bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential Aluminum Exposure from Parenteral Nutrition in Patients with Acute Kidney Injury
Authors: Brown Rex O , Morgan Laurie M , Bhattacharya Syamal K , Johnson Patti L , Minard Gayle , Dickerson Roland N
Published: August 2008

Background:

Patients' exposure to and potential toxicity from aluminum in parenteral nutrition (PN) formulations is an important concern of healthcare providers.

Objective:

To determine the potential for aluminum toxicity caused by PN in hospitalized adults who have risk factors of both acute kidney injury and PN.

Methods:

Adults who required PN and had a serum creatinine (SCr) level at least 1.5 times greater than the admission SCr on the first day of PN were studied in a retrospective fashion. Protein was administered based on whether hemodialysis was being used (0 6-1 g/kg/day without hemodialysis; 1.2-1.5 g/kg/day with hemodialysis). Aluminum exposure was determined for each patient by multiplying the volume of each PN component by its concentration of aluminum Unpaired f-tests, Fisher's exact test, and analysis of variance were used for statistical analysis. Data are presented as mean ± SD.

Results:

Thirty-six patients (aged 50.4 ± 20.4 y; weight 90.2 ± 32.8 kg) were studied. Initial serum urea nitrogen and SCr were 47 ± 23 and 3.3 ± 1.4 mg/dL. respectively. Twelve patients received hemodialysis. The mean aluminum exposure was 3.8 ± 2 μg/kg/day in the 36 patients, Of these, 29 had safe calculated aluminum exposure (<5 μg/kg/day) and 7 had high calculated aluminum exposure (>5 μg/kg/day), Patients with safe aluminum exposure had significantly higher SCr levels than did those with high aluminum exposure (3.5 ± 1.5 vs 2.2 ± 0.7 mg/dL; p < 0.04). Patients with high aluminum exposure received significantly more aluminum from calcium gluconate compared with those who had safe aluminum exposure (357 ± 182 vs 250 ± 56 μg/day; p < 0.02). Limitations of the study include its retrospective design, which resulted in calculated versus direct measurement of aluminum.

Conclusions:

Using our calculations, we believe that most patients with acute kidney injury who require PN do not receive excessive exposure to aluminum from the PN formulation, despite having 2 risk factors (acute kidney injury, PN) for aluminum toxicity,
Duloxetine-Associated Tachycardia
Authors: Stevens Debra L
Published: August 2008

Objective:

To report a case of symptomatic tachycardia that was successfully treated with propranolol in a patient receiving duloxetine.

Case Summary:

A 26-year-old man presented with episodes of fatigue, tachycardia, diaphoresis, and chest pain approximately 2 months after the initiation of duloxetine 20 mg/day for dysthymic disorder. Cardiac workup including echocardiogram, exercise treadmill testing, and Holter monitoring was negative, except for tachycardia (heart rate 110-120 beats/min). Duloxetine was withheld, and the patient's heart rate returned to normal in less than a week. Duloxetine was restarted at the same dosage, and tachycardia returned within 2 days. Propranolol was added to the treatment regimen to lower the heart rate. Because of therapeutic failure of other antidepressants, duloxetine was continued because of its beneficial effects on mood.

Discussion:

One published case report describing tachycardia in association with duloxetine in 2 heart failure patients was found in a MEDLINE search (1966-July 2008). Increased blood pressure and heart rate have been reported in duloxetine trials. The proposed mechanism for duloxetine-induced tachycardia is its effects on norepinephrine, which impact the cardiovascular system. Use of the Naranjo probability scale indicated duloxetine as a probable cause of this patient's tachycardia.

Conclusions:

Clinicians should be aware of the possibility of clinically significant tachycardia in patients receiving duloxetine, even in low doses.
Assessing the Reporting and Scientific Quality of Meta-Analyses of Randomized Controlled Trials of Treatments for Anxiety Disorders
Authors: Bereza Basil G , Machado Márcio , Einarson Thomas R
Published: August 2008

Background:

Mela-analyses of randomized controlled trials (RCTs) constitute the highest level of evidence, but their usefulness depends on their quality.

Objective:

To assess tho reporting and scientific quality of meta-analyses of RCTs on treatments for anxiety disorders.

Methods:

Criteria for peer-reviewed, full-text retrieval included meta-analyses of RCTs of drugs versus active ingredient placebo, standard care, or psychotherapy. Sample populations were required to meet Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases and Related Health Problems diagnostic criteria for anxiety disorders. Two reviewers independently searched EMBASE, EBM Reviews. Ovid MEDLINE, Ovid HealthSTAR, and International Pharmaceutical Abstracts from inception to August 2007. Search terms Included meta-analysis, randomized controlled trials, anxiety, anxiolytic, anti-depressant/antidepressant, and pharmacotherapy, without language restrictions. References and reviews were searched manually. Quality was assessed independently by 2 raters, using the Quality of Reporting of Meta-anatyses (QUOROM) and the Overview Quality Assessment Questionnaire (OQAQ). The QUOROM was used to assess the reporting quality of the study, using an 18-item checklist, and the scientific quality was assessed with the OQAQ's 10-item checklist, Kendall's - measured Interrater reliability with statistical significance at p less than or equal to 0.01. Means and standard deviations described the overall quality. A time series analysis was performed.

Results:

A total of 136 titles and abstracts were reviewed; 48 were retrieved, including 6 from the manual search. Thirty-two were excluded (not pooled analyses, inappropriate condition/treatment, duplications), leaving 16 studies published between 1995 and 2007. Agreement was high: t = 0.801 (p < 0.01) for QUOROM and 0.834 (p < 0.01) for OQAQ. QUOROM quality scored 61% ± 19%. Overall, the results sections of the studies scored lowest, while the introduction and discussion sections scored highest. The overall scientific qualify was 58% ± 28%. Most studies appropriately linked results to priman/ objectives but did not report how bias was avoided or how study validity was assessed. Quality Increased nonsignificantly over time.

Conclusions:

Reporting/scientific quality was considered less than fair-to-good. Stakeholders should strive for higher scientific quality of meta-analyses.
Suppression of Mutant Huntingtin Aggregate Formation by Cdk5/p35 through the Effect on Microtubule Stability
Authors: Kaminosono Sayuko , Saito Taro , Oyama Fumitaka , Ohshima Toshio , Asada Akiko , Nagai Yoshitaka , Nukina Nobuyuki , Hisanaga Shin-ichi
Published: August 2008

Huntington's disease (HD) is a polyglutamine [poly(Q)] disease with an expanded poly(Q) stretch in the N terminus of the huntingtin protein (htt). A major pathological feature of HD neurons is inclusion bodies, detergent-insoluble aggregates composed of poly(Q)-expanded mutant htt (mhtt). Misfolding of mhtt is thought to confer a toxic property via formation of aggregates. Although toxic molecular species are still debated, it is important to clarify the aggregation mechanism to understand the pathogenesis of mhtt. We show Cdk5/p35 suppresses the formation of mhtt inclusion bodies in cell lines and primary neurons. Although we expressed the N-terminal exon 1 fragment of htt lacking phosphorylation sites for Cdk5 in COS-7 cells, the kinase activity of Cdk5 was required for the suppression. Furthermore, Cdk5/p35 suppressed inclusion formation of atrophin-1, another poly(Q) protein, raising the possibility that Cdk5/p35 generally suppresses inclusion formation of poly(Q) proteins. Microtubules (MTs) were a downstream component of Cdk5/p35 in the suppression of inclusion formation; Cdk5/p35 disrupted MTs, which were required for the formation of inclusions. Moreover, stabilization of MTs by Taxol induced inclusions even with overexpression of Cdk5/p35. The formation of inclusions was also regulated by manipulating the Cdk5/p35 activity in primary rat or mouse cortical neuron cultures. These results indicate that Cdk5-dependent regulation of MT organization is involved in the development of aggregate formation and subsequent pathogenesis of poly(Q) diseases. This Cdk5 inhibition of htt aggregates is a novel mechanism different from htt phosphorylation and interaction with Cdk5 reported previously (Luo et al., 2005; Anne et al., 2007).
Manipulating Robo ExpressionIn VivoPerturbs Commissural Axon Pathfinding in the Chick Spinal Cord
Authors: Reeber Stacey L. , Sakai Nozomi , Nakada Yuji , Dumas Judy , Dobrenis Kostantin , Johnson Jane E. , Kaprielian Zaven
Published: August 2008

In vertebrate embryos, most spinal commissural axons cross the ventral midline (VM) and project either alongside or significant distances away from the floor plate (FP). The upregulation of repulsive Robo1/2 receptors on postcrossing commissural axons, in mammals, presumably allows these axons to respond to the midline-associated repellents, Slit1–3, facilitating their expulsion from, and prohibiting their reentry into, the FP. Compelling data suggest that Robo3 represses Robo1/2 function on precrossing axons and that Robo1/2 inhibit attractive guidance receptors on postcrossing axons, thereby ensuring that decussated axons are selectively responsive to midline Slits. However, whether Robo1/2 expel decussated commissural axons from the VM and/or prevent their reentry into the FP has not been explicitly establishedin vivo. Furthermore, some commissural axons do not require Robo1/2 to elaborate appropriate contralateral projections in the mouse spinal cord. Here, we use unilateralin ovoelectroporation together withAtoh1andNeurog1enhancer elements to visualize, and assess the consequences of manipulating Robo expression on, dl1 and dl2 chick commissural axons. In response to misexpressing a cytoplasmic truncation of Robo1 and/or Robo2, which should block all Robo–ligand interactions, postcrossing commissural axons extend alongside, but do not project away from or reenter the FP. In contrast, misexpression of full-length Robo2 prevents many commissural axons from crossing the VM. Together, these findings support key and selectivein vivoroles for Robo receptors in presumably altering the responsiveness of decussated commissural axons and facilitating their expulsion from the VM within the chick spinal cord.
Kisspeptin–GPR54 Signaling Is Essential for Preovulatory Gonadotropin-Releasing Hormone Neuron Activation and the Luteinizing Hormone Surge
Authors: Clarkson Jenny , d'Anglemont de Tassigny Xavier , Moreno Adriana Santos , Colledge William H. , Herbison Allan E.
Published: August 2008

Kisspeptin and its receptor GPR54 have recently been identified as key signaling partners in the neural control of fertility in animal models and humans. The gonadotropin-releasing hormone (GnRH) neurons represent the final output neurons of the neural network controlling fertility and are suspected to be the primary locus of kisspeptin–GPR54 signaling. Using mouse models, the present study addressed whether kisspeptin and GPR54 have a key role in the activation of GnRH neurons to generate the luteinizing hormone (LH) surge responsible for ovulation. Dual-label immunocytochemistry experiments showed that 40–60% of kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) expressed estrogen receptor α and progesterone receptors. Using an ovariectomized, gonadal steroid-replacement regimen, which reliably generates an LH surge, ∼30% of RP3V kisspeptin neurons were found to express c-FOS in surging mice compared with 0% in nonsurging controls. A strong correlation was found between the percentage of c-FOS-positive kisspeptin neurons and the percentage of c-FOS-positive GnRH neurons. To evaluate whether kisspeptin and/or GPR54 were essential for GnRH neuron activation and the LH surge,Gpr54- andKiss1-null mice were examined. Whereas wild-type littermates all exhibited LH surges and c-FOS in ∼50% of their GnRH neurons, none of the mutant mice from either line showed an LH surge or any GnRH neurons with c-FOS. These observations provide the first evidence that kisspeptin–GPR54 signaling is essential for GnRH neuron activation that initiates ovulation. This broadens considerably the potential roles and therapeutic possibilities for kisspeptin and GPR54 in fertility regulation.
Genetic Dissection of the Role of Catechol-O-Methyltransferase in Cognition and Stress Reactivity in Mice
Authors: Papaleo Francesco , Crawley Jacqueline N. , Song Jian , Lipska Barbara K. , Pickel Jim , Weinberger Daniel R. , Chen Jingshan
Published: August 2008

TheCOMT(catechol-O-methyltransferase) gene has been linked to a spectrum of human phenotypes, including cognition, anxiety, pain sensitivity and psychosis. Doubts about its clinical impact exist, however, because of the complexity of humanCOMTpolymorphism and clinical variability. We generated transgenic mice overexpressing a humanCOMT-Valpolymorphism (Val-tg), and compared them with mice containing a nullCOMTmutation. Increased COMT enzyme activity inVal-tgmice resulted in disrupted attentional set-shifting abilities, and impaired working and recognition memory, but blunted stress responses and pain sensitivity. Conversely,COMTdisruption improved working memory, but increased stress responses and pain sensitivity. Amphetamine ameliorated recognition memory deficits inCOMT-Val-tgmice but disrupted it in wild types, illustratingCOMTmodulation of the inverted-U relationship between cognition and dopamine.COMT-Val-tgmice showed increased prefrontal cortex (PFC) calcium/calmodulin-dependent protein kinase II (CaMKII) levels, whereasCOMTdeficiency decreased PFC CaMKII but increased PFC CaMKKβ and CaMKIV levels, suggesting the involvement of PFC CaMK pathways inCOMT-regulated cognitive function and adaptive stress responses. Our data indicate a critical role for theCOMTgene in an apparent evolutionary trade-off between cognitive and affective functions.
Multiple Mechanisms for Integrating Proprioceptive Inputs That Converge on the Same Motor Pattern-Generating Network
Authors: Barrière Gregory , Simmers John , Combes Denis
Published: August 2008

Movement-derived sensory feedback adapts centrally generated motor programs to changing behavioral demands. Motor circuit output may also be shaped by distinct proprioceptive systems with different central actions, although little is known about the integrative processes by which such convergent sensorimotor regulation occurs. Here, we explore the combined actions of two previously identified proprioceptors on the gastric mill motor network in the lobster stomatogastric nervous system. Both mechanoreceptors [anterior gastric receptor (AGR) and posterior stomach receptor (PSR)] access the gastric circuit via the same pair of identified projection interneurons that either excite [commissural gastric (CG)] or inhibit [gastric inhibitor (GI)] different subsets of gastric network neurons. Mechanosensory information from the two receptors is integrated upstream to the gastric circuit at two levels: (1) postsynaptically, where both receptors excite the GI neuron while exerting opposing effects on the CG neuron, and (2) presynaptically, where PSR reduces AGR's excitation of the CG projection neuron. Concomitantly PSR selectively enhances AGR's activation of the GI neuron, possibly also via a presynaptic action. PSR's influences also far outlast its transient synaptic effects, indicating the additional involvement of modulatory processes. Consequently, PSR activation causes parallel input from AGR to be conveyed preferentially via the GI interneuron, resulting in a prolonged switch in the pattern of gastric circuit output. Therefore, via a combination of short- and long-lasting, presynaptic and postsynaptic actions, one proprioceptive system is able to promote its impact on a target motor network by biasing the access of a different sensory system to the same circuit.
High-Frequency Stimulation of the Anterior Subthalamic Nucleus Reduces Stereotyped Behaviors in Primates
Authors: Baup Nicolas , Grabli David , Karachi Carine , Mounayar Stéphanie , François Chantal , Yelnik Jérôme , Féger Jean , Tremblay Léon
Published: August 2008

Growing evidence shows that dysfunction of the limbic basal ganglia (BG) network is implicated in repetitive behaviors, such as obsessive compulsive disorder (OCD) and Tourette's syndrome (TS), in humans. Because deep brain stimulation (DBS) of the posterior subthalamic nucleus (STN), which modulates the sensorimotor BG network, is beneficial in movement disorders, stimulation of the anterior, limbic STN might improve intractable behavioral disorders. We therefore evaluated the effect of anterior STN stimulation on the repetitive behaviors induced in two monkeys after bicuculline-induced dysfunction of the limbic external globus pallidus. DBS in the anterior STN dramatically reduced the stereotypies, but had no effect on the performance of a simple food retrieval task. Stimulations outside the STN were less effective in reducing the stereotypies. Electrode trajectories, reconstructed postmortem, confirmed that the effective contacts were in the anterior STN. DBS in the limbic STN might therefore provide relief from the severe stereotyped behaviors observed in OCD and TS.
GABAergic Circuits Control Input–Spike Coupling in the Piriform Cortex
Authors: Luna Victor M. , Schoppa Nathan E.
Published: August 2008

Odor coding in mammals is widely believed to involve synchronized gamma frequency (30–70 Hz) oscillations in the first processing structure, the olfactory bulb. How such inputs are read in downstream cortical structures however is not known. Here we used patch-clamp recordings in rat piriform cortex slices to examine cellular mechanisms that shape how the cortex integrates inputs from bulb mitral cells. Electrical stimulation of mitral cell axons in the lateral olfactory tract (LOT) resulted in excitation of pyramidal cells (PCs), which was followed ∼10 ms later by inhibition that was highly reproducible between trials in its onset time. This inhibition was somatic in origin and appeared to be driven through a feedforward mechanism, wherein GABAergic interneurons were directly excited by mitral cell axons. The precise inhibition affected action potential firing in PCs in two distinct ways. First, by abruptly terminating PC excitation, it limited the PC response to each EPSP to exactly one, precisely timed action potential. In addition, inhibition limited the summation of EPSPs across time, such that PCs fired action potentials in strong preference for synchronized inputs arriving in a time window of <5 ms. Both mechanisms would help ensure that PCs respond faithfully and selectively to mitral cell inputs arriving as a synchronized gamma frequency pattern.
Glutamate Transporters Regulate Extrasynaptic NMDA Receptor Modulation of Kv2.1 Potassium Channels
Authors: Mulholland Patrick J. , Carpenter-Hyland Ezekiel P. , Hearing Matthew C. , Becker Howard C. , Woodward John J. , Chandler L. Judson
Published: August 2008

Delayed-rectifier Kv2.1 potassium channels regulate somatodendritic excitability during periods of repetitive, high-frequency activity. Recent evidence suggests that Kv2.1 channel modulation is linked to glutamatergic neurotransmission. Because NMDA-type glutamate receptors are critical regulators of synaptic plasticity, we investigated NMDA receptor modulation of Kv2.1 channels in rodent hippocampus and cortex. Bath application of NMDA potently unclustered and dephosphorylated Kv2.1 and produced a hyperpolarizing shift in voltage-dependent activation of voltage-sensitive potassium currents (IK). In contrast, driving synaptic activity in Mg2+-free media to hyperactivate synaptic NMDA receptors had no effect on Kv2.1 channels, and moderate pentylenetetrazole-induced seizure activity in adult mice did not dephosphorylate hippocampal Kv2.1 channels. Selective activation of extrasynaptic NMDA receptors unclustered and dephosphorylated Kv2.1 channels and produced a hyperpolarizing shift in neuronalIK. In addition, inhibition of glutamate uptake rapidly activated NMDA receptors and dephosphorylated Kv2.1 channels. These observations demonstrate that regulation of intrinsic neuronal activity by Kv2.1 is coupled to extrasynaptic but not synaptic NMDA receptors. These data support a novel mechanism for glutamate transporters in regulation of neuronal excitability and plasticity through extrasynaptic NMDA receptor modulation of Kv2.1 channels.
Recurrent Inhibitory Network among Striatal Cholinergic Interneurons
Authors: Sullivan Matthew A. , Chen Huanmian , Morikawa Hitoshi
Published: August 2008

The striatum plays a central role in sensorimotor learning and action selection. Tonically active cholinergic interneurons in the striatum give rise to dense axonal arborizations and significantly shape striatal output. However, it is not clear how the activity of these neurons is regulated within the striatal microcircuitry. In this study, using rat brain slices, we find that stimulation of intrastriatal cholinergic fibers evokes polysynaptic GABAAIPSCs in cholinergic interneurons. These polysynaptic GABAAIPSCs were abolished by general nicotinic acetylcholine receptor antagonists and also by a specific antagonist of nicotinic receptors containing β2 subunits. Dopamine receptor antagonists or dopamine depletion failed to block polysynaptic IPSCs, indicating that phasic dopamine release does not directly mediate the polysynaptic transmission. Dual recording from pairs of cholinergic interneurons revealed that activation of a single cholinergic interneuron is capable of eliciting polysynaptic GABAAIPSCs both in itself and in nearby cholinergic interneurons. Although polysynaptic transmission arising from a single cholinergic interneuron was depressed during repetitive 2 Hz firing, intrastriatal stimulation reliably evoked large polysynaptic IPSCs by recruiting many cholinergic fibers. We also show that polysynaptic GABAergic inhibition leads to a transient suppression of tonic cholinergic interneuron firing. We propose a novel microcircuit in the striatum, in which cholinergic interneurons are connected to one another through GABAergic interneurons. This may provide a mechanism to convert activation of cholinergic interneurons into widespread recurrent inhibition of these neurons via nicotinic excitation of striatal GABAergic neurons.
Necdin Regulates p53 Acetylation via Sirtuin1 to Modulate DNA Damage Response in Cortical Neurons
Authors: Hasegawa Koichi , Yoshikawa Kazuaki
Published: August 2008

Sirtuin1 (Sirt1), a mammalian homolog of yeast Sir2, deacetylates the tumor suppressor protein p53 and attenuates p53-mediated cell death. Necdin, a p53-interacting protein expressed predominantly in postmitotic neurons, is a melanoma antigen family protein that promotes neuronal differentiation and survival. In mammals, the necdin gene (Ndn) is maternally imprinted, and mutant mice carrying mutated paternalNdnshow abnormalities of neuronal development. Here we report that necdin regulates the acetylation status of p53 via Sirt1 to suppress p53-dependent apoptosis in postmitotic neurons. Double-immunostaining analysis demonstrated that necdin colocalizes with Sirt1 in postmitotic neurons of mouse embryonic forebrainin vivo. Coimmunoprecipitation andin vitrobinding analyses revealed that necdin interacts with both p53 and Sirt1 to potentiate Sirt1-mediated p53 deacetylation by facilitating their association. Primary cortical neurons prepared from paternalNdn-deficient mice have high p53 acetylation levels and are sensitive to the DNA-damaging compounds camptothecin and hydrogen peroxide. Moreover, DNA transfection per se increases p53 acetylation and apoptosis in paternalNdn-deficient neurons, whereas small interfering RNA-mediated p53 knockdown completely blocks these changes. However, Sirt1 knockdown increases both acetylated p53 level and apoptosis in wild-type neurons but fails to affect them in paternalNdn-deficient neurons. In organotypic forebrain slice cultures treated with hydrogen peroxide, p53 is accumulated and colocalized with necdin and Sirt1 in cortical neurons. These results suggest that necdin downregulates p53 acetylation levels by forming a stable complex with p53 and Sirt1 to protect neurons from DNA damage-induced apoptosis.
Undescended testes: a consensus on management
Authors: Ritzén E Martin
Published: August 2008

The mode of treatment best for undescended testes is controversial, and local traditions often override knowledge gained from randomized controlled studies. In order to reach a consensus within the Nordic countries on the current state-of-the-art of treatment, a group of specialists in testicular physiology, paediatric surgery/urology, endocrinology, andrology, pathology and anaesthesiology from all the Nordic countries met for 2 days. Before the meeting, reviews of the literature had been prepared by the participants. Judging from published meta-analyses, hormonal treatment has low efficacy. Although 15–20% of retained testes descend during hormonal treatment, one-fifth of these re-ascend later on. Also, treatment with human chorionic gonadotropin (hCG) may be harmful to future spermatogenesis through increased apoptosis of germ cells. Orchiopexy, on the contrary, results in about 95% anatomical success, with a low (about 1%) risk of complications. The optimal time for orchiopexy has also been debated. However, a recent randomized controlled study shows that surgery at 9 months of age is followed by a better post-operative growth of the testes than surgery at 3 years, which supports previous arguments for early surgery. The unanimous conclusion of the group was that surgery is generally the preferred mode of treatment, rather than hCG or GnRH treatments. Orchiopexy should be performed between 6 and 12 months of age, or soon after diagnosis, if that occurs later. If a testis is found to be undescended at any age after 6 months, the patient should be referred for surgery. Referral should be to paediatric rather than general surgeons/urologists if the boy is less than 1 year old, if he has bilateral or non-palpable testes, or if he has got relapse of cryptorchidism.
Polymorphisms in the adiponutrin gene are associated with increased insulin secretion and obesity
Authors: Johansson Lovisa E , Lindblad Ulf , Larsson Charlotte A , Råstam Lennart , Ridderstråle Martin
Published: August 2008

Objective

The insulin responsive adiponutrin or patatin-like phospholipase 3 (PNPLA3, previously ADPN) gene shows association with obesity and in vitro adipocyte lipolysis. This study aimed to replicate the association between PNPLA3 variants and obesity, and to investigate their effect on insulin resistance and β-cell function.

Methods

rs738409 (Met148Ile) and rs2072907 (C to G) were genotyped using TaqMan allelic discrimination assay in a Swedish population-based sample (n=1811). Oral glucose tolerance test (OGTT) with data from three time points (0, 30, and 120 min) were available from individuals under the age of 50 years (n=973).

Results

Both variant alleles were associated with decreased prevalence of obesity (P<0.05); odds ratio 0.75 (0.61–0.93) per carried Ile-allele for rs738409 and 0.80 (0.64–1.00) per carried G-allele for rs2072907. For obesity as a quantitative trait, there was no association in the whole population, but in obese subjects body mass index (BMI; P=0.023) and waist (P=0.0098) were higher in carriers of the Ile-allele. The Ile-carriers also displayed decreased insulin secretion in response to OGTT (30 min insulin; P=0.007, insulinogenic index; P=0.0051) with no significant differences in fasting plasma glucose (P=0.31), β-cell function (disposition index; P=0.17) or homeostasis model of assessment insulin resistance (HOMA-IR; P=0.063). The correlation between BMI and HOMA-IR differed (Met/X versus Ile/Ile, P=0.028), Met-allele carriers were seemingly more insulin resistant at a lower BMI. The rs2072907 variant shows similar results for insulin secretion. The significance of this finding remained after adjusting for age, gender, and level of self-reported leisure-time physical activity.

Conclusion

We confirm the association between PNPLA3 and obesity. In addition, the rs738409 variant was associated with insulin secretion. There seems to be a differential effect of the Ile-allele depending on the degree of obesity, possibly as a consequence of insulin resistance.
Warfarin Pharmacogenetics
Authors: Limdi Nita A. , Veenstra David L.
Published: August 2008

Significant interest in the pharmacogenetics of warfarin therapy has been triggered with the recent package insert update that highlights the potential role of pharmacogenetics in improving the safety and effectiveness of warfarin. We review the evidence of the influence of the two key genes of interest, the cytochrome P450 2C9 gene, CYP2C9, and the vitamin K epoxide reductase complex 1 gene, VKORC1, on warfarin response and discuss the implications of current knowledge for clinical practice. The influence of CYP2C9 and VKORC1 genotypes on warfarin dose requirements has been consistently demonstrated in diverse racial and ethnic patient groups in observational studies and randomized clinical trials. Dosing algorithms have been developed that incorporate clinical, demographic, and genetic information to help select a warfarin starting dose. Furthermore, CYP2C9 variant genotypes have been associated with a significantly increased risk of serious bleeding events. However, evidence to date from prospective, controlled studies has not demonstrated an added benefit of incorporating genotype‐guided therapy in improving anticoagulation control or in preventing or reducing the risk of hemorrhagic or thromboembolic complications. Research efforts designed to evaluate the effectiveness of genotype‐guided therapy in improving outcomes are under way. However, the routine use of CYP2C9 and VKORC1 genotyping in the general patient population who begin warfarin therapy is not supported by evidence currently available.
Discrepancies in Identification of Major Bleeding Events in Patients Taking Warfarin
Authors: Seto Anna C. , Kenyon Kenneth , Wittkowsky Ann K.
Published: August 2008

Study Objective. To assess the level of agreement between one subjective definition of major bleeding (criteria A) and two objective definitions: the International Society on Thrombosis and Haemostasis ([ISTH] criteria B) and the Italian Study of Complications of Anticoagulant Therapy ([ISCOAT] criteria C).

Design. Retrospective cohort study.

Setting. Four anticoagulation clinics at a university‐affiliated medical center.

Patients. One hundred twenty patients aged 21–96 years who were taking long‐term warfarin therapy and experienced a nonminor bleeding event between July 1, 2001, and June 30, 2006.

Measurements and Main Results. Bleeding events were evaluated using three definitions of major bleeding: criteria A—event was fatal or required hospitalization; criteria B—event was fatal, was symptomatic in a critical area or organ, caused a decrease in hemoglobin level of 2 g/dl or more, and/or led to transfusion of 2 or more units of whole blood or red blood cells; and criteria C—event met criteria B definition (but less inclusively identifies critical areas or organs) and/or necessitated surgical or angiographic intervention. One hundred thirty‐eight bleeding events in the 120 patients met at least one of the definitions of major bleeding and thus were included in the analysis. Level of agreement among the definitions was determined by the κ statistic. The level of agreement between criteria B and C was excellent; no discrepancies were found; however, the level of agreement between criteria A and criteria B or C was poor, with a κ statistic value of −0.134 (95% confidence interval −0.196 to −0.071). Use of criteria A resulted in underreporting of 31 major bleeding events by excluding events that were managed on an outpatient basis.

Conclusion. The discrepant event rates determined by using three different definitions of major bleeding underscore the need for implementation of a standardized objective definition. Use of a standardized definition in clinical trials to accurately predict and compare patient outcomes and in clinical practice as a marker for patient safety will increase quality of care and decrease total costs of care in patients treated with warfarin. We suggest implementation of the ISTH criteria in clinical practice as a method to standardize the reporting of major bleeding events.
Continuous versus Intermittent Infusion of Prophylactic Cefoxitin After Colorectal Surgery: A Pilot Study
Authors: Suffoletta Terri J. , Jennings Heath R. , Oh Jennifer J. , Stephens Dana , Poe Kevin L.
Published: August 2008

Study Objective. To compare 30‐day postoperative surgical site infections (SSIs) and rates of antibiotic discontinuation within 24 hours after surgery in patients receiving continuous‐infusion versus intermittent‐infusion cefoxitin for postoperative antibiotic prophylaxis.

Design. Retrospective, cohort‐matched pilot study.

Setting. Tertiary‐care medical center.

Patients. One hundred sixteen adults undergoing colorectal surgery between August 1, 2004, and February 28, 2007.

Intervention. Cefoxitin prophylaxis was administered as a continuous infusion in 58 patients and as an intermittent infusion in 58 patients (controls). The controls received weight‐based doses of cefoxitin (1 g if 80 kg or 2 g if > 80 kg) every 8 hours for three doses, starting 3 hours after surgery and completed within 24 hours. The continuous‐infusion group were given weight‐based doses of cefoxitin (3 g if 80 kg, 6 g if > 80 kg), started immediately after surgery and infused over 20 hours.

Measurements and Main Results. Patients and controls were matched according to colorectal procedure and risk index category. They were stratified by medium risk (50 patients) and low risk (66 patients) for the end point of 30‐day postoperative SSI. For the 25 medium‐risk patients who received the continuous infusion, a 50% relative reduction in the 30‐day postoperative SSI rate was observed with continuous versus intermittent infusion (4% vs 8%, p=0.55). For the 66 low‐risk patients, 30‐day postoperative SSI rates were equal (3%) with both intermittent and continuous infusions. Risk stratification was not performed for the proportion of patients who discontinued antibiotic prophylaxis within 24 hours after surgery. All patients receiving the continuous infusion met this end point compared with 47 (83.9%) of the 56 controls (p=0.0015) included in the analysis.

Conclusion. Compared with intermittent infusion, continuous infusion of cefoxitin for postoperative prophylaxis resulted in a nonsignificant reduction in 30‐day postoperative SSI rates in medium‐risk patients undergoing colorectal surgery. Continuous infusion also resulted in reliable discontinuation of postoperative prophylaxis within 24 hours.
Treatment Options for Patients with Hepatitis C: Role of Pharmacists in Optimizing Treatment Response and Managing Adverse Events
Authors: Smith Jason P.
Published: August 2008

Chronic hepatitis C is associated with substantial morbidity and mortality and poses a considerable socioeconomic burden. Improved treatment regimens, including the standard of care pegylated interferon alfa and ribavirin, have increased sustained virologic response rates; however, treatment has a long duration and is often associated with adverse events that may affect adherence. The goal of therapy is viral eradication and reduced disease‐related complications such as fibrosis, cirrhosis, and hepatocellular carcinoma. The clinical outcome of hepatitis C virus infection is altered with antiviral treatment, which can be influenced by host (e.g., weight, ethnicity, health) and viral (e.g., genotype, baseline viremia) factors. Overall, sustained virologic response was attained by 54–63% of patients in clinical trials treated with pegylated interferon alfa−2a or −2b and ribavirin. However, this benefit is not without risk. Interferon‐induced adverse events include flu‐like symptoms, bone marrow suppression, and emotional or cognitive effects, whereas hemolytic anemia accounts for most ribavirin dosage reductions. These adverse events may be ameliorated with dosage adjustments, symptom therapy, and judicious use of preventive strategies (e.g., antidepressants, hematopoietic growth factors). Appropriate management of adverse events can increase treatment adherence, thereby enhancing outcomes and improving quality of life. Pharmacists are in an ideal position to improve the treatment of patients with chronic hepatitis C by providing education about the disease and its treatments and associated adverse events and by emphasizing the importance of treatment adherence for successful outcomes.
Ibuprofen Lysine for the Prevention and Treatment of Patent Ductus Arteriosus
Authors: Pai Vinita B. , Sakadjian Arpi , Puthoff Teresa D.
Published: August 2008

Approximately 70–80% of newborns less than 28 weeks' gestational age require pharmacologic and/or surgical intervention to close a hemodynamically significant patent ductus arteriosus (PDA). Indomethacin has been the pharmacologic treatment of choice and has also been used prophylactically in very premature neonates to prevent PDA. The drug, however, is associated with renal and gastrointestinal adverse effects. In July 2006, intravenous ibuprofen lysine became available in the United States for treatment of hemodynamically significant PDA. The mechanism of action for both indomethacin and ibuprofen lysine is through inhibition of prostaglandin synthesis, resulting in ductal constriction. Both drugs appear to be equally efficacious in closing echocardiographically confirmed PDA. Ibuprofen lysine has demonstrated significantly less effects on cerebral, renal, and mesenteric blood flow in premature neonates when compared with indomethacin. A transient but significant increase in serum creatinine concentration, decrease in urine output, and increase in frequency of oliguria were observed with indomethacin when compared with ibuprofen lysine. However, the rate of reopening of the ductus after pharmacologic closure and the need for rescue therapy were not different between the two drugs. In addition, no differences were noted in other outcomes such as frequency of intraventricular hemorrhage, necrotizing enterocolitis, or chronic lung disease, as well as in duration of mechanical ventilation and length of hospital stay. When administered prophylactically, ibuprofen lysine did not prevent intraventricular hemorrhage nor provide any neurodevelopmental benefits. In addition, ibuprofen lysine has not been adequately studied in neonates of 27 weeks' gestational age or younger. Ibuprofen lysine is as efficacious as indomethacin in treating hemodynamically significant PDA in neonates greater than 27 weeks' gestational age.
The role of thyroid hormone in testicular development and function
Authors: Wagner Márcia Santos , Wajner Simone Magagnin , Maia Ana Luiza
Published: August 2008

Thyroid hormone is a critical regulator of growth, development, and metabolism in virtually all tissues, and altered thyroid status affects many organs and systems. Although for many years testis has been regarded as a thyroid hormone unresponsive organ, it is now evident that thyroid hormone plays an important role in testicular development and function. A considerable amount of data show that thyroid hormone influences steroidogenesis as well as spermatogenesis. The involvement of tri-iodothyronine (T3) in the control of Sertoli cell proliferation and functional maturation is widely accepted, as well as its role in postnatal Leydig cell differentiation and steroidogenesis. The presence of thyroid hormone receptors in testicular cells throughout development and in adulthood implies that T3 may act directly on these cells to bring about its effects. Several recent studies have employed different methodologies and techniques in an attempt to understand the mechanisms underlying thyroid hormone effects on testicular cells. The current review aims at presenting an updated picture of the recent advances made regarding the role of thyroid hormones in male gonadal function.
Briefing: A30 environment work wins global award
Authors: Hughes David
Published: August 2008

Award-winning work on the A30 Bodmin to Indian Queens improvement scheme, Cornwall, UK, has reduced the environmental impact of the road that forms the key arterial route for the county of Cornwall.
A best practice policy for recycling and reuse in building
Authors: Brewer G. , Mooney J.
Published: August 2008

Industrial ecologists, recognising the impact of industry on the environment, have developed reduction strategies including the reuse and recycling of materials. World wide, the reduction of natural resource consumption has been investigated and applied to various industries with varying degrees of success. This paper focuses on the construction industry, using thematic analysis to locate the world's best practice with respect to construction and demolition (C&D) waste legislation. It identifies the Netherlands and Denmark as current leaders in C&D waste management and reports on the results of a policy analysis, which concluded that landfill levies, landfill material bans, material segregation and certification are the main contributors to waste reduction. A meta-analysis of Australian state legislation reveals that these policies are largely absent, rendering current legislation ineffective. A model of legislative best practice is presented that is applicable to the Australian context and which incorporates the concept of designing for disassembly—a technique that already exists in other manufacturing industries. By implementing these policies, there is potential to decrease waste through reuse and recycling within the building industry.
Educating for urban sustainability: a transdisciplinary approach
Authors: Brewer G. , Gajendran T. , Landorf C. , Williams T.
Published: August 2008

An understanding of sustainability issues should be a key component of degree programmes. It is widely regarded as being a central attribute to professional practice and responsible global citizenship, arguably more so for the training of teachers since they potentially influence their students. This issue was brought to the fore when responsibility for delivering the ‘design and the environment’ course was transferred to the building discipline at the University of Newcastle in Australia as a result of restructuring. The attractiveness of the subject as an elective, the need to make it accessible to distance learning students and the desirability of applying transdisciplinary approaches to solving environmental problems presented the course designers with both challenges and opportunities, particularly in devising an assessment context within which students from multiple disciplines could be exposed to, and learn from each other's professional environmental evaluation norms. This paper describes an innovative holistic, multi-criteria problem-solving course design that allows a diverse mix of undergraduates to develop a transdisciplinary understanding of sustainability issues through the use of learning contracts. It reports the experiences of staff and students involved with the course, highlighting the beneficial outcomes.
Why biodiversity is important to the functioning of real‐world ecosystems
Authors: Duffy J Emmett
Published: August 2008

Controlled experiments have substantially advanced our understanding of the links between changing biodiversity and ecosystem functioning (BEF) in recent years. However, controversy continues regarding the relevance of BEF experiments to the complex ecosystems and large spatial and temporal scales of interest in conservation and management. Here, I address some of the persistent criticisms regarding experimental BEF research and argue that these have been overstated. Contrary to some suggestions, many putative artifacts attributed to experiments render their conclusions about BEF links stronger, rather than weaker. Like other broad ecological concepts, BEF focuses on general patterns, rather than looking at species‐level, applied conservation problems. Nevertheless, insights from BEF experiments conducted to date are likely to underestimate, rather than overestimate, the importance of biodiversity to ecosystem functioning and the provision of ecosystem services in the real world. These experiments suggest that managing ecosystems to promote biodiversity can have important practical benefits.
Ablation of AMP-Activated Protein Kinase α2 Activity Exacerbates Insulin Resistance Induced by High-Fat Feeding of Mice
Authors: Fujii Nobuharu , Ho Richard C. , Manabe Yasuko , Jessen Niels , Toyoda Taro , Holland William L. , Summers Scott A. , Hirshman Michael F. , Goodyear Laurie J.
Published: August 2008

OBJECTIVE—We determined whether muscle AMP-activated protein kinase (AMPK) has a role in the development of insulin resistance.

RESEARCH DESIGN AND METHODS—Muscle-specific transgenic mice expressing an inactive form of the AMPK α2 catalytic subunit (α2i TG) and their wild-type littermates were fed either a high-fat (60% kcal fat) or a control (10% kcal fat) diet for 30 weeks.

RESULTS—Compared with wild-type mice, glucose tolerance in α2i TG mice was slightly impaired on the control diet and significantly impaired on the high-fat diet. To determine whether the whole-body glucose intolerance was associated with impaired insulin sensitivity in skeletal muscle, glucose transport in response to submaximal insulin (450 μU/ml) was measured in isolated soleus muscles. On the control diet, insulin-stimulated glucose transport was reduced by ∼50% in α2i TG mice compared with wild-type mice. High-fat feeding partially decreased insulin-stimulated glucose transport in wild-type mice, while high-fat feeding resulted in a full blunting of insulin-stimulated glucose transport in the α2i TG mice. High-fat feeding in α2i TG mice was accompanied by decreased expression of insulin signaling proteins in gastrocnemius muscle.

CONCLUSIONS—The lack of skeletal muscle AMPK α2 activity exacerbates the development of glucose intolerance and insulin resistance caused by high-fat feeding and supports the thesis that AMPK α2 is an important target for the prevention/amelioration of skeletal muscle insulin resistance through lifestyle (exercise) and pharmacologic (e.g., metformin) treatments.
Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats
Authors: Shibata Taiga , Naruse Keiko , Kamiya Hideki , Kozakae Mika , Kondo Masaki , Yasuda Yutaka , Nakamura Nobuhisa , Ota Kimiko , Tosaki Takahiro , Matsuki Takashi , Nakashima Eitaro , Hamada Yoji , Oiso Yutaka , Nakamura Jiro
Published: August 2008

OBJECTIVE—Mesenchymal stem cells (MSCs) have been reported to secrete various cytokines that exhibit angiogenic and neurosupportive effects. This study was conducted to investigate the effects of MSC transplantation on diabetic polyneuropathy (DPN) in rats.

RESEARCH DESIGN AND METHODS—MSCs were isolated from bone marrow of adult rats and transplanted into hind limb skeletal muscles of rats with an 8-week duration of streptozotocin (STZ)-induced diabetes or age-matched normal rats by unilateral intramuscular injection. Four weeks after transplantation, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) productions in transplanted sites, current perception threshold, nerve conduction velocity (NCV), sciatic nerve blood flow (SNBF), capillary number–to–muscle fiber ratio in soleus muscles, and sural nerve morphometry were evaluated.

RESULTS—VEGF and bFGF mRNA expression were significantly increased in MSC-injected thigh muscles of STZ-induced diabetic rats. Furthermore, colocalization of MSCs with VEGF and bFGF in the transplanted sites was confirmed. STZ-induced diabetic rats showed hypoalgesia, delayed NCV, decreased SNBF, and decreased capillary number–to–muscle fiber ratio in soleus muscles, which were all ameliorated by MSC transplantation. Sural nerve morphometry showed decreased axonal circularity in STZ-induced diabetic rats, which was normalized by MSC transplantation.

CONCLUSIONS—These results suggest that MSC transplantation could have therapeutic effects on DPN through paracrine actions of growth factors secreted by MSCs.