bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk of venous thromboembolism in people admitted to hospital with selected immune-mediated diseases: record-linkage study
Authors: Ramagopalan Sreeram V , Wotton Clare J , Handel Adam E , Yeates David , Goldacre Michael J
Published: January 2011

Background

Venous thromboembolism (VTE) is a common complication during and after a hospital admission. Although it is mainly considered a complication of surgery, it often occurs in people who have not undergone surgery, with recent evidence suggesting that immune-mediated diseases may play a role in VTE risk. We, therefore, decided to study the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in people admitted to hospital with a range of immune-mediated diseases.

Methods

We analysed databases of linked statistical records of hospital admissions and death certificates for the Oxford Record Linkage Study area (ORLS1:1968 to 1998 and ORLS2:1999 to 2008) and the whole of England (1999 to 2008). Rate ratios for VTE were determined, comparing immune-mediated disease cohorts with comparison cohorts.

Results

Significantly elevated risks of VTE were found, in all three populations studied, in people with a hospital record of admission for autoimmune haemolytic anaemia, chronic active hepatitis, dermatomyositis/polymyositis, type 1 diabetes mellitus, multiple sclerosis, myasthenia gravis, myxoedema, pemphigus/pemphigoid, polyarteritis nodosa, psoriasis, rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus. Rate ratios were considerably higher for some of these diseases than others: for example, for systemic lupus erythematosus the rate ratios were 3.61 (2.36 to 5.31) in the ORLS1 population, 4.60 (3.19 to 6.43) in ORLS2 and 3.71 (3.43 to 4.02) in the England dataset.

Conclusions

People admitted to hospital with immune-mediated diseases may be at an increased risk of subsequent VTE. Our findings need independent confirmation or refutation; but, if confirmed, there may be a role for thromboprophylaxis in some patients with these diseases.
Reduced spiral ganglion neuronal loss by adjunctive neurotrophin-3 in experimental pneumococcal meningitis
Authors: Demel Cornelia , Hoegen Tobias , Giese Armin , Angele Barbara , Pfister Hans-Walter , Koedel Uwe , Klein Matthias
Published: January 2011

Background

Hearing loss is a frequent long-term complication of pneumococcal meningitis (PM). Its main pathological correlate is damage to the organ of Corti and loss of spiral ganglion neurons. The only current treatment option is cochlear implants which require surviving neurons. Here, we investigated the impact of systemically applied neurotrophin-3 (NT-3) on long-term hearing loss and the survival of neurons.

Methods

Eighteen hours after infection with S. pneumoniae, C57BL/6 mice were treated with a combination of ceftriaxone with NT-3 or dexamethasone or placebo. Hearing, cochlear damage, and brain damage were assessed by audiometry and histology.

Results

The main findings from immunohistochemical visualization of neurotrophins (NT-3, BDNF) and their receptors (TrkB, TrkC, and p75) in the cochlea were (i) enhanced staining for the cell survival-promoting receptor TrkB and (ii) increased NT-3 staining in NT-3 treated mice, showing that systemically applied NT-3 reaches the cochlea. The major effects of adjunctive NT-3 treatment were (i) a reduction of meningitis-induced hearing impairment and (ii) a reduction of spiral ganglion neuronal loss. The efficacy of NT-3 therapy was comparable to that of dexamethasone.

Conclusion

Systemically applied NT-3 might be an interesting candidate to improve hearing outcome after pneumococcal meningitis.
Cooperative contributions of Interferon regulatory factor 1 (IRF1) and IRF8 to interferon-γ-mediated cytotoxic effects on oligodendroglial progenitor cells
Authors: Horiuchi Makoto , Itoh Aki , Pleasure David , Ozato Keiko , Itoh Takayuki
Published: January 2011

Background

Administration of exogenous interferon-γ (IFNγ) aggravates the symptoms of multiple sclerosis (MS), whereas interferon-β (IFNβ) is used for treatment of MS patients. We previously demonstrated that IFNγ induces apoptosis of oligodendroglial progenitor cells (OPCs), suggesting that IFNγ is more toxic to OPCs than IFNβ. Thus we hypothesized that a difference in expression profiles between IFNγ-inducible and IFNβ-inducible genes in OPCs would predict the genes responsible for IFNγ-mediated cytotoxic effects on OPCs. We have tested this hypothesis particularly focusing on the interferon regulatory factors (IRFs) well-known transcription factors up-regulated by IFNs.

Methods

Highly pure primary rat OPC cultures were treated with IFNγ and IFNβ. Cell death and proliferation were assessed by MTT reduction, caspse-3-like proteinase activity, Annexin-V binding, mitochondrial membrane potential, and BrdU-incorporation. Induction of all nine IRFs was comprehensively compared by quantitative PCR between IFNγ-treated and IFNβ-treated OPCs. IRFs more strongly induced by IFNγ than by IFNβ were selected, and tested for their ability to induce OPC apoptosis by overexpression and by inhibition by dominant-negative proteins or small interference RNA either in the presence or absence of IFNγ.

Results

Unlike IFNγ, IFNβ did not induce apoptosis of OPCs. Among nine IRFs, IRF1 and IRF8 were preferentially up-regulated by IFNγ. In contrast, IRF7 was more robustly induced by IFNβ than by IFNγ. Overexpressed IRF1 elicited apoptosis of OPCs, and a dominant negative IRF1 protein partially protected OPCs from IFNγ-induced apoptosis, indicating a substantial contribution of IRF1 to IFNγ-induced OPC apoptosis. On the other hand, overexpression of IRF8 itself had only marginal proapoptotic effects. However, overexpressed IRF8 enhanced the IFNγ-induced cytotoxicity and the proapoptotic effect of overexpressed IRF1, and down-regulation of IRF8 by siRNA partially but significantly reduced preapoptotic cells after treatment with IFNγ, suggesting that IRF8 cooperatively enhances IFNγ-induced OPC apoptosis.

Conclusions

This study has identified that IRF1 and IRF8 mediate IFNγ-signaling leading to OPC apoptosis. Therapies targeting at these transcription factors and their target genes could reduce IFNγ-induced OPC loss and thereby enhance remyelination in MS patients.
Antinociception Produced by Thalassia Testudinum Extract BM-21 is Mediated by the Inhibition of Acid Sensing Ionic Channels by the Phenolic Compound Thalassiolin B
Authors: Garateix Anoland , Salceda Emilio , Menéndez Roberto , Regalado Erik L , López Omar , García Teidy , Morales Ruth A , Laguna Abilio , Thomas Olivier P , Soto Enrique
Published: January 2011

Background:

Acid-sensing ion channels (ASICs) have a significant role in the sensation of pain and constitute an important target for the search of new antinociceptive drugs. In this work we studied the antinociceptive properties of the BM-21 extract, obtained from the sea grass Thalassia testudinum, in chemical and thermal models of nociception in mice. The action of the BM-21 extract and the major phenolic component isolated from this extract, a sulphated flavone glycoside named thalassiolin B, was studied in the chemical nociception test and in the ASIC currents of the dorsal root ganglion (DRG) neurons obtained from Wistar rats.

Results:

Behavioral antinociceptive experiments were made on male OF-1 mice. Single oral administration of BM-21 produced a significant inhibition of chemical nociception caused by acetic acid and formalin (specifically during its second phase), and increased the reaction time in the hot plate test. Thalassiolin B reduced the licking behavior during both the phasic and tonic phases in the formalin test. It was also found that BM-21 and thalassiolin B selectively inhibited the fast desensitizing (τ < 400 ms) ASIC currents in DRG neurons obtained from Wistar rats, with a nonsignificant action on ASIC currents with a slow desensitizing time-course. The action of thalassiolin B shows no pH or voltage dependence nor is it modified by steady-state ASIC desensitization or voltage. The high concentration of thalassiolin B in the extract may account for the antinociceptive action of BM-21.

Conclusions:

To our knowledge, this is the first report of an ASIC-current inhibitor derived of a marine-plant extract, and in a phenolic compound. The antinociceptive effects of BM-21 and thalassiolin B may be partially because of this action on the ASICs. That the active components of the extract are able to cross the blood-brain barrier gives them an additional advantage for future uses as tools to study pain mechanisms with a potential therapeutic application.
Influence of lip closure on alveolar cleft width in patients with cleft lip and palate
Authors: Eichhorn Wolfgang , Blessmann Marco , Vorwig Oliver , Gehrke Gerd , Schmelzle Rainer , Heiland Max
Published: January 2011

Background

The influence of surgery on growth and stability after treatment in patients with cleft lip and palate are topics still under discussion. The aim of the present study was to investigate the influence of early lip closure on the width of the alveolar cleft using dental casts.

Methods

A total of 44 clefts were investigated using plaster casts, 30 unilateral and 7 bilateral clefts. All infants received a passive molding plate a few days after birth. The age at the time of closure of the lip was 2.1 month in average (range 1-6 months). Plaster casts were obtained at the following stages: shortly after birth, prior to lip closure, prior to soft palate closure. We determined the width of the alveolar cleft before lip closure and prior to soft palate closure measuring the alveolar cleft width from the most lateral point of the premaxilla/anterior segment to the most medial point of the smaller segment.

Results

After lip closure 15 clefts presented with a width of 0 mm, meaning that the mucosa of the segments was almost touching one another. 19 clefts showed a width of up to 2 mm and 10 clefts were still over 2 mm wide. This means a reduction of 0% in 5 clefts, of 1-50% in 6 clefts, of 51-99% in 19 clefts, and of 100% in 14 clefts.

Conclusions

Early lip closure reduces alveolar cleft width. In most cases our aim of a remaining cleft width of 2 mm or less can be achieved. These are promising conditions for primary alveolar bone grafting to restore the dental bony arch.
An ultrasonographic evaluation of skin thickness in breast cancer patients after postmastectomy radiation therapy
Authors: Wong Sharon , Kaur Amarjit , Back Michael , Lee Khai Mun , Baggarley Shaun , Lu Jiade Jay
Published: January 2011

Background

To determine the usefulness of ultrasonography in the assessment of post radiotherapy skin changes in postmastectomy breast cancer patients.

Methods

Patients treated for postmastectomy radiotherapy in National University Hospital (NUH) and Tan Tock Seng Hospital (TTSH), Singapore between January 2004- December 2005 was recruited retrospectively. Ultrasound scan was performed on these Asian patients who had been treated to a total dose of 46-50 Gy with 1 cm bolus placed on the skin. The ultrasound scans were performed blinded to the RTOG scores, and the skin thickness of the individually marked points on the irradiated chest wall was compared to the corresponding points on the non-irradiated breast.

Results

The mean total skin thickness inclusive of the epidermis and the dermis of the right irradiated chest wall was 0.1712 mm (± 0.03392 mm) compared with the contra-lateral non-irradiated breast which was 0.1845 mm (± 0.04089 mm; p = 0.007). The left irradiated chest wall had a mean skin thickness of 0.1764 mm (± 0.03184 mm) compared with the right non-irradiated breast which was 0.1835 mm (± 0.02584 mm; p = 0.025). These independent t-tests produced a significant difference of reduced skin thickness on the right irradiated chest wall, p = 0.007 (p < 0.05) and left irradiated chest wall p = 0.025 (p < 0.025) in comparison to the non-irradiated skin thickness investigating chronic skin reactions. Patients with grade 2 acute skin toxicity presented with thinner skin as compared to patients with grade 1 (p = 0.006).

Conclusions

This study has shown that there is a statistically significant difference between the skin thicknesses of the irradiated chest wall and the contra-lateral non-irradiated breast and a predisposition to chronic reactions was found in patients with acute RTOG scoring of grade1 and grade 2.
Meningeal cells and glia establish a permissive environment for axon regeneration after spinal cord injury in newts
Authors: Zukor Katherine A , Kent David T , Odelberg Shannon J
Published: January 2011

Background

Newts have the remarkable ability to regenerate their spinal cords as adults. Their spinal cords regenerate with the regenerating tail after tail amputation, as well as after a gap-inducing spinal cord injury (SCI), such as a complete transection. While most studies on newt spinal cord regeneration have focused on events occurring after tail amputation, less attention has been given to events occurring after an SCI, a context that is more relevant to human SCI. Our goal was to use modern labeling and imaging techniques to observe axons regenerating across a complete transection injury and determine how cells and the extracellular matrix in the injury site might contribute to the regenerative process.

Results

We identify stages of axon regeneration following a spinal cord transection and find that axon regrowth across the lesion appears to be enabled, in part, because meningeal cells and glia form a permissive environment for axon regeneration. Meningeal and endothelial cells regenerate into the lesion first and are associated with a loose extracellular matrix that allows axon growth cone migration. This matrix, paradoxically, consists of both permissive and inhibitory proteins. Axons grow into the injury site next and are closely associated with meningeal cells and glial processes extending from cell bodies surrounding the central canal. Later, ependymal tubes lined with glia extend into the lesion as well. Finally, the meningeal cells, axons, and glia move as a unit to close the gap in the spinal cord. After crossing the injury site, axons travel through white matter to reach synaptic targets, and though ascending axons regenerate, sensory axons do not appear to be among them. This entire regenerative process occurs even in the presence of an inflammatory response.

Conclusions

These data reveal, in detail, the cellular and extracellular events that occur during newt spinal cord regeneration after a transection injury and uncover an important role for meningeal and glial cells in facilitating axon regeneration. Given that these cell types interact to form inhibitory barriers in mammals, identifying the mechanisms underlying their permissive behaviors in the newt will provide new insights for improving spinal cord regeneration in mammals.
Pathophysiology, treatment, and animal and cellular models of human ischemic stroke
Authors: Woodruff Trent M , Thundyil John , Tang Sung-Chun , Sobey Christopher G , Taylor Stephen M , Arumugam Thiruma V
Published: January 2011

Stroke is the world's second leading cause of mortality, with a high incidence of severe morbidity in surviving victims. There are currently relatively few treatment options available to minimize tissue death following a stroke. As such, there is a pressing need to explore, at a molecular, cellular, tissue, and whole body level, the mechanisms leading to damage and death of CNS tissue following an ischemic brain event. This review explores the etiology and pathogenesis of ischemic stroke, and provides a general model of such. The pathophysiology of cerebral ischemic injury is explained, and experimental animal models of global and focal ischemic stroke, andin vitrocellular stroke models, are described in detail along with experimental strategies to analyze the injuries. In particular, the technical aspects of these stroke models are assessed and critically evaluated, along with detailed descriptions of the current best-practice murine models of ischemic stroke. Finally, we review preclinical studies using different strategies in experimental models, followed by an evaluation of results of recent, and failed attempts of neuroprotection in human clinical trials. We also explore new and emerging approaches for the prevention and treatment of stroke. In this regard, we note that single-target drug therapies for stroke therapy, have thus far universally failed in clinical trials. The need to investigate new targets for stroke treatments, which have pleiotropic therapeutic effects in the brain, is explored as an alternate strategy, and some such possible targets are elaborated. Developing therapeutic treatments for ischemic stroke is an intrinsically difficult endeavour. The heterogeneity of the causes, the anatomical complexity of the brain, and the practicalities of the victim receiving both timely and effective treatment, conspire against developing effective drug therapies. This should in no way be a disincentive to research, but instead, a clarion call to intensify efforts to ameliorate suffering and death from this common health catastrophe. This review aims to summarize both the present experimental and clinical state-of-the art, and to guide future research directions.
The role of fibrocytes in fibrotic diseases of the lungs and heart
Authors: Keeley Ellen C , Mehrad Borna , Strieter Robert M
Published: January 2011

Fibrosis is the end result of a complex series of events that follow tissue injury and inflammation. Pathophysiologic fibrosis results in permanent scar formation, and can impair organ function. Fibrocytes are circulating, bone-marrow-derived progenitor cells that traffic from the bone marrow to the injured organ via the bloodstream, where they differentiate into fibroblasts and myofibroblasts, and play a pivotal role in both physiologic and aberrant fibrosis. In this review, we focus on the contribution of fibrocytes to fibrotic diseases of the lungs and the heart, including interstitial lung diseases, asthma, pulmonary hypertension, atherosclerosis and ischemic cardiomyopathy.
Building prognostic models for breast cancer patients using clinical variables and hundreds of gene expression signatures
Authors: Fan Cheng , Prat Aleix , Parker Joel S , Liu Yufeng , Carey Lisa A , Troester Melissa A , Perou Charles M
Published: January 2011

Background

Multiple breast cancer gene expression profiles have been developed that appear to provide similar abilities to predict outcome and may outperform clinical-pathologic criteria; however, the extent to which seemingly disparate profiles provide additive prognostic information is not known, nor do we know whether prognostic profiles perform equally across clinically defined breast cancer subtypes. We evaluated whether combining the prognostic powers of standard breast cancer clinical variables with a large set of gene expression signatures could improve on our ability to predict patient outcomes.

Methods

Using clinical-pathological variables and a collection of 323 gene expression "modules", including 115 previously published signatures, we build multivariate Cox proportional hazards models using a dataset of 550 node-negative systemically untreated breast cancer patients. Models predictive of pathological complete response (pCR) to neoadjuvant chemotherapy were also built using this approach.

Results

We identified statistically significant prognostic models for relapse-free survival (RFS) at 7 years for the entire population, and for the subgroups of patients with ER-positive, or Luminal tumors. Furthermore, we found that combined models that included both clinical and genomic parameters improved prognostication compared with models with either clinical or genomic variables alone. Finally, we were able to build statistically significant combined models for pathological complete response (pCR) predictions for the entire population.

Conclusions

Integration of gene expression signatures and clinical-pathological factors is an improved method over either variable type alone. Highly prognostic models could be created when using all patients, and for the subset of patients with lymph node-negative and ER-positive breast cancers. Other variables beyond gene expression and clinical-pathological variables, like gene mutation status or DNA copy number changes, will be needed to build robust prognostic models for ER-negative breast cancer patients. This combined clinical and genomics model approach can also be used to build predictors of therapy responsiveness, and could ultimately be applied to other tumor types.
Cyclooxygenase-2 up-regulates vascular endothelial growth factor via a protein kinase C pathway in non-small cell lung cancer
Authors: Luo Honghe , Chen Zhenguang , Jin Hui , Zhuang Mei , Wang Tao , Su Chunhua , Lei Yiyan , Zou Jianyong , Zhong Beilong
Published: January 2011

Background

Vascular endothelial growth factor (VEGF) expression is up-regulated via a cyclooxygenase-2 (COX-2)-dependent mechanism in non-small cell lung cancer (NSCLC), but the specific signaling pathway involved is unclear. Our aim was to investigate the signaling pathway that links COX-2 with VEGF up-regulation in NSCLC.

Material and methods

COX-2 expression in NSCLC samples was detected immunohistochemically, and its association with VEGF, microvessel density (MVD), and other clinicopathological characteristics was determined. The effect of COX-2 treatment on the proliferation of NSCLC cells (A549, H460 and A431 cell lines) was assessed using the tetrazolium-based MTT method, and VEGF expression in tumor cells was evaluated by flow cytometry. COX-2-induced VEGF expression in tumor cells was monitored after treatment with inhibitors of protein kinase C (PKC), PKA, prostaglandin E2 (PGE2), and an activator of PKC.

Results

COX-2 over-expression correlated with MVD (P = 0.036) and VEGF expression (P = 0.001) in NSCLC samples, and multivariate analysis demonstrated an association of VEGF with COX-2 expression (P = 0.001). Exogenously applied COX-2 stimulated the growth of NSCLCs, exhibiting EC50 values of 8.95 × 10-3, 11.20 × 10-3, and 11.20 × 10-3 μM in A549, H460, and A431 cells, respectively; COX-2 treatment also enhanced tumor-associated VEGF expression with similar potency. Inhibitors of PKC and PGE2 attenuated COX-2-induced VEGF expression in NLCSCs, whereas a PKC activator exerted a potentiating effect.

Conclusion

COX-2 may contribute to VEGF expression in NSCLC. PKC and downstream signaling through prostaglandin may be involved in these COX-2 actions.
Finding a cure for HIV: will it ever be achievable?
Authors: Lewin Sharon R , Evans Vanessa A , Elliott Julian H , Spire Bruno , Chomont Nicolas
Published: January 2011

Combination antiretroviral therapy (cART) has led to a major reduction in HIV‐related mortality and morbidity. However, HIV still cannot be cured. With the absence of an effective prophylactic or therapeutic vaccine, increasing numbers of infected people, emerging new toxicities secondary to cART and the need for life‐long treatment, there is now a real urgency to find a cure for HIV.

There are currently multiple barriers to curing HIV. The most significant barrier is the establishment of a latent or “silent” infection in resting CD4+ T cells. In latent HIV infection, the virus is able to integrate into the host cell genome, but does not proceed to active replication. As a consequence, antiviral agents, as well as the immune system, are unable to eliminate these long‐lived, latently infected cells. Reactivation of latently infected resting CD4+ T cells can then re‐establish infection once cART is stopped. Other significant barriers to cure include residual viral replication in patients receiving cART, even when the virus is not detectable by conventional assays. In addition, HIV can be sequestered in anatomical reservoirs, such as the brain, gastrointestinal tract and genitourinary tract.

Achieving either a functional cure (long‐term control of HIV in the absence of cART) or a sterilizing cure (elimination of all HIV‐infected cells) remains a major challenge. Several studies have now demonstrated that treatment intensification appears to have little impact on latent reservoirs. Some potential and promising approaches that may reduce the latent reservoir include very early initiation of cART and the use of agents that could potentially reverse latent infection.

Agents that reverse latent infection will promote viral production; however, simultaneous administration of cART will prevent subsequent rounds of viral replication. Such drugs as histone deacetylase inhibitors, currently used and licensed for the treatment of some cancers, or activating latently infected resting cells with cytokines, such as IL‐7 or prostratin, show promising results in reversing latency in vitro when used either alone or in combination. In order to move forward toward clinical trials that target eradication, there needs to be careful consideration of the risks and benefits of these approaches, agreement on the most informative endpoints for eradication studies and greater engagement of the infected community.
Development and implementation of a performance improvement project in adult intensive care units: overview of the Improving Medicine Through Pathway Assessment of Critical Therapy in Hospital-Acquired Pneumonia (IMPACT-HAP) study
Authors: Mangino Julie E , Peyrani Paula , Ford Kimbal D , Kett Daniel H , Zervos Marcus J , Welch Verna L , Scerpella Ernesto G , Ramirez Julio A ,   the IMPACT-HAP Study Group
Published: January 2011

Introduction

In 2005 the American Thoracic Society and Infectious Diseases Society of America (ATS/IDSA) published guidelines for managing hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and healthcare-associated pneumonia (HCAP). Although recommendations were evidence based, collective guidelines had not been validated in clinical practice and did not provide specific tools for local implementation. We initiated a performance improvement project designated Improving Medicine Through Pathway Assessment of Critical Therapy in Hospital-Acquired Pneumonia (IMPACT-HAP) at four academic centers in the United States. Our objectives were to develop and implement the project, and to assess compliance with quality indicators in adults admitted to intensive care units (ICUs) with HAP, VAP, or HCAP.

Methods

The project was conducted in three phases over 18 consecutive months beginning 1 February 2006: 1) a three-month planning period for literature review to create the consensus pathway for managing nosocomial pneumonia in these ICUs, a data collection form, quality performance indicators, and internet-based repository; 2) a six-month implementation period for customizing ATS/IDSA guidelines into center-specific guidelines via educational forums; and 3) a nine-month post-implementation period for continuing education and data collection. Data from the first two phases were combined (pre-implementation period) and compared with data from the post-implementation period.

Results

We developed a consensus pathway based on ATS/IDSA guidelines and customized it at the local level to accommodate formulary and microbiologic considerations. We implemented multimodal educational activities to teach ICU staff about the guidelines and continued education throughout post-implementation. We registered 432 patients (pre- vs post-implementation, 274 vs 158). Diagnostic criteria for nosocomial pneumonia were more likely to be met during post-implementation (247/257 (96.1%) vs 150/151 (99.3%); P = 0.06). Similarly, empiric antibiotics were more likely to be compliant with ATS/IDSA guidelines during post-implementation (79/257 (30.7%) vs 66/151 (43.7%); P = 0.01), an effect that was sustained over quarterly intervals (P = 0.0008). Between-period differences in compliance with obtaining cultures and use of de-escalation were not statistically significant.

Conclusions

Developing a multi-center performance improvement project to operationalize ATS/IDSA guidelines for HAP, VAP, and HCAP is feasible with local consensus pathway directives for implementation and with quality indicators for monitoring compliance with guidelines.
Polymorphism of the 5-HT transporter and response to
antidepressants: randomised controlled trial
Authors: Lewis Glyn , Mulligan Jean , Wiles Nicola , Cowen Philip , Craddock Nick , Ikeda Masashi , Grozeva Detelina , Mason Victoria , Nutt David , Sharp Deborah , Tallon Debbie , Thomas Laura , O'Donovan Michael C. , Peters Tim J.
Published: January 2011

Background

Antidepressants exhibit a variety of pharmacological actions including
inhibition of the serotonin and noradrenaline transporters. We wished to
investigate whether genetic variation could be used to target or
personalise treatment, in a comparison of selective serotonin reuptake
inhibitors (SSRIs) with noradrenaline reuptake inhibitors (NARIs).

Aims

To test the hypothesis that patients homozygous for the long (insertion)
polymorphism of the serotonin transporter (5-HTTLPR) have an increased
response to SSRI antidepressants but not to NARI antidepressants.

Method

In an individually randomised, parallel-group controlled trial, people
meeting criteria for a depressive episode who were referred by their
general practitioner were randomised to receive either citalopram (an
SSRI) or reboxetine (an NARI). Randomisation was by means of a remote
automated system accessed by telephone. The main outcome was depressive
symptoms, measured by Beck Depression Inventory (BDI) total score 6 weeks
after randomisation. The trial was registered with the International
Standard Randomised Controlled Trials Number registry
(ISRCTN31345163).

Results

Altogether 298 participants were randomised to receive citalopram and 303
were randomised to reboxetine. At 6 weeks follow-up, complete data were
available for 258 participants taking citalopram and 262 taking
reboxetine. We found no evidence to support an influence of 5-HTTLPR on
outcome following antidepressant treatment. The interaction term for BDI
score at 6 weeks was 0.50 (95% CI −2.04 to 3.03, P =
0.70), which indicated that responses to the SSRI and NARI were similar
irrespective of 5-HTTLPR genotype.

Conclusions

It is unlikely that the 5-HTTLPR polymorphism alone will be clinically
useful in predicting response to antidepressants in people with
depression.
Treatment of suicidal people around the world
Authors: Bruffaerts R. , Demyttenaere K. , Hwang I. , Chiu W.-T. , Sampson N. , Kessler R. C. , Alonso J. , Borges G. , de Girolamo G. , de Graaf R. , Florescu S. , Gureje O. , Hu C. , Karam E. G. , Kawakami N. , Kostyuchenko S. , Kovess-Masfety V. , Lee S. , Levinson D. , Matschinger H. , Posada-Villa J. , Sagar R. , Scott K. M. , Stein D. J. , Tomov T. , Viana M. C. , Nock M. K.
Published: January 2011

Background

Suicide is a leading cause of death worldwide; however, little
information is available about the treatment of suicidal people, or about
barriers to treatment.

Aims

To examine the receipt of mental health treatment and barriers to care
among suicidal people around the world.

Method

Twenty-one nationally representative samples worldwide
(n=55 302; age 18 years and over) from the World
Health Organization's World Mental Health Surveys were interviewed
regarding past-year suicidal behaviour and past-year healthcare use.
Suicidal respondents who had not used services in the past year were
asked why they had not sought care.

Results

Two-fifths of the suicidal respondents had received treatment (from 17%
in low-income countries to 56% in high-income countries), mostly from a
general medical practitioner (22%), psychiatrist (15%) or
non-psychiatrist (15%). Those who had actually attempted suicide were
more likely to receive care. Low perceived need was the most important
reason for not seeking help (58%), followed by attitudinal barriers such
as the wish to handle the problem alone (40%) and structural barriers
such as financial concerns (15%). Only 7% of respondents endorsed stigma
as a reason for not seeking treatment.

Conclusions

Most people with suicide ideation, plans and attempts receive no
treatment. This is a consistent and pervasive finding, especially in
low-income countries. Improving the receipt of treatment worldwide will
have to take into account culture-specific factors that may influence the
process of help-seeking.
Palliative Cancer Care: An Epidemiologic Study
Authors: Becker Gerhild , Hatami Isaak , Xander Carola , Dworschak-Flach Bettina , Olschewski Manfred , Momm Felix , Deibert Peter , Higginson Irene J. , Blum Hubert E.
Published: January 2011

Purpose

To analyze the need for palliative care in hospital patients who have cancer. Palliative care is an essential component of comprehensive cancer care and identification of palliative care needs (PCNs) of patients with cancer is a topic that has not been thoroughly studied.

Patients and Methods

Data were collected prospectively from inpatients of University Medical Center Freiburg in Freiburg, Germany, with 982 hospital beds included in the study. During the observation period of 17 months, each patient discharged from a hospital ward was screened by surveying the treating physician who was responsible for dismissal about patients' PCNs based on the WHO 1990 definition of palliative care. To complete obligatory electronic discharge management, a modified dismissal form asking to classify the patient as having PCN “yes/no” had to be filled out for each patient discharged.

Results

The response rate was 96% with data for 39,849 patients that could be analyzed. A total of 6.9% of all hospital patients and 9.1% of patients older than age 65 years were considered to have PCNs. Of the 2,757 patients with PCNs, 67% (n = 1,836) had cancer. Among the 11,584 patients with cancer, 15.8% were classified as having PCNs. PCNs were particularly high in patients with head and neck cancer (28.3%), malignant melanoma (26.0%), and brain tumors (18.2%). Suffering from cancer increases the probability of developing PCNs by a factor of 3.63 (95% CI, 3.27 to 4.04). For patients with metastatic cancer, the risk of developing PCNs is increased 12-fold (odds ratio, 12.27; 95% CI, 11.07 to 13.60).

Conclusion

Structures to provide palliative care for patients with cancer are needed.
Phase III Trial of Weekly Methotrexate or Pulsed Dactinomycin for Low-Risk Gestational Trophoblastic Neoplasia: A Gynecologic Oncology Group Study
Authors: Osborne Raymond J. , Filiaci Virginia , Schink Julian C. , Mannel Robert S. , Alvarez Secord Angeles , Kelley Joseph L. , Provencher Diane , Scott Miller David , Covens Allan L. , Lage Janice M.
Published: January 2011

Purpose

There is no consensus on the best regimen for the primary treatment of low-risk gestational trophoblastic neoplasia (GTN).

Patients and Methods

Two commonly used single-drug regimens were compared with respect to the proportion of patients meeting the criteria for a complete response (CR) in a randomized phase III trial conducted by the Gynecologic Oncology Group. Eligibility was purposefully broad to maximize the generalizability of the results and included patients with a WHO risk score of 0 to 6 and patients with metastatic disease (limited to lung lesions < 2 cm, adnexa, or vagina) or choriocarcinoma.

Results

Two hundred forty women were enrolled, and 216 were deemed eligible. Biweekly intravenous dactinomycin 1.25 mg/m2 was statistically superior to weekly intramuscular (IM) methotrexate 30 mg/m2 (CR: 70% v 53%; P = .01). Similarly, in patients with low-risk GTN as defined before the 2002 WHO risk score revisions (risk score of 0 to 4 and excluding choriocarcinoma), response was 58% and 73% in the methotrexate and dactinomycin arms, respectively (P = .03). Both regimens were less effective if the WHO risk score was 5 or 6 or if the diagnosis was choriocarcinoma (CR: 9% and 42%, respectively). There were two potential recurrences; one at 4 months (dactinomycin) and one at 22 months (methotrexate). Not all patients completed follow-up. Both regimens were well tolerated.

Conclusion

The biweekly dactinomycin regimen has a higher CR rate than the weekly IM methotrexate regimen in low-risk GTN, a generally curable disease.
High Survival Rate After Two-Stage Resection of Advanced Colorectal Liver Metastases: Response-Based Selection and Complete Resection Define Outcome
Authors: Brouquet Antoine , Abdalla Eddie K. , Kopetz Scott , Garrett Christopher R. , Overman Michael J. , Eng Cathy , Andreou Andreas , Loyer Evelyne M. , Madoff David C. , Curley Steven A. , Vauthey Jean-Nicolas
Published: January 2011

Purpose

Prolonged survival after two-stage resection (TSR) of advanced colorectal liver metastases (CLM) may be the result of selection of best responders to chemotherapy. The impact of complete resection in this well-selected group is controversial.

Patients and Methods

Data on 890 patients undergoing resection and 879 patients who received only chemotherapy for CLM were collected prospectively. We used intent-to-treat analysis to evaluate the survival of patients who underwent TSR. Additionally, we evaluated a cohort of nonsurgically treated patients selected to mirror the TSR population: colorectal metastases with liver-only disease, objective response to chemotherapy, and alive 1 year after chemotherapy initiation.

Results

Sixty-five patients underwent the first stage of TSR; 62 patients fulfilled the inclusion criteria for the medical group. TSR patients had a mean of 6.7 ± 3.4 CLM with mean size of 4.5 ± 3.1 cm. Nonsurgical patients had a mean of 5.9 ± 2.9 CLM with mean size of 5.4 ± 3.4 cm (not significant). Forty-seven TSR patients (72%) completed the second stage. Progression between stages was the main cause of noncompletion of the second stage (61%). After 50 months median follow-up, the 5-year survival rate was 51% in the TSR group and 15% in the medical group (P = .005). In patients who underwent TSR, noncompletion of TSR and major postoperative complications were independently associated with worse survival.

Conclusion

TSR is associated with excellent outcome in patients with advanced CLM as a result of both selection by chemotherapy and complete resection of metastatic disease.
Clinical Evidence for Predominance of Delta-5 Steroid Production in Women with Polycystic Ovary Syndrome
Authors: Rosencrantz Marcus A. , Coffler Mickey S. , Haggan Annette , Duke Kimberly B. , Donohue Michael C. , Shayya Rana F. , Su H. Irene , Chang R. Jeffrey
Published: January 2011

Context:

In women with polycystic ovary syndrome (PCOS), the basis for ovarian androgen overproduction involves an overall increase of steroidogenesis, notably in the delta-4 pathway. However, in vitro studies have suggested that excessive androgen production occurs predominantly through the delta-5 pathway.

Objective:

This study was performed to assess androgen dose-responses after human chorionic gonadotropin (hCG) stimulation in PCOS and normal women.

Design:

We conducted a prospective study to compare androgen production after iv hCG in PCOS and normal women.

Setting:

The study was conducted in a General Clinical Research Center in an academic medical center.

Participants:

Women with PCOS (age, 18–37 yr; n = 10) and normal ovulatory controls (age, 18–37 yr; n = 11) were recruited.

Interventions:

For dose-response studies, blood samples were obtained before and at 0.5, 24, and 48 h after iv recombinant hCG (1, 10, 25, 100, and 250 μg). A subset of subjects underwent frequent blood sampling over 24 h after iv injection of 25 μg of recombinant hCG.

Main Outcome Measure(s):

We measured basal and stimulated serum 17-hydroxyprogesterone (17-OHP), androstenedione (A), testosterone (T), dehydroepiandrosterone, estradiol, and progesterone responses after hCG administration.

Results:

In PCOS women, maximal A and T production was observed at the lowest doses of hCG, whereas responses were minimal in normal women. Incremental responses of 17-OHP, estradiol, and progesterone were greater in PCOS compared to normal women.

Conclusion:

In PCOS women, maximal A and T responses to hCG relative to those of 17-OHP are consistent with ovarian androgen overproduction via the delta-5 pathway.
Insufficient Activation of Autophagy Allows Cellular Damage to Accumulate in Critically Ill Patients
Authors: Vanhorebeek Ilse , Gunst Jan , Derde Sarah , Derese Inge , Boussemaere Magaly , Güiza Fabian , Martinet Wim , Timmermans Jean-Pierre , D'Hoore André , Wouters Pieter J. , Van den Berghe Greet
Published: January 2011

Context:

Responses to critical illness, such as excessive inflammation and hyperglycemia, may trigger detrimental chain reactions that damage cellular proteins and organelles. Such responses to illness contribute to the risk of (nonresolving) multiple organ dysfunction and adverse outcome.

Objective:

We studied autophagy as a bulk degradation pathway able to remove toxic protein aggregates and damaged organelles and how these are affected by preventing hyperglycemia with insulin during critical illness.

Design and Setting:

Patients participated in a randomized study, conducted at a university hospital surgical/medical intensive care unit.

Patients:

We studied adult prolonged critically ill patients vs. controls.

Interventions:

Tolerating excessive hyperglycemia was compared with intensive insulin therapy targeting normoglycemia.

Main Outcome Measures:

We quantified (ultra)structural abnormalities and hepatic and skeletal muscle protein levels of key players in autophagy.

Results:

Morphologically, both liver and muscle revealed an autophagy-deficiency phenotype. Proteins involved in initiation and elongation steps of autophagy were induced 1.3- to 6.5-fold by critical illness (P ≤ 0.01), but mature autophagic vacuole formation was 62% impaired (P = 0.05) and proteins normally degraded by autophagy accumulated up to 97-fold (P ≤ 0.03). Mitophagy markers were unaltered or down-regulated (P = 0.05). Although insulin preserved hepatocytic mitochondrial integrity (P = 0.05), it further reduced the number of autophagic vacuoles by 80% (P = 0.05).

Conclusions:

Insufficient autophagy in prolonged critical illness may cause inadequate removal of damaged proteins and mitochondria. Such incomplete clearance of cellular damage, inflicted by illness and aggravated by hyperglycemia, could explain lack of recovery from organ failure in prolonged critically ill patients. These data open perspectives for therapies that activate autophagy during critical illness.
Role of IGF signaling in catch-up growth and accelerated temporal development in zebrafish embryos in response to oxygen availability
Authors: Kamei Hiroyasu , Ding Yonghe , Kajimura Shingo , Wells Michael , Chiang Peter , Duan Cunming
Published: January 2011

Animals respond to adverse environments by slowing down or arresting growth and development. Upon returning to normal conditions, they often show compensatory acceleration in growth and developmental rate. This phenomenon, known as `catch-up' growth, is widely documented in the animal kingdom. The underlying molecular mechanisms, however, are poorly understood. Using the zebrafish embryo as an experimental model system, we tested the hypothesis that changes in IGF signaling activities play an important role in the accelerated growth and temporal development resulting from re-oxygenation following hypoxia. We show that chronic hypoxia reduced, and re-oxygenation accelerated, embryonic growth and developmental rate. Whereas hypoxia repressed the Igf1 receptor and its downstream Erk1/2 and Akt signaling activities, re-oxygenation restored their activities. Specific inhibition of Igf1 receptor signaling during re-oxygenation by genetic and pharmacological approaches attenuated catch-up growth. Further analysis showed that whereas PI3K-Akt is required in both normal and catch-up growth, Mek1/2-Erk1/2 activation induced by elevated IGF signaling during re-oxygenation is particularly crucial for catch-up growth. These results suggest that the evolutionarily conserved IGF signaling pathway coordinates growth and temporal development in zebrafish embryos in response to oxygen availability.
Brassinosteroids control meristem size by promoting cell cycle progression in Arabidopsis roots
Authors: González-García Mary-Paz , Vilarrasa-Blasi Josep , Zhiponova Miroslava , Divol Fanchon , Mora-García Santiago , Russinova Eugenia , Caño-Delgado Ana I.
Published: January 2011

Brassinosteroids (BRs) play crucial roles in plant growth and development. Previous studies have shown that BRs promote cell elongation in vegetative organs in several plant species, but their contribution to meristem homeostasis remains unexplored. Our analyses report that both loss- and gain-of-function BR-related mutants in Arabidopsis thaliana have reduced meristem size, indicating that balanced BR signalling is needed for the optimal root growth. In the BR-insensitive bri1-116 mutant, the expression pattern of the cell division markers CYCB1;1, ICK2/KRP2 and KNOLLE revealed that a decreased mitotic activity accounts for the reduced meristem size; accordingly, this defect could be overcome by the overexpression of CYCD3;1. The activity of the quiescent centre (QC) was low in the short roots of bri1-116, as reported by cell type-specific markers and differentiation phenotypes of distal stem cells. Conversely, plants treated with the most active BR, brassinolide, or mutants with enhanced BR signalling, such as bes1-D, show a premature cell cycle exit that results in early differentiation of meristematic cells, which also negatively influence meristem size and overall root growth. In the stem cell niche, BRs promote the QC renewal and differentiation of distal stem cells. Together, our results provide evidence that BRs play a regulatory role in the control of cell-cycle progression and differentiation in the Arabidopsis root meristem.
Disruption of reelin signaling alters mammary gland morphogenesis
Authors: Khialeeva Elvira , Lane Timothy F. , Carpenter Ellen M.
Published: January 2011

Reelin signaling is required for appropriate cell migration and ductal patterning during mammary gland morphogenesis. Dab1, an intracellular adaptor protein activated in response to reelin signaling, is expressed in the developing mammary bud and in luminal epithelial cells in the adult gland. Reelin protein is expressed in a complementary pattern, first in the epithelium overlying the mammary bud during embryogenesis and then in the myoepithelium and periductal stroma in the adult. Deletion in mouse of either reelin or Dab1 induced alterations in the development of the ductal network, including significant retardation in ductal elongation, decreased terminal branching, and thickening and disorganization of the luminal wall. At later stages, some mutant glands overcame these early delays, but went on to exhibit enlarged and chaotic ductal morphologies and decreased terminal branching: these phenotypes are suggestive of a role for reelin in spatial patterning or structural organization of the mammary epithelium. Isolated mammary epithelial cells exhibited decreased migration in response to exogenous reelin in vitro, a response that required Dab1. These observations highlight a role for reelin signaling in the directed migration of mammary epithelial cells driving ductal elongation into the mammary fat pad and provide the first evidence that reelin signaling may be crucial for regulating the migration and organization of non-neural tissues.