyroid hormone (TH) plays a critical role in development, growth, and cellular metabolism. TH production is controlled by a complex mechanism of positive and negative regulation. Hypothalamic TSH-releasing hormone (TRH) stimulates TSH secretion from the anterior pituitary. TSH then initiates TH synthesis and release from the thyroid gland. The synthesis of TRH and TSH subunit genes is inhibited at the transcriptional level by TH, which also inhibits posttranslational modification and release of TSH. Although opposing TRH and TH inputs regulate the hypothalamic-pituitary-thyroid axis, TH negative feedback at the pituitary was thought to be the primary regulator of serum TSH levels. However, study of transgenic animals showed an unexpected, dominant role for TRH in regulating the hypothalamic-pituitary-thyroid axis and an unanticipated involvement of the thyroid hormone receptor ligand-dependent activation function (AF-2) domain in TH negative regulation. These results are summarized in the review.

The thyrotropin-releasing hormone neuron is well-positioned to integrate information about the environment as well as circulating TH levels and ultimately affect metabolism in response to these physiological changes.
Gonadotropin-Releasing Hormone and Protein Kinase C Signaling to ERK: Spatiotemporal Regulation of ERK by Docking Domains and Dual-Specificity Phosphatases
Authors: Armstrong Stephen Paul , Caunt Christopher James , McArdle Craig Alexander
Published: January 2009

Activated ERK translocates to the nucleus to regulate transcription. Spatiotemporal aspects of this response dictate biological consequences and are influenced by dual-specificity phosphatases (DUSPs) that can scaffold and dephosphorylate ERK. In HeLa cells, GnRH causes transient and protein kinase C (PKC)-dependent ERK activation, but termination mechanisms are unknown. We now explore DUSP roles using short inhibitory RNA to knock down endogenous ERK, adenoviruses to express GnRH receptors and add-back ERK2-GFP, and automated microscopy to monitor ERK location and activation. GnRH caused rapid and transient increases in dual phosphorylated ERK2 (ppERK2) and nuclear to cytoplasmic ERK2-green fluorescent protein (GFP) ratio, whereas responses to a PKC-activating phorbol ester were more sustained. In cells expressing D319N ERK2-GFP (D319N mutation impairs docking-domain-dependent binding to DUSPs), GnRH caused more sustained increases in ppERK2 and nuclear to cytoplasmic ERK2-GFP ratio and also had more pronounced effects on Egr-1 luciferase (a transcriptional reporter for ERK activation). Cycloheximide caused more sustained effects of GnRH and phorbol ester on ppERK, suggesting termination by nuclear-inducible DUSPs. GnRH also increased expression of nuclear-inducible DUSP1 and -4, but their knockdown did not alter GnRH-mediated ERK signaling. Screening a short inhibitory RNA library targeting 16 DUSPs (nuclear-inducible DUSPs, cytoplasmic ERK MAPK phosphatases, c-Jun N-terminal kinase/p38 MAPK phosphatases, and atypical DUSPs) revealed GnRH effects to be influenced by DUSPs 5, 9, 10, 16, and 3 (i.e. by each DUSP class). Thus, GnRH-mediated ERK responses (like PKC-mediated ERK responses) are dependent on protein neosynthesis and docking-domain-dependent binding, but for GnRH activation (unlike PKC activation), this does not reflect dependence on nuclear-inducible DUSPs. Termination of these GnRH effects is apparently dependent upon a preexisting rapid turnover protein.
Exploring the mechanical basis for acceleration: pelvic limb locomotor function during accelerations in racing greyhounds (Canis familiaris)
Authors: Williams S. B. , Usherwood J. R. , Jespers K. , Channon A. J. , Wilson A. M.
Published: January 2009

Animals in their natural environments are confronted with a regular need to perform rapid accelerations (for example when escaping from predators or chasing prey). Such acceleration requires net positive mechanical work to be performed on the centre of mass by skeletal muscle. Here we determined how pelvic limb joints contribute to the mechanical work and power that are required for acceleration in galloping quadrupeds. In addition, we considered what, if any, biomechanical strategies exist to enable effective acceleration to be achieved. Simultaneous kinematic and kinetic data were collected for racing greyhounds undergoing a range of low to high accelerations. From these data, joint moments and joint powers were calculated for individual hindlimb joints. In addition, the mean effective mechanical advantage (EMA) of the limb and the `gear ratio' of each joint throughout stance were calculated. Greatest increases in joint work and power with acceleration appeared at the hip and hock joints, particularly in the lead limb. Largest increases in absolute positive joint work occurred at the hip, consistent with the hypothesis that quadrupeds power locomotion by torque about the hip. In addition, hindlimb EMA decreased substantially with increased acceleration – a potential strategy to increase stance time and thus ground impulses for a given peak force. This mechanism may also increase the mechanical advantage for applying the horizontal forces necessary for acceleration.
Increase in Presenilin 1 (PS1) levels in senescence-accelerated mice(SAMP8) may indirectly impair memory by affecting amyloid precursor protein(APP) processing
Authors: Kumar Vijaya B. , Franko Mark , Banks William A. , Kasinadhuni Pranav , Farr Susan A. , Vyas Kamlesh , Choudhuri Veena , Morley John E.
Published: January 2009

Senescence-accelerated mice (SAMP8) serve as a model for Alzheimer's disease (AD) as they exhibit early loss of memory and increased amyloid precursor protein (APP) expression. APP is a ubiquitous membrane protein that is physiologically processed by site-specific proteolysis firstly by α-or β-secretases, releasing a large fragment called APPS that contains most of the extracellular sequences of APP, a small extracellular stub, the transmembrane region and the cytoplasmic tail of APP (`AICD'-APP intracellular domain). These are subsequently cleaved by γ-secretase at multiple sites in the transmembrane region, releasing small peptides,Aβ1-40 and Aβ1-42, the major components of AD-associated amyloid fibrils. γ-secretase is a high-molecular-mass complex composed of presenilin-1 (PS1), nicastrin, APH-1 and Pen-2. As PS1 has been shown to play a critical role in facilitating γ-secretase activity,and mutations in this protein are associated with familial AD (FAD), we have cloned it from SAMP8 mouse hippocampus and compared its sequence with those of other species. Furthermore, changes in the expression of PS1 with age in the hippocampal tissue of SAMP8 were studied. The results showed that the SAMP8 PS1 cDNA sequence is identical to that of normal mice. However, its expression in the hippocampus of SAMP8 exhibited an increase, while CD-1 mice, a strain that does not exhibit premature memory loss, showed no change with age. An increased amount or mutation(s) in PS1, which alters the stoichiometric balance of the γ-secretase complex, may be the cause of aberrant or increased processing of APP, resulting in Aβ accumulation leading to loss of memory.
The specific binding sites of eyestalk- and pericardial organ-crustacean hyperglycaemic hormones (CHHs) in multiple tissues of the blue crab,Callinectes sapidus
Authors: Katayama Hidekazu , Chung J. Sook
Published: January 2009

Crustacean hyperglycaemic hormone from the pericardial organ (PO-CHH) is a CHH-related neuropeptide but its function and target tissues are not known in crustaceans. To investigate this issue, we employed radiolabelled ligand binding and cGMP assays, using eyestalk-CHH (ES-CHH) as a reference neuropeptide. The membranes were prepared from various tissues of Callinectes sapidus: hepatopancreas, hindgut, midgut, gills, heart,abdominal muscles and scaphognathites. Like ES-CHH, recombinant PO-CHH(rPO-CHH) specifically bound to the membranes of scaphognathites=abdominal muscles>midgut>gills> heart>hindgut and hepatopancreas (list order corresponds to the number of binding sites). The specific binding sites of 125I-ES-CHH in hepatopancreas and gills were saturable and displaceable. The abdominal muscle membrane binding sites were specific and saturable to both CHHs. These binding sites were displaced by homologous neuropeptides, but poorly displaced by the heterologous counterpart. As for the second messenger, the expected increment (3- to >20-fold) in the amount of cGMP produced by ES-CHH was noted in most tissues tested except midgut. Recombinant PO-CHH increased cGMP production 1.5- to 4-fold in scaphognathites, heart, midgut, hindgut and abdominal muscles. The results obtained from the binding study suggest that PO-CHH also has multiple target tissues of which abdominal muscles and scaphognathites are the primary ones. The differences in the primary amino acid sequences of PO-CHH and ES-CHH,particularly in the C-terminal region and in the amidation at C-terminus, may contribute to the truncated responses of hyperglycaemia, cGMP stimulation and binding affinity.
Priority rules govern the organization of traffic on foraging trails under crowding conditions in the leaf-cutting ant Atta colombica
Authors: Dussutour A. , Beshers S. , Deneubourg J. L. , Fourcassié V.
Published: January 2009

Foraging in leaf-cutting ants is generally organized along well-defined recruitment trails supporting a bi-directional flow of outbound and nestbound individuals. This study attempts to reveal the priority rules governing the organization of traffic on these trails. Ants were forced to move on a narrow trail, allowing the passage of only two individuals at a time. In this condition, a desynchronization of inbound and outbound traffic was observed,involving the formation of alternating clusters of inbound and outbound ants. Most clusters of inbound ants were headed by laden ants followed by unladen ants. This occurred because inbound unladen ants did not attempt to overtake the laden ants in front of them. As unladen ants move on average faster than laden ants, these ants were thus forced to decrease their speed. By contrast,this decrease was counterbalanced by the fact that, by staying in a cluster instead of moving in isolation, inbound unladen ants limit the number of head-on encounters with outbound ants. Our analysis shows that the delay induced by these head-on encounters would actually be twice as high as the delay induced by the forced decrease in speed incurred by ants staying in a cluster. The cluster organization also promotes information transfer about the level of food availability by increasing the number of contacts between outbound and inbound laden ants, which could possibly stimulate these former to cut and retrieve leaf fragments when reaching the end of the trail.