bluuebunny/crossref_metadata_2025 huggingface dataset:
ADHD Symptom Rebound and Emotional Lability With Lisdexamfetamine Dimesylate in Children Aged 6 to 12 Years
Authors: López Frank A. , Childress Ann , Adeyi Ben , Dirks Bryan , Babcock Thomas , Scheckner Brian , Lasser Robert A. , Shepski John , Arnold Valerie
Published: February 2013

Objective: To describe symptom rebound in children with ADHD treated with lisdexamfetamine dimesylate (LDX) or placebo. Method: During a 4-week, randomized, double-blind, placebo-controlled trial of LDX, parents/caregivers completed the Conners’ Parent Rating Scale–Revised: Short Form symptom rating scale throughout the day. Response, rebound, and emotional lability (EL) were assessed post hoc based on predefined criteria. Results: Most participants given LDX ( n = 207) were responders throughout the day (50.7%-55.6%) versus placebo ( n = 72; 11.1%-22.2%). A total of seven (3.4%) LDX participants showed rebound in the afternoon and/or evening versus seven (9.7%) with placebo. In both groups, most incidences of rebound occurred in the evening. EL (mean) was higher in LDX rebounders and nonresponders (range = 4.2-9.0) versus LDX responders (range = 1.3-1.6) and versus placebo rebounders (range = 0.7-1.9). Conclusion: ADHD symptom rebound occurred in few participants (3.3%) given LDX (accompanied by clinically significant EL). Overall, more participants given LDX versus placebo responded throughout the day.
Discourse of the real kind: A post-foundational approach to organizational discourse analysis
Authors: Cederström Carl , Spicer André
Published: February 2013

In response to the postmodern invasion of organization studies, some critics have issued increasingly loud cries that we should ‘get real’ about organizational discourse analysis. But what precisely do these proponents take to be the ‘real’? In this article we trace out some of the attempts of ‘getting real’, arguing that these approaches have some important limitations. We then explore the relevance of a post-foundational approach to discourse, which, we argue, have far reaching implications for the study of organizational discourse. We argue that such approach offers us a way of theoretically linking the ‘real’ with (1) the way discourses are structured around fundamental gaps, (2) how discourses are brought together through nodal points and (3) how discourses generate affective and emotional attachment. We then offer some suggestions of how these points can be used to study organizational processes. We conclude by reflecting on some of the limitations of this approach to studying discourse.
At the ‘heart’ of the matter: An exploration of the psychological impact of living with congenital heart disease in adulthood
Authors: Cornett Loraine , Simms Jane
Published: February 2013

The psychological impact of living with congenital heart disease in adulthood was explored using semi-structured interviews with seven adults. Participants described living with congenital heart disease as a constant and limiting presence, which impacts upon the relationship with self and others. Psychological and emotional reactions ranged from depression, shame, trauma, lack of control and an ongoing struggle with issues of uncertainty and life expectancy. Various coping strategies were identified such as denial and overcompensation. Participants reported that they were not psychologically supported by health professionals. Implications of findings are discussed with regard to service provision.
Psychological aspects and hospitalization for pain crises in youth with sickle-cell disease
Authors: Tsao Jennie CI , Jacob Eufemia , Seidman Laura C , Lewis Mary A , Zeltzer Lonnie K
Published: February 2013

Sickle-cell disease is a genetic disorder characterized by severe pain episodes or “vaso-occlusive crises” that may require hospitalization. This study examined the associations among emotion regulation, somatization, positive and negative affect, and hospitalizations for pain crises in youth with sickle-cell disease. Multivariate analyses indicated that emotional suppression and somatization were significantly associated with more frequent hospitalizations for pain crises in the previous year after controlling for sickle-cell disease type and pain. These results suggest that efforts to reduce emotional suppression and somatization may assist in decreasing the frequency of hospitalizations for pain crises among youth with sickle-cell disease.
What bothers the sick-listed employee with severe MUPS?
Authors: Hoedeman R , Blankenstein AH , Koopmans PC , Groothoff JW
Published: February 2013

Aims: The aim of this study was to explore what employees with severe medically unexplained physical symptoms (MUPS) experience as causes of distress with regard to employees with mild or no MUPS. Methods: This study is an additional analysis of a cross-sectional study in which 486 sick-listed employees, were assessed with Patient Health Questionnaire (PHQ)-15 for self-rated levels of MUPS. A cut-off score of 15 (≥15) was used to categorise employees with severe MUPS. Distress was qualitatively categorised with the answers on the open question in the PHQ-15 “if you experience distress at this moment, what are you distressed about?” Results: Sick-listed employees with severe MUPS were most distressed by their medical, mental, and financial problems. Employees with mild or no MUPS by their medical, work-related, and return to work-related problems. Employees with severe MUPS had more often distress by their mental and financial problems, compared to the employees with mild and no MUPS, who had more often no problems. Conclusions: There are differences in the causes of distress in sick-listed employees with severe MUPS compared to those with mild or no MUPS. Exploring these causes create possibilities for the physician to improve the quality of explanations and reassurance to the employee and to remove barriers for the return to work process.
Socioeconomic status and differences in medication use among older people according to ATC categories and urban–rural residency
Authors: Sigurdardottir Arun K , Arnadottir Solveig A , Gunnarsdottir Elin Dianna
Published: February 2013

Aims: To study how selected indicators of socioeconomic status and urban–rural residency associate with medication use in form of number of daily medications, polypharmacy, and medication use according to Anatomic Therapeutic Classification (ATC) system. Methods: Cross-sectional, population-based study among older community-dwelling Icelanders. Criteria for participation were: age ≥65 years, community-dwelling, and able to communicate verbally and to set up a time for a face-to-face interview. Information on medication use was obtained by interviews and by examining each person’s medication record. Medications were categorised according to ATC system. A questionnaire and the physical and mental health summary scales of SF-36 Health Survey were used to assess potential influential factors associated with medication use. Results: On average, participants ( n=186) used 3.9 medications, and the prevalence of polypharmacy was 41%. No indicators of socioeconomic status had significant association to any aspects of medication use. Compared to urban residents, rural residents had more diagnosed diseases, were less likely to live alone, were less likely to report having adequate income, and had fewer years of education. Controlling for these differences, urban people were more likely to use medication from the B and C categories. Moreover, older urban men, with worse physical health, and greater number of diagnosed diseases used more medications from the B category. Conclusions: There are unexplained regional differences in medications use, from categories B and C, by older Icelanders. Further studies are needed on why urban residents used equal number of medications, or even more medications, compared to rural residents, despite better socioeconomic status and fewer diagnosed diseases.
Building partnerships in social work education: Towards achieving collaborative advantage for employers and universities
Authors: Wilson George
Published: February 2013

Better partnership working between employers and academic institutions has recently been identified as one of the key developments needed to improve social work education and practice in the UK (Social Work Reform Board, 2010). However, the praxis of collaborative working in social work education remains under-researched and it is unclear what factors are significant in promoting effective partnership. This article contributes to this debate by reporting research that examined the experience of social work academics working with employers to deliver qualifying level social work education in Northern Ireland.

Findings

This analysis explores key factors in the dynamics of the collaborative process and identifies both congruence and discord in academic and employer perspectives. The findings highlight the collaborative advantage accruing from partnership working, which include the benefits of a centrally coordinated system for the management and delivery of practice learning. However, the results also indicate that engaging in partnership working is a complex process that can create conflict and tensions, and that it is important to ground collaborations in realistic expectations of what can be achieved.

Application

This article identifies opportunities for achieving collaborative advantage and the challenges. It identifies lessons learned about the value of partnership working in social work education and ways to increase its efficacy.
Experimental Exposure Therapy for Posttraumatic Nightmares
Authors: Cavera Robert S. , Jacobs Leah , Motta Robert W.
Published: February 2013

Nightmares are one of the most troubling features of posttraumatic stress disorder (PTSD), yet imagery rehearsal training (IRT) is currently the only empirically supported treatment for posttraumatic nightmares. Although IRT is effective, it is unknown whether IRT or the exposure, which is inherent in this procedure, causes the decrease in nightmares. This study will attempt to clarify this issue by using exposure therapy alone to treat a patient with PTSD. The participant is a 39-year-old male who experienced a single traumatic event. Data were collected on his sleep habits, as well as on the frequency and intensity of the nightmares. Results indicate that exposure-based nightmare treatment for PTSD sufferers should be considered in conjunction with standard treatment packages.
On profust reliability of coherent systems: signature-based expressions
Authors: Eryilmaz Serkan , Rouyendegh Babak Daneshvar
Published: February 2013

In this article we study profust reliability of non-repairable coherent systems through the concept of system signature. We obtain explicit expressions for the profust reliability and mean time to fuzzy failure of coherent systems. We compute and present mean time to failure and mean time to fuzzy failure of all coherent systems with three and four components. Finally, we illustrate the results for a well known class of coherent systems called m-consecutive- k-out-of- n:F.
School Health Councils
Authors: Holstein Paula
Published: February 2013

School nurses are diligent guardians of children’s health. Health promotion is becoming more and more difficult due to the increase in childhood obesity across the nation. Bold new strategies must be undertaken to reverse this alarming trend. School nurses in New Jersey teamed up with local health departments and the Medical Reserve Corps to implement a creative approach to this problem.
Microstructure and mechanical property of cold rolled low carbon steel after prolonged annealing treatment
Authors: Hasan S M , Haldar A , Chakrabarti D
Published: February 2013

The effects of ferrite–pearlite and ferrite–martensite starting microstructures on ferrite grain sizes and carbide particle sizes after cold rolling and prolonged annealing treatment have been investigated. Ferrite–martensite starting microstructures showed finer grain and particle sizes and improved tensile properties after cold rolling annealing cycle compared to ferrite–pearlite starting microstructures. A ‘fibrous’ martensite morphology developed by intermediate quenching treatment is more beneficial in that respect compared to the ‘blocky’ martensite morphology obtained from the step quenching treatment.
Microhardness characterisation in developing high strength, high toughness and superior ballistic resistance low carbon Ni steel
Authors: Zhang X J
Published: February 2013

To develop new steels that exceed the ballistic resistance, strength and toughness of current naval ship steel plates, we designed optimally quenching–lamellarising–tempering treated low carbon 10Ni steel plates. These plates displayed exceptional properties in all aspects; when compared to the widely used HSLA-100 steel plates, they showed superior toughness and an improvement of over 15 in strength and 20 mm fragment simulation projectile ballistic limit V50. A preliminary vibrating sample magnetometer study on the effect of quenching–lamellarising–tempering process and dynamic deformation on the microstructure evolution of the 10Ni steel during ballistic impact was valuable to our understanding of the steel. The data led us to conclude that dynamic deformation during ballistic perforation induced an austenite to martensite phase transformation, which improves the global dynamic plasticity and ballistic resistance of the steel target. This mechanism, similar to the transformation induced plasticity effect, can be appropriately named ballistic induced plasticity. Characteristics of the microhardness maps of the sectioned craters created by ballistics are consistent with ballistic induced plasticity.
VCAM-1 and VAP-1 recruit myeloid cells that promote pulmonary metastasis in mice
Authors: Ferjančič Špela , Gil-Bernabé Ana M. , Hill Sally A. , Allen Philip D. , Richardson Peter , Sparey Tim , Savory Edward , McGuffog Jane , Muschel Ruth J.
Published: February 2013

Key Points

Metastatic tumor cell attachment induces endothelial VCAM-1 and VAP-1. VCAM-1 and VAP-1 promote metastatic tumor cell survival by recruiting myeloid cells, pointing to VAP-1 as a therapeutic target.
Solvability and iterative algorithms for a system of generalized nonlinear mixed quasivariational inclusions with "Equation missing"-monotone operators
Authors: Liu Zeqing , Wang Lili , Ume Jeong Sheok , Kang Shin Min
Published: February 2013

In this paper, we introduce and discuss a new system of generalized nonlinear mixed quasivariational inclusions with(Hi,ηi)-monotone operators in Hilbert spaces, which includes several systems of variational inequalities and variational inclusions as special cases. By employing the resolvent operator technique associated with(Hi,ηi)-monotone operators, we suggest two iterative algorithms for computing the approximate solutions of the system of generalized nonlinear mixed quasivariational inclusions. Under certain conditions, we obtain the existence of solutions for the system of generalized nonlinear mixed quasivariational inclusions and prove the convergence of the iterative sequences generated by the iterative algorithms. The results presented in this paper extend, improve and unify many known results in recent literature.

MSC:47J20, 49J40.
Reversible tetraplegia after percutaneous nephrostolithotomy and septic shock: a case of critical illness polyneuropathy and myopathy with acute onset and complete recovery
Authors: Li Hai , Wu Li-Min , Kong Xiang-Bo , Hou Yi , Zhao Rui , Li Hong-Yan , Zhang Hong-Liang
Published: February 2013

Background

Critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) are complications causing weakness of respiratory and limb muscles in critically ill patients. As an important differential diagnosis of Guillain-Barré syndrome (GBS), CIP and CIM should be diagnosed with caution, after a complete clinical and laboratory examination. Although not uncommon in ICU, CIP and CIM as severe complications of percutaneous nephrostolithotomy (PNL) have not been documented in literature.

Case presentation

A 48-year-old Chinese woman was referred to our hospital, complaining of occasional pain in the right lower back for one month. Lithiasis was diagnosed by ultrasonographical and radiological examinations on the urinary system. PNL was indicated and performed. The patient developed CIP and CIM on the fourth day after PNL. Early recognition and treatment of the severe complications contributed to a satisfactory recovery of the patient.

Conclusion

This case expands our understanding of the complications of PNL and underscores the importance of differentiating CIP/CIM from GBS in case of such patients developing weakness after the treatment. Clinical characteristics and examination results should be carefully evaluated to make the diagnosis of CIP or CIM. Both anti-septic prophylaxis and control of hyperglycemia might be effective for the prevention of CIP or CIM; aggressive treatment on sepsis and multiple organ failure is considered to be the most effective measure to reduce the incidence of CIP/CIM.
A new method to customize protein expression vectors for fast, efficient and background free parallel cloning
Authors: Scholz Judith , Besir Hüseyin , Strasser Claudia , Suppmann Sabine
Published: February 2013

Background

Expression and purification of correctly folded proteins typically require screening of different parameters such as protein variants, solubility enhancing tags or expression hosts. Parallel vector series that cover all variations are available, but not without compromise. We have established a fast, efficient and absolutely background free cloning approach that can be applied to any selected vector.

Results

Here we describe a method to tailor selected expression vectors for parallel Sequence and Ligation Independent Cloning. SLIC cloning enables precise and sequence independent engineering and is based on joining vector and insert with 15–25 bp homologies on both DNA ends by homologous recombination. We modified expression vectors based on pET, pFastBac and pTT backbones for parallel PCR-based cloning and screening in E.coli, insect cells and HEK293E cells, respectively. We introduced the toxic ccdB gene under control of a strong constitutive promoter for counterselection of insert less vector. In contrast to DpnI treatment commonly used to reduce vector background, ccdB used in our vector series is 100% efficient in killing parental vector carrying cells and reduces vector background to zero. In addition, the 3’ end of ccdB functions as a primer binding site common to all vectors. The second shared primer binding site is provided by a HRV 3C protease cleavage site located downstream of purification and solubility enhancing tags for tag removal. We have so far generated more than 30 different parallel expression vectors, and successfully cloned and expressed more than 250 genes with this vector series. There is no size restriction for gene insertion, clone efficiency is > 95% with clone numbers up to 200. The procedure is simple, fast, efficient and cost-effective. All expression vectors showed efficient expression of eGFP and different target proteins requested to be produced and purified at our Core Facility services.

Conclusion

This new expression vector series allows efficient and cost-effective parallel cloning and thus screening of different protein constructs, tags and expression hosts.
Vasorelaxant effect of Prunus yedoensis bark
Authors: Lee Kyungjin , Ham Inhye , Yang Gabsik , Lee Mihwa , Bu Youngmin , Kim Hocheol , Choi Ho-Young
Published: February 2013

Background

Prunus yedoensis Matsum. is used as traditional medicine—‘Yaeng-Pi’ or ‘Hua-Pi’—in Japan and Korea. However, no studies have examined the pharmacological activities of the P. yedoensis bark. Only the antioxidant and antiviral activities of P. yedoensis fruit and the anti-hyperglycaemic effect of P. yedoensis leaf have been investigated. While studying the antihypertensive effects of several medicinal plants, we found that a methanol extract of P. yedoensis bark (MEPY) had distinct vasorelaxant effects on rat aortic rings.

Methods

The aortic rings were removed from Sprague–Dawley rats and suspended in organ chambers containing 10 ml Krebs-Henseleit solution. The aortic rings were placed between 2 tungsten stirrups and connected to an isometric force transducer. Changes in tension were recorded via isometric transducers connected to a data acquisition system.

Results

MEPY relaxed the contraction induced by phenylephrine (PE) both in endothelium-intact and endothelium-denuded aortic rings concentration dependently. However, the vasorelaxant effects of MEPY on endothelium-denuded aortic rings were lower than endothelium-intact aortic rings. The vasorelaxant effects of MEPY on endothelium-intact aortic rings were reduced by pre-treatment with l-NAME, methylene blue, or ODQ. However, pre-treatment with indomethacin, atropine, glibenclamide, tetraethylammonium, or 4-aminopyridine had no affection. In addition, MEPY inhibited the contraction induced by extracellular Ca2+ in endothelium-denuded rat thoracic aorta rings pre-contracted by PE (1 μM) or KCl (60 mM) in Ca2+-free solution.

Conclusions

Our results suggest that MEPY exerts its vasorelaxant effects via the activation of NO formation by means of l-Arg and NO-cGMP pathways and via the blockage of extracellular Ca2+ channels.
Src-mediated morphology transition of lung cancer cells in three-dimensional organotypic culture
Authors: Nguyen Hong T , Zhuang Yan , Sun Lichun , Kantrow Steven P , Kolls Jay K , You Zongbing , Zhuo Ying , Shan Bin
Published: February 2013

A fribotic tumor microenvironment promotes progression of cancer. In this study, we utilize a reconstituted basement membrane mimics Matrigel based three-dimensional organotypic culture (rBM 3-D) to investigate the mechanisms that mediate the tumor promoting effects of the fibrogenic mediators TGF-β1 and type I collagen (Col-1) on lung adenocarcinoma cells. Similar to normal alveolar epithelial cells, the well-differentiated lung adenocarcinoma cells in rBM 3-D culture undergo acinar morphogeneis that features polarized epithelial cell spheres with a single central lumen. Either TGF-β1 or Col-1 modestly distorts acinar morphogenesis. On the other hand, TGF-β1 and Col-1 synergistically induce a transition from acinar morphology into stellate morphology that is characteristic of invasive and metastatic cancer cells. Inhibition of the Src kinase activity abrogates induction of stellate morphology, activation of Akt and mTOR, and the expression of tumor promoting genes by TGF-β1 and Col-1. To a similar extent, pharmacological inhibition of mTOR abrogates the cellular responses to TGF-β1 and Col-1. In summary, we demonstrate that TGF-β1 and Col-1 promote stellate morphogenesis of lung cancer cells. Our findings further suggest that the Src-Akt-mTOR axis mediates stellate morphogenesis. These findings also indicate that rBM 3-D culture can serve as an ideal platform for swift and cost-effective screening of therapeutic candidates at the interface of the tumor and its microenvironment.
Improvement of left ventricular remodeling after myocardial infarction with eight weeks L-thyroxine treatment in rats
Authors: Chen Yue-Feng , Weltman Nathan Y , Li Xiang , Youmans Steven , Krause David , Gerdes Anthony Martin
Published: February 2013

Background

Left ventricular (LV) remodeling following large transmural myocardial infarction (MI) remains a pivotal clinical issue despite the advance of medical treatment over the past few decades. Identification of new medications to improve the remodeling process and prevent progression to heart failure after MI is critical. Thyroid hormones (THs) have been shown to improve LV function and remodeling in animals post-MI and in the human setting. However, changes in underlying cellular remodeling resulting from TH treatment are not clear.

Methods

MI was produced in adult female Sprague–Dawley rats by ligation of the left descending coronary artery. L-thyroxine (T4) pellet (3.3 mg, 60 days sustained release) was used to treat MI rats for 8 weeks. Isolated myocyte shape, arterioles, and collagen deposition in the non-infarcted area were measured at terminal study.

Results

T4 treatment improved LV ±dp/dt, normalized TAU, and increased myocyte cross-sectional area without further increasing myocyte length in MI rats. T4 treatment increased the total LV tissue area by 34%, increased the non-infarcted tissue area by 41%, and increased the thickness of non-infarcted area by 36% in MI rats. However, myocyte volume accounted for only ~1/3 of the increase in myocyte mass in the non-infarct area, indicating the presence of more myocytes with treatment. T4 treatment tended to increase the total length of smaller arterioles (5 to 15 μm) proportional to LV weight increase and also decreased collagen deposition in the LV non-infarcted area. A tendency for increased metalloproteinase-2 (MMP-2) expression and tissue inhibitor of metalloproteinases (TIMPs) -1 to −4 expression was also observed in T4 treated MI rats.

Conclusions

These results suggest that long-term T4 treatment after MI has beneficial effects on myocyte, arteriolar, and collagen matrix remodeling in the non-infarcted area. Most importantly, results suggest improved survival of myocytes in the peri-infarct area.
Characterization of antiviral resistance mutations among the Eastern Indian Hepatitis B virus infected population
Authors: Panigrahi Rajesh , Biswas Avik , De Binay Krishna , Chakrabarti Sekhar , Chakravarty Runu
Published: February 2013

Background

Antiviral therapy using nucleos(t)ide analogues (NAs) is an effective control measure of chronic hepatitis B virus (HBV) infection; however they need long term treatment. Presence of drug-resistance mutations may get in the way of the efficacy of antiviral therapy. Our study was aimed at defining the prevalence of HBV drug-resistance in HBVrt region in a population of 147 HBsAg positive patients.

Findings

HBV/D has shown multiple types of HBVrt mutations both among treatment naïve (65.0%, 13 of 20 HBV/D) and treated patients (56.2%, 9 of 16 HBV/D). In additional, several mutations, with a suggested role in drug resistance, were detected among the treatment naïve as well as the treated patients. The mutations reported to be involved in reduction of drug effectiveness, was common among non-responders to therapy as well as among the naïve patients. Notably, classical antiviral resistance mutations (rtL80I/V-rtI169T-rtV173L-rtL180M-rtA181T/V/S-rtT184A/S/G/C-rtA194T-rtS202C /G/I -rtM204V/I-rtN236T-rtM250V) were not detected.

Conclusion

The prevalence of putative NAr mutations among non responders to therapy suggests that they might have role in reduced efficacy of currently available antivirals and requires further investigations.
A retrospective analysis of geriatric trauma patients: venous lactate is a better predictor of mortality than traditional vital signs
Authors: Salottolo Kristin M , Mains Charles W , Offner Patrick J , Bourg Pamela W , Bar-Or David
Published: February 2013

Background

Traditional vital signs (TVS), including systolic blood pressure (SBP), heart rate (HR) and their composite, the shock index, may be poor prognostic indicators in geriatric trauma patients. The purpose of this study is to determine whether lactate predicts mortality better than TVS.

Methods

We studied a large cohort of trauma patients age ≥ 65 years admitted to a level 1 trauma center from 2009-01-01 - 2011-12-31. We defined abnormal TVS as hypotension (SBP < 90 mm Hg) and/or tachycardia (HR > 120 beats/min), an elevated shock index as HR/SBP ≥ 1, an elevated venous lactate as ≥ 2.5 mM, and occult hypoperfusion as elevated lactate with normal TVS. The association between these variables and in-hospital mortality was compared using Chi-square tests and multivariate logistic regression.

Results

There were 1987 geriatric trauma patients included, with an overall mortality of 4.23% and an incidence of occult hypoperfusion of 20.03%. After adjustment for GCS, ISS, and advanced age, venous lactate significantly predicted mortality (OR: 2.62, p < 0.001), whereas abnormal TVS (OR: 1.71, p = 0.21) and SI ≥ 1 (OR: 1.18, p = 0.78) did not. Mortality was significantly greater in patients with occult hypoperfusion compared to patients with no sign of circulatory hemodynamic instability (10.67% versus 3.67%, p < 0.001), which continued after adjustment (OR: 2.12, p = 0.01).

Conclusions

Our findings demonstrate that occult hypoperfusion was exceedingly common in geriatric trauma patients, and was associated with a two-fold increased odds of mortality. Venous lactate should be measured for all geriatric trauma patients to improve the identification of hemodynamic instability and optimize resuscitative efforts.
Profiling of hepatic clearance pathways of Pittsburgh compound B and human liver cytochrome p450 phenotyping
Authors: Van Vlaslaer Anne , Mortishire-Smith Russell J , Mackie Claire , Langlois Xavier , Schmidt Mark E
Published: February 2013

Background

11C-PiB has been developed as a positron-emission tomography (PET) ligand for evaluating fibrillar β-amyloid (Aβ) in the human brain. The ligand is rapidly metabolized, with approximately 10% of intact tracer remaining 30 min after injection. When 11C-PiB is used as a treatment endpoint in intervention studies for Alzheimer’s disease (AD), a concern is whether the clearance of the tracer changes from one scan to the next, increasing within subject variability in the PET signal. Subjects enrolled in AD trials may start or stop medications that inhibit or induce xenobiotic metabolizing enzymes such as the cytochrome P450 (CYP) isozymes.

Findings

We conducted CYP phenotyping in recombinantly expressed systems, and in human liver microsomes, to evaluate CYP isozyme contributions to the metabolism of PiB (carrier) and profiled microsomal and hepatocyte incubations for metabolites. The metabolism of PiB appears to be polyzymic, with direct conjugation via UDP-glucuronosyltransferases (UGTs) also occurring.

Conclusion

It is unlikely that CYP inhibition or induction will significantly influence the clearance of 11C-PiB.
Pervasive and dynamic protein binding sites of the mRNA transcriptome in Saccharomyces cerevisiae
Authors: Freeberg Mallory A , Han Ting , Moresco James J , Kong Andy , Yang Yu-Cheng , Lu Zhi John , Yates John R , Kim John K
Published: February 2013

Background

Protein-RNA interactions are integral components of nearly every aspect of biology, including regulation of gene expression, assembly of cellular architectures, and pathogenesis of human diseases. However, studies in the past few decades have only uncovered a small fraction of the vast landscape of the protein-RNA interactome in any organism, and even less is known about the dynamics of protein-RNA interactions under changing developmental and environmental conditions.

Results

Here, we describe the gPAR-CLIP (global photoactivatable-ribonucleoside-enhanced crosslinking and immunopurification) approach for capturing regions of the untranslated, polyadenylated transcriptome bound by RNA-binding proteins (RBPs) in budding yeast. We report over 13,000 RBP crosslinking sites in untranslated regions (UTRs) covering 72% of protein-coding transcripts encoded in the genome, confirming 3' UTRs as major sites for RBP interaction. Comparative genomic analyses reveal that RBP crosslinking sites are highly conserved, and RNA folding predictions indicate that secondary structural elements are constrained by protein binding and may serve as generalizable modes of RNA recognition. Finally, 38% of 3' UTR crosslinking sites show changes in RBP occupancy upon glucose or nitrogen deprivation, with major impacts on metabolic pathways as well as mitochondrial and ribosomal gene expression.

Conclusions

Our study offers an unprecedented view of the pervasiveness and dynamics of protein-RNA interactions in vivo.
Follistatin-like 3 (FSTL3) Mediated Silencing of Transforming Growth Factor β (TGFβ) Signaling Is Essential for Testicular Aging and Regulating Testis Size
Authors: Oldknow Karla J. , Seebacher Jan , Goswami Tapasree , Villen Judit , Pitsillides Andrew A. , O'Shaughnessy Peter J. , Gygi Steven P. , Schneyer Alan L. , Mukherjee Abir
Published: February 2013

Follistatin-like 3 (FSTL3) is a glycoprotein that binds and inhibits the action of TGFβ ligands such as activin. The roles played by FSTL3 and activin signaling in organ development and homeostasis are not fully understood. The authors show mice deficient in FSTL3 develop markedly enlarged testes that are also delayed in their age-related regression. These FSTL3 knockout mice exhibit increased Sertoli cell numbers, allowing for increased spermatogenesis but otherwise showing normal testicular function. The data show that FSTL3 deletion leads to increased AKT signaling and SIRT1 expression in the testis. This demonstrates a cross-talk between TGFβ ligand and AKT signaling and leads to a potential mechanism for increased cellular survival and antiaging. The findings identify crucial roles for FSTL3 in limiting testis organ size and promoting age-related testicular regression.
The pro-Forms of Insulin-Like Growth Factor I (IGF-I) Are Predominant in Skeletal Muscle and Alter IGF-I Receptor Activation
Authors: Durzyńska Julia , Philippou Anastassios , Brisson Becky K. , Nguyen-McCarty Michelle , Barton Elisabeth R.
Published: February 2013

IGF-I is a key regulator of muscle development and growth. The pre-pro-peptide produced by the Igf1gene undergoes several posttranslational processing steps to result in a secreted mature protein, which is thought to be the obligate ligand for the IGF-I receptor (IGF-IR). The goals of this study were to determine what forms of IGF-I exist in skeletal muscle, and whether the mature IGF-I protein was the only form able to activate the IGF-IR. We measured the proportion of IGF-I species in murine skeletal muscle and found that the predominant forms were nonglycosylated pro-IGF-I and glycosylated pro-IGF-I, which retained the C-terminal E peptide extension, instead of mature IGF-I. These forms were validated using samples subjected to viral expression of IGF-I combined with furin and glycosidase digestion. To determine whether the larger molecular weight IGF-I forms were also ligands for the IGF-IR, we generated each specific form through transient transfection of 3T3 cells and used the enriched media to perform kinase receptor activation assays. Compared with mature IGF-I, nonglycosylated pro-IGF-I had similar ability to activate the IGF-IR, whereas glycosylation of pro-IGF-I significantly reduced receptor activation. Thus, it is important to understand not only the quantity, but also the proportion of IGF-I forms produced, to evaluate the true biological activity of this growth factor.
Myod and H19-Igf2 locus interactions are required for diaphragm formation in the mouse
Authors: Borensztein Maud , Monnier Paul , Court Franck , Louault Yann , Ripoche Marie-Anne , Tiret Laurent , Yao Zizhen , Tapscott Stephen J. , Forné Thierry , Montarras Didier , Dandolo Luisa
Published: February 2013

The myogenic regulatory factor Myod and insulin-like growth factor 2 (Igf2) have been shown to interact in vitro during myogenic differentiation. In order to understand how they interact in vivo, we produced double-mutant mice lacking both the Myod and Igf2 genes. Surprisingly, these mice display neonatal lethality due to severe diaphragm atrophy. Alteration of diaphragm muscle development occurs as early as 15.5 days post-coitum in the double-mutant embryos and leads to a defect in the terminal differentiation of muscle progenitor cells. A negative-feedback loop was detected between Myod and Igf2 in embryonic muscles. Igf2 belongs to the imprinted H19-Igf2 locus. Molecular analyses show binding of Myod on a mesodermal enhancer (CS9) of the H19 gene. Chromatin conformation capture experiments reveal direct interaction of CS9 with the H19 promoter, leading to increased H19 expression in the presence of Myod. In turn, the non-coding H19 RNA represses Igf2 expression in trans. In addition, Igf2 also negatively regulates Myod expression, possibly by reducing the expression of the Srf transcription factor, a known Myod activator. In conclusion, Igf2 and Myod are tightly co-regulated in skeletal muscles and act in parallel pathways in the diaphragm, where they affect the progression of myogenic differentiation. Igf2 is therefore an essential player in the formation of a functional diaphragm in the absence of Myod.
Smad4-Irf6 genetic interaction and TGFβ-mediated IRF6 signaling cascade are crucial for palatal fusion in mice
Authors: Iwata Jun-ichi , Suzuki Akiko , Pelikan Richard C. , Ho Thach-Vu , Sanchez-Lara Pedro A. , Urata Mark , Dixon Michael J. , Chai Yang
Published: February 2013

Cleft palate is one of the most common human birth defects and is associated with multiple genetic and environmental risk factors. Although mutations in the genes encoding transforming growth factor beta (TGFβ) signaling molecules and interferon regulatory factor 6 (Irf6) have been identified as genetic risk factors for cleft palate, little is known about the relationship between TGFβ signaling and IRF6 activity during palate formation. Here, we show that TGFβ signaling regulates expression of Irf6 and the fate of the medial edge epithelium (MEE) during palatal fusion in mice. Haploinsufficiency of Irf6 in mice with basal epithelial-specific deletion of the TGFβ signaling mediator Smad4 (Smad4fl/fl;K14-Cre;Irf6+/R84C) results in compromised p21 expression and MEE persistence, similar to observations in Tgfbr2fl/fl;K14-Cre mice, although the secondary palate of Irf6+/R84C and Smad4fl/fl;K14-Cre mice form normally. Furthermore, Smad4fl/fl;K14-Cre;Irf6+/R84C mice show extra digits that are consistent with abnormal toe and nail phenotypes in individuals with Van der Woude and popliteal pterygium syndromes, suggesting that the TGFβ/SMAD4/IRF6 signaling cascade might be a well-conserved mechanism in regulating multiple organogenesis. Strikingly, overexpression of Irf6 rescued p21 expression and MEE degeneration in Tgfbr2fl/fl;K14-Cre mice. Thus, IRF6 and SMAD4 synergistically regulate the fate of the MEE, and TGFβ-mediated Irf6 activity is responsible for MEE degeneration during palatal fusion in mice.
Quantitative parametric MRI of articular cartilage: a review of progress and open challenges
Authors: Binks D A , Hodgson R J , Ries M E , Foster R J , Smye S W , McGonagle D , Radjenovic A
Published: February 2013

With increasing life expectancies and the desire to maintain active lifestyles well into old age, the impact of the debilitating disease osteoarthritis (OA) and its burden on healthcare services is mounting. Emerging regenerative therapies could deliver significant advances in the effective treatment of OA but rely upon the ability to identify the initial signs of tissue damage and will also benefit from quantitative assessment of tissue repair in vivo. Continued development in the field of quantitative MRI in recent years has seen the emergence of techniques able to probe the earliest biochemical changes linked with the onset of OA. Quantitative MRI measurements including T  1, T  2 and T  1ρ relaxometry, diffusion weighted imaging and magnetisation transfer have been studied and linked to the macromolecular structure of cartilage. Delayed gadolinium-enhanced MRI of cartilage, sodium MRI and glycosaminoglycan chemical exchange saturation transfer techniques are sensitive to depletion of cartilage glycosaminoglycans and may allow detection of the earliest stages of OA. We review these current and emerging techniques for the diagnosis of early OA, evaluate the progress that has been made towards their implementation in the clinic and identify future challenges in the field.
Intercollegiate Surgical Curriculum Programme: Where are We Now?
Authors: Saleh DB , Coulson SG , Rawlins J
Published: February 2013

The compulsory Intercollegiate Surgical Curriculum Programme (ISCP) was introduced in 2007 for all surgical trainees in a bid to provide a platform for better trainee evaluation and assessment. Its introduction received a mixed response and a compulsory annual fee of £125 added to the financial burden now on surgical trainees as they undertake their training. An early appraisal among users discovered general dissatisfaction with the fee and, most importantly, what the ISCP actually offered them in terms of their training. Parallel to these findings, there has been anecdotal and published evidence that the ISCP format for assessment is not adhered to by senior trainers and that this is a result of a general apathy toward the ISCP among senior clinicians.
Saints and Sinners: George Guthrie
Authors: Hurt Raymond
Published: February 2013

Who says exams are getting easier? Born on 1 May 1785, the prodigious George Guthrie passed the entrance examination of the Royal College of Surgeons in 1800 when he was just 15 years old. While today's teenagers may struggle to find a local youth club that has survived the coalition government's cull, by the time Guthrie joined the College he was practically an old hand at surgery, having been apprenticed to a senior army surgeon since the tender age of 13.
Are Patients' Expectations of Recovery After Hip and Knee Replacement Similar to Those of the Surgeons?
Authors: Atrey Amit , Sandhu Harinderjeet , Butt David , Chettiar Krissen , Butler-Manuel Adrian , Slater RN
Published: February 2013

There are a number of nonoperative factors affecting both the functional outcome of hip and knee replacements and postoperative satisfaction. Some are difficult to modify such as marked, functional limitation, severe pain, low mental health score and other co-morbidities prior to arthroplasty. Surgeons are limited in their ability to effect change in these variables. Consequently, in attempting to identify scope for improving outcome and satisfaction, we have focused on whether patients undergoing hip and knee replacements have realistic expectations when it comes to the time it will take them to rehabilitate to certain defined levels of function and pain relief. A number of other studies have investigated the importance of patient expectation on surgical outcome. Instead, we focus on the discrepancy between surgeon and patient expectation for the time taken to reach defined landmarks in rehabilitation.
How will dental surgery services be commissioned in the future?
Authors: Speculand Bernie , Noble Rachel
Published: February 2013

While most secondary care services will be commissioned by GP-led clinical commissioning groups (CCGs), the majority of primary care services – including all primary and secondary care dental services – will be the responsibility of the NHS Commissioning Board (NHS CB). This was first established in shadow form in April 2012, following the passage of the Health and Social Care Act. The Act brings with it a number of new organisations, and several new acronyms to learn.
Outpatient Clinics: A Lost Training Opportunity?
Authors: Milburn J A , Brittenden J , Bachoo P
Published: February 2013

As a consequence of the introduction of the European Working Time Regulations and the New Deal, there has been a significant reduction in the number of hours worked by surgical trainees in the UK and Europe. A number of studies have highlighted how reduced working hours have negatively affected operative exposure in surgical specialties. Surgical training requires the accumulation of increasingly complex technical competencies. In order to produce a complete surgeon, these competencies must be complemented by non-technical skills. Traditionally, these have been acquired through ward and outpatient experience without strict time limitation. With reduced daytime clinical experience, not only will there be a reduction in technical skills training but inevitably reduced outpatient clinic (OPC) experience.
Training Foundation Year Doctors in the Operating Theatre: A Missed Opportunity?
Authors: Dash I , Bickley JE , Morgan JD
Published: February 2013

Foundation trainees replaced the pre-registration house officers in August 2005 after Modernising Medical Careers was set up to 'drive up the quality of care for patients through reform and improvement in postgraduate medical education and training'. Doctors qualifying from UK medical schools entered into the foundation years, which consisted of two years of training designed to form a bridge between medical school and specialty training. All doctors wanting to apply for specialty training in the UK must complete their foundation programme or equivalent.
Changes in surgical training: more than just European Working Time Regulations and Modernising Medical Careers
Authors: Leonard C G , Hoo C , Hill C
Published: February 2013

Since the introduction of European Working Time Regulations (ETWR) and Modernising Medical Careers (MMC), the impact on and changes to surgical training have been discussed in this forum, the wider medical literature and the public domain. Concerns have been raised regarding reduction in exposure to surgical techniques and procedures, and time in theatre has been shown to be of significant value. It has also led to efforts to optimise management of trainees' time and to balance service provision and training appropriately.
The times they are a-changin'
Authors: Williams Norman
Published: February 2013

There is no question that change is unsettling and I can well appreciate how the flurry of recent announcements from the new NHS Commissioning Board (NHS CB) and the Department of Health might have concerned fellows and members. I hope many of you have read the e-newsletter I sent out just before Christmas, explaining some of these announcements and the stance we have taken, particularly around the outcomes agenda.
Cannibale, Frigidaire and the multitude: Post-1977 italian comics through radical theory
Authors: Pagello Federico
Published: February 2013

A direct connection between comics and contemporary critical theory is to be found in the activity of the collective of artists who created Cannibale and Frigidaire, the two most innovative Italian comics magazines of the late 1970s and early 1980s. The work of Andrea Pazienza, Filippo
Scòzzari, Stefano Tamburini, Tanino Liberatore and Massimo Mattioli should be regarded as an expression of the radical movements from which Marxist Autonomist thinkers such as Antonio Negri, Franco ‘Bifo’ Berardi and Paolo Virno also emerged in the same period. As a consequence,
the writings of the latter can be used to analyse the narrative and visual style, the recurring themes, and the editorial characteristics of the comics of the former. Moreover, an interesting parallel can also be drawn between the work of the most influential of these artists, Andrea Pazienza,
and the thought of another prominent Italian philosopher, Giorgio Agamben, whose earliest books were published at that time too. The aim of this article is to show that the ideas of a number of the thinkers who have recently become internationally known as representatives of Radical Italian
theory, are useful to understand the work of this group of comics authors. In the first section, I examine the direct links between Cannibale, Frigidaire and the Italian social movements of the 1970s. The artists discussed here were active participants in the cultural activities and political
struggles promoted by the Autonomists. In the second section, a series of concepts central to (post-) Autonomist theory, such as post-Fordism, multitude, general intellect and virtuosity, are used to analyse the comics published in Cannibale and Frigidaire. Finally, I show how Agamben’s
reflections on the ‘destruction of experience’ in modern society can help us to read Andrea Pazienza’s Le straordinarie avventure di Pentothal (1982), Zanardi (1983) and Gli ultimi giorni di Pompeo (1987).