bluuebunny/crossref_metadata_2025 huggingface dataset:
A narrative synthesis of the impact of primary health care delivery models for refugees in resettlement countries on access, quality and coordination
Authors: Joshi Chandni , Russell Grant , Cheng I-Hao , Kay Margaret , Pottie Kevin , Alston Margaret , Smith Mitchell , Chan Bibiana , Vasi Shiva , Lo Winston , Wahidi Sayed Shukrullah , Harris Mark F
Published: November 2013

Introduction

Refugees have many complex health care needs which should be addressed by the primary health care services, both on their arrival in resettlement countries and in their transition to long-term care. The aim of this narrative synthesis is to identify the components of primary health care service delivery models for such populations which have been effective in improving access, quality and coordination of care.

Methods

A systematic review of the literature, including published systematic reviews, was undertaken. Studies between 1990 and 2011 were identified by searching Medline, CINAHL, EMBASE, Cochrane Library, Scopus, Australian Public Affairs Information Service – Health, Health and Society Database, Multicultural Australian and Immigration Studies and Google Scholar. A limited snowballing search of the reference lists of all included studies was also undertaken. A stakeholder advisory committee and international advisers provided papers from grey literature. Only English language studies of evaluated primary health care models of care for refugees in developed countries of resettlement were included.

Results

Twenty-five studies met the inclusion criteria for this review of which 15 were Australian and 10 overseas models. These could be categorised into six themes: service context, clinical model, workforce capacity, cost to clients, health and non-health services. Access was improved by multidisciplinary staff, use of interpreters and bilingual staff, no-cost or low-cost services, outreach services, free transport to and from appointments, longer clinic opening hours, patient advocacy, and use of gender-concordant providers. These services were affordable, appropriate and acceptable to the target groups. Coordination between the different health care services and services responding to the social needs of clients was improved through case management by specialist workers. Quality of care was improved by training in cultural sensitivity and appropriate use of interpreters.

Conclusion

The elements of models most frequently associated with improved access, coordination and quality of care were case management, use of specialist refugee health workers, interpreters and bilingual staff. These findings have implications for workforce planning and training.
Fixed and periodic points of generalized contractions in metric spaces
Authors: Abbas Mujahid , Ali Basit , Romaguera Salvador
Published: November 2013

Wardowski (Fixed Point Theory Appl. 2012:94, 2012, doi:10.1186/1687-1812-2012-94) introduced a new type of contraction called F-contraction and proved a fixed point result in complete metric spaces, which in turn generalizes the Banach contraction principle. The aim of this paper is to introduce F-contractions with respect to a self-mapping on a metric space and to obtain common fixed point results. Examples are provided to support results and concepts presented herein. As an application of our results, periodic point results for the F-contractions in metric spaces are proved.

MSC:47H10, 47H07, 54H25.
Existence and multiplicity of solutions for second-order impulsive differential equations on the half-line
Authors: Yan Lizhao , Liu Jian , Luo Zhiguo
Published: November 2013

In this paper, we use variational methods to investigate the solutions of impulsive differential equations on the half-line. The conditions for the existence and multiplicity of solutions are established. The main results are also demonstrated with examples.
Effects of tai chi program on neuromuscular function for patients with knee osteoarthritis: study protocol for a randomized controlled trial
Authors: Wang Xue-Qiang , Huang Ling-Yan , Liu Yu , Li Jing-Xian , Wu Xie , Li Hai-Peng , Wang Lin
Published: November 2013

Background

Knee osteoarthritis (OA) is a major cause of disability as well as a burden on healthcare resources. Tai chi has been proposed as an alternative and complementary treatment for the management of knee osteoarthritis, but there appears to be no consensus on its usefulness. This study aims to develop an innovative tai chi rehabilitation program (ITCRP) for patients with knee OA, and to investigate the effect of ITCRP intervention on a range of outcomes including pain, function, balance, neuromuscular response, and biomechanics in knee OA.

Methods/Design

We will conduct a prospective, single-blind, randomized controlled trial of 140 individuals with symptomatic knee OA. Patients will be randomly assigned into either an ITCRP group or a control group. The ITCRP group will participate in tai chi two or three times a week for 6 months. The control group will receive health education. After the 6-month intervention period, there will be a 6-month follow-up period with no active intervention in either group. The primary and secondary outcomes will be assessed at baseline, 6 months, and 12 months. Primary outcome measures will be a visual analog scale for pain, the Western Ontario and McMaster Universities Osteoarthritis Index,and the Lequesne Knee Score. The secondary outcome measures will include the Berg balance scale, knee and ankle proprioception, neuromuscular response, and 3D functional biomechanics. Furthermore, adverse events will be recorded and analyzed. If any participants withdraw from the trial, intention-to-treat analysiswill be performed.

Discussion

Important features of this trial include the randomization procedures, large sample size, and a standardized protocol for ITCRP for knee OA. This study aims to determine the feasibility of ITCRP for knee OA and provide data on the effects of ITCRP. Hence, our results will be useful for patients with knee OA as well as for medical staff and healthcare decision makers.

Trial registration

Chinese Clinical Trial Registry:ChiCTR-TRC-13003264.
Long-term effects on carotid intima-media thickness after radiotherapy in patients with nasopharyngeal carcinoma
Authors: Huang Tai Lin , Hsu Hsuan Chih , Chen Hui Chun , Lin Hsin Ching , Chien Chih Yen , Fang Fu Min , Huang Chih Cheng , Chang Hsueh Wen , Chang Wen Neng , Huang Chi Ren , Tsai Nai Wen , Kung Chia Te , Wang Hung Chen , Lin Wei Che , Cheng Ben Chung , Su Yu Jih , Chang Ya Ting , Chang Chuang Rung , Tan Teng Yeow , Lu Cheng Hsien
Published: November 2013

Background

Vascular abnormalities are the predominant histologic changes associated with radiation in nasopharyngeal carcinoma (NPC). This study examined if the duration after radiotherapy correlates with the progression of carotid intima-media thickness (IMT) and investigated its relationship with inflammatory markers.

Methods

One hundred and five NPC patients post-radiotherapy for more than one year and 25 healthy control subjects were examined by B-mode ultrasound for IMT measurement at the far wall of the common carotid artery (CCA). Surrogate markers including lipid profile, HbA1c, and high sensitive C-reactive protein (hs-CRP) were assessed.

Results

The IMT of CCA was significantly increased in NPC patients and carotid plaque was detected in 38 NPC patients (38/105, 36.2%). Significant risk factors for carotid plaques included age, duration after radiotherapy, and HbA1c levels. Age, duration after radiotherapy, hs-CRP, HbA1c, and platelet count positively correlated with IMT. The cut-off value of age and duration after radiotherapy for the presence of plaque was 52.5 years and 42.5 months, respectively. In NPC subjects, multiple linear regression analysis revealed that age, gender, duration after radiotherapy and platelet counts were independently associated with CCA IMT. After adjustments for age, gender and platelet counts, IMT increased in a linear manner with duration after radiotherapy.

Conclusions

Radiation-induced vasculopathy is a dynamic and progressive process due to late radiation effects. Extra-cranial color-coded duplex sonography can be part of routine follow-up in NPC patients aged ≥50 years at 40 months post-radiotherapy.
Transcription factors and genetic circuits orchestrating the complex, multilayered response of Clostridium acetobutylicum to butanol and butyrate stress
Authors: Wang Qinghua , Venkataramanan Keerthi Prasad , Huang Hongzhan , Papoutsakis Eleftherios T , Wu Cathy H
Published: November 2013

Background

Organisms of the genusClostridiumare Gram-positive endospore formers of great importance to the carbon cycle, human normo- and pathophysiology, but also in biofuel and biorefinery applications. Exposure ofClostridiumorganisms to chemical and in particular toxic metabolite stress is ubiquitous in both natural (such as in the human microbiome) and engineered environments, engaging both the general stress response as well as specialized programs. Yet, despite its fundamental and applied significance, it remains largely unexplored at the systems level.

Results

We generated a total of 96 individual sets of microarray data examining the transcriptional changes inC. acetobutylicum,a modelClostridiumorganism,in response to three levels of chemical stress from the native metabolites, butanol and butyrate. We identified 164 significantly differentially expressed transcriptional regulators and detailed the cellular programs associated with general and stressor-specific responses, many previously unexplored. Pattern-based, comparative genomic analyses enabled us, for the first time, to construct a detailed picture of the genetic circuitry underlying the stress response. Notably, a list of the regulons and DNA binding motifs of the stress-related transcription factors were identified: two heat-shock response regulators, HrcA and CtsR; the SOS response regulator LexA; the redox sensor Rex; and the peroxide sensor PerR. Moreover, several transcriptional regulators controlling stress-responsive amino acid and purine metabolism and their regulons were also identified, including ArgR (arginine biosynthesis and catabolism regulator), HisR (histidine biosynthesis regulator), CymR (cysteine metabolism repressor) and PurR (purine metabolism repressor).

Conclusions

Using an exceptionally large set of temporal transcriptional data and regulon analyses, we successfully built a STRING-based stress response network model integrating important players for the general and specialized metabolite stress response inC. acetobutylicum. Since the majority of the transcription factors and their target genes are highly conserved in other organisms of theClostridiumgenus, this network would be largely applicable to otherClostridiumorganisms. The network informs the molecular basis ofClostridiumresponses to toxic metabolites in natural ecosystems and the microbiome, and will facilitate the construction of genome-scale models with added regulatory-network dimensions to guide the development of tolerant strains.
Pulmonary nodular amyloidosis in a patient undergoing lobectomy: a case report
Authors: Liu Min , Wei Sen , Li Xin , Liu Hongyu , Zhou Qinghua , Chen Jun
Published: November 2013

Introduction

Pulmonary amyloidosis is rare and is often misdiagnosed due a lack of general awareness.

Case presentation

In this case report we describe a 69-year-old Chinese woman who presented with a right lower lobe pulmonary nodule. After video-assisted thoracoscopic lobectomy, a histopathologic diagnosis of pulmonary nodular amyloidosis was rendered. She has done well postoperatively, showing no local recurrence or distal disease in an 8-month follow-up period.

Conclusions

Distinguishing parenchymal nodular amyloidosis from a malignant lung tumor is often quite difficult. In the differential diagnosis of pulmonary nodules, nodular amyloidosis should be considered to avoid unnecessary lobectomy.
Extramammary Paget’s disease affecting the external auditory canal: a case report
Authors: Bomfim Francisco de Assis Castro , Mendes Walber de Oliveira , Veras Igor Moreira , de Freitas Jônatas Catunda , Castro Ana Maria da Silva , de Castro Francisco Monteiro
Published: November 2013

Introduction

Extramammary Paget’s disease is a rare histological type of intraepithelial adenocarcinoma that mainly affects apocrine sweat gland-rich areas. Predilection sites include the anogenital region and, less commonly, the axillae. These tumors rarely occur in non-apocrine regions. The aim of this case report is to describe a case of extramammary Paget’s disease in the external auditory canal with extensive temporal bone involvement and skull base invasion.

Case presentation

A 40-year-old Caucasian man presented with a progressively growing, vegetating lesion localized in his right-hand external auditory canal. He had peripheral facial nerve paralysis and complete ipsilateral hearing loss. An incisional biopsy suggested extramammary Paget’s disease, and the immunohistochemical analysis confirmed the diagnosis. The tumor was considered inoperable because of the extensive skull base involvement, and he was referred for palliative radiotherapy.

Conclusion

We report here the third case of extramammary Paget’s disease affecting the external auditory canal to be described in the literature. In all the three cases, the prognosis was unfavorable despite treatment.
Utility of magnetic resonance imaging in the diagnosis of unsuspected cases of Parsonage-Turner syndrome: two case reports
Authors: Kumar Ishan , Verma Ashish , Srivastava Arvind , Shukla Ram C
Published: November 2013

Introduction

MRI is becoming increasingly important in the evaluation of shoulder pain, especially in the diagnosis of rotator cuff injuries and conditions that mimic them. Parsonage-Turner syndrome is a well-defined clinical entity that presents with acute-onset shoulder pain and weakness, often first recognized on magnetic resonance imaging scans.

Case presentation

We studied magnetic resonance imaging features of two Asian men (ages 24 and 31 years) who presented with variable-onset shoulder pain and weakness. Magnetic resonance imaging revealed increased T2-weighted signal intensity of supraspinatus and infraspinatus muscles in both patients.

Conclusion

Magnetic resonance imaging findings are distinctive, although nonspecific, in cases of Parsonage-Turner syndrome, and knowledge of the imaging and clinical features of this disease enable clinicians to arrive at the correct diagnosis and guide appropriate management.
Mechanical thrombectomy – an alternative treatment option in a patient with acute ischemic stroke and multiple contraindications for systemic thrombolysis: a case report
Authors: Sczesni Katrin Christina , Wiebringhaus Reinhard , Heuser Lothar , Skodda Sabine , Eyding Jens
Published: November 2013

Introduction

Acute ischemic stroke is a common cause of disability and death in developed countries. Standard therapy for patients who present within 4.5 hours from the onset of symptoms is intravenous thrombolysis if contraindications such as oral anticoagulation, cancer or recent surgery are ruled out. Apart from that, mechanical recanalization is a new treatment option for patients with occlusion of major cerebral arteries as a cause of ischemic stroke.

Case presentation

In this case report we describe a 55-year-old Caucasian man with a right hemispheric ischemic syndrome who presented in time but who had multiple contraindications against systemic thrombolysis. He was then treated with mechanical recanalization and recovered. On discharge from the hospital he had only a slight left-sided facial paresis and discrete impairment of motion smoothness in his left hand.

Conclusion

We conclude that multimodal imaging should be performed in all patients with an acute onset of neurological symptoms suspicious of ischemic stroke, even if they have contraindications against an intravenous thrombolytic treatment.
Sex chromosome complement regulates expression of mood-related genes
Authors: Seney Marianne L , Ekong Kokomma I , Ding Ying , Tseng George C , Sibille Etienne
Published: November 2013

Background

Studies on major depressive and anxiety disorders suggest dysfunctions in brain corticolimbic circuits, including altered gamma-aminobutyric acid (GABA) and modulatory (serotonin and dopamine) neurotransmission. Interestingly, sexual dimorphisms in GABA, serotonin, and dopamine systems are also reported. Understanding the mechanisms behind these sexual dimorphisms may help unravel the biological bases of the heightened female vulnerability to mood disorders. Here, we investigate the contribution of sex-related factors (sex chromosome complement, developmental gonadal sex, or adult circulating hormones) to frontal cortex expression of selected GABA-, serotonin-, and dopamine-related genes.

Methods

As gonadal sex is determined by sex chromosome complement, the role of sex chromosomes cannot be investigated individually in humans. Therefore, we used the Four Core Genotypes (FCG) mouse model, in which sex chromosome complement and gonadal sex are artificially decoupled, to examine the expression of 13 GABA-related genes, 6 serotonin- and dopamine-related genes, and 8 associated signal transduction genes under chronic stress conditions. Results were analyzed by three-way ANOVA (sex chromosome complement × gonadal sex × circulating testosterone). A global perspective of gene expression changes was provided by heatmap representation and gene co-expression networks to identify patterns of transcriptional activities related to each main factor.

Results

We show that under chronic stress conditions, sex chromosome complement influenced GABA/serotonin/dopamine-related gene expression in the frontal cortex, with XY mice consistently having lower gene expression compared to XX mice. Gonadal sex and circulating testosterone exhibited less pronounced, more complex, and variable control over gene expression. Across factors, male conditions were associated with a tightly co-expressed set of signal transduction genes.

Conclusions

Under chronic stress conditions, sex-related factors differentially influence expression of genes linked to mood regulation in the frontal cortex. The main factor influencing expression of GABA-, serotonin-, and dopamine-related genes was sex chromosome complement, with an unexpected pro-disease effect in XY mice relative to XX mice. This effect was partially opposed by gonadal sex and circulating testosterone, although all three factors influenced signal transduction pathways in males. Since GABA, serotonin, and dopamine changes are also observed in other psychiatric and neurodegenerative disorders, these findings have broader implications for the understanding of sexual dimorphism in adult psychopathology.
Are temporary work agencies stepping stones into regular employment?
Authors: Hveem Joakim
Published: November 2013

This paper estimates the causal effect of temporary work agency (TWA) employment on the subsequent probability of employment in the regular labor market. The main purpose is to estimate the stepping-stone effect separately for natives and immigrants, where the latter group potentially benefits the most from TWA employment. Since no quasi-experiment is available, individual Differences-in-Differences and matching is used to deal with the potential selection bias. The results point at a negative regular employment effect, which slowly fades away over a couple of years. Thus no evidence of a stepping-stone effect is found. When conditioning on immigrants, this negative effect is absent. A long-run significant effect is found on overall employment probability (including TWA employment), there is even a long-run positive effect on annual earnings (mainly driven by women). Unemployment probabilities decreased, however the results in the estimation were less stable over time compared to the employment estimates, suggesting that the TWAs might keep individuals from exiting the labor market.
Calmodulin levels in blood cells as a potential biomarker of Alzheimer’s disease
Authors: Esteras Noemí , Alquézar Carolina , de la Encarnación Ana , Villarejo Alberto , Bermejo-Pareja Félix , Martín-Requero Ángeles
Published: November 2013

Introduction

The clinical features of Alzheimer’s disease (AD) overlap with a number of other dementias and conclusive diagnosis is only achieved at autopsy. Accurate in-life diagnosis requires finding biomarkers suitable for early diagnosis, as well as for discrimination from other types of dementia. Mounting evidence suggests that AD-dependent processes may also affect peripheral cells. We previously reported that calmodulin (CaM) signaling is impaired in AD lymphoblasts. Here, we address the issue as to whether the assessment of CaM levels in peripheral cells could serve as a diagnostic biomarker.

Methods

A total of 165 subjects were enrolled in the study, including 56 AD patients, 15 patients with mild cognitive impairment, 7 with frontotemporal dementia associated with progranulin mutations, 4 with dementia with Lewy bodies, 20 patients with Parkinson’s disease, 10 with amyotrophic lateral sclerosis, 5 with progressive supranuclear palsy, and 48 cognitively normal individuals. CaM levels were then analyzed in lymphoblasts, peripheral blood mononuclear cells and plasma. Receiver operating characteristic (ROC) curve analyses were employed to evaluate the diagnostic performance of CaM content in identifying AD patients.

Results

Compared with control individuals, CaM levels were significantly increased in AD cells, but not in the other neurodegenerative disorders. CaM levels differentiated AD from control with a sensitivity of 0.89 and a specificity of 0.82 and were not dependent on disease severity or age. MCI patients also showed higher levels of the protein.

Conclusions

CaM levels could be considered a peripheral biomarker for AD in its early stage and help to discriminate from other types of dementia.
Differences in synovial fluid cytokine levels but not in synovial tissue cell infiltrate between anti-citrullinated peptide/protein antibody-positive and –negative rheumatoid arthritis patients
Authors: Gómez-Puerta José A , Celis Raquel , Hernández M Victoria , Ruiz-Esquide Virginia , Ramírez Julio , Haro Isabel , Cañete Juan D , Sanmartí Raimon
Published: November 2013

Introduction

Comparative data on synovial cell infiltrate and cytokine levels in anti citrullinated peptide/protein antibody (ACPA)-positive and ACPA negative rheumatoid arthritis (RA) patients are scarce. Our aim was to analyze synovial cell infiltrate and synovial fluid (SF) levels of cytokines in patients with RA according to the presence or absence of ACPA in serum.

Methods

A cross-sectional study in a single center including consecutive RA patients was performed. Patients were defined as 'ACPA negative' if serum was negative to two different ACPAs [second generation commercial anti-cyclic citrullinated peptide antibodies (CCP2) and chimeric fibrin/filaggrin citrullinated antibodies]. Parallel synovial tissue (ST) biopsies and SF were obtained by knee arthroscopy. Synovial cell infiltrate and endothelial cells were analyzed by immunohistochemistry and SF levels of Th1, Th2, Th17 and pro-inflammatory cytokines by Quantibody(R) Human Array.

Results

A total of 83 patients underwent arthroscopy, with a mean age of 55.9 ± 12 years, and mean disease duration of 45 months (interquartile range, IQR 10.8 to 122). 62% were female and 77% were ACPA positive. No significant differences were found in clinical variables, acute phase reactants, synovial cell infiltrate or lymphoid neogenesis (LN) between ACPA positive and negative patients. However ACPA positive patients had significantly higher levels of IL-1β, IL-10, IL-17 F and CC chemokine ligand 20 (CCL-20) than ACPA negative patients.

Conclusions

In our cohort of patients with RA no significant differences were found in synovial cell infiltrate or synovial LN according to ACPA status. However, ACPA positive patients had higher levels of T-cell derived and pro-inflammatory cytokines than ACPA negative patients. As systemic and local inflammation was similar in the two groups, these findings support a distinct synovial physiopathology.
Natural killer cells and natural killer T cells in Lyme arthritis
Authors: Katchar Kia , Drouin Elise E , Steere Allen C
Published: November 2013

Introduction

Natural killer (NK) and natural killer T (NKT) cells provide a first line of defense against infection. However, these cells have not yet been examined in patients with Lyme arthritis, a late disease manifestation. Lyme arthritis usually resolves with antibiotic treatment. However, some patients have persistent arthritis after spirochetal killing, which may result from excessive inflammation, immune dysregulation and infection-induced autoimmunity.

Methods

We determined the frequencies and phenotypes of NK cells and invariant NKT (iNKT) cells in paired peripheral blood (PB) and synovial fluid (SF) samples from eight patients with antibiotic-responsive arthritis and fifteen patients with antibiotic-refractory arthritis using flow cytometry and cytokine analyses.

Results

In antibiotic-responsive patients, who were seen during active infection, high frequencies of CD56bright NK cells were found in SF, the inflammatory site, compared with PB (P <0.001); at both sites, a high percentage of cells expressed the activation receptor NKG2D and the chaperone CD94, a low percentage expressed inhibitory killer immunoglobulin-like receptors (KIR), and a high percentage produced IFN-γ. In antibiotic-refractory patients, who were usually evaluated near the conclusion of antibiotics when few if any live spirochetes remained, the phenotype of CD56bright cells in SF was similar to that in patients with antibiotic-responsive arthritis, but the frequency of these cells was significantly less (P = 0.05), and the frequencies of CD56dim NK cells tended to be higher. However, unlike typical NKdim cells, these cells produced large amounts of IFN-γ, suggesting that they were not serving a cytotoxic function. Lastly, iNKT cell frequencies in the SF of antibiotic-responsive patients were significantly greater compared with that of antibiotic-refractory patients where these cells were often absent (P = 0.003).

Conclusions

In patients with antibiotic-responsive arthritis, the high percentage of activated, IFN-γ-producing CD56bright NK cells in SF and the presence of iNKT cells suggest that these cells still have a role in spirochetal killing late in the illness. In patients with antibiotic-refractory arthritis, the frequencies of IFN-γ-producing CD56bright and CD56dim NK cells remained high in SF, even after spirochetal killing, suggesting that these cells contribute to excessive inflammation and immune dysregulation in joints, and iNKT cells, which may have immunomodulatory effects, were often absent.
Transforming growth factor-β signalling controls human breast cancer metastasis in a zebrafish xenograft model
Authors: Drabsch Yvette , He Shuning , Zhang Long , Snaar-Jagalska B Ewa , ten Dijke Peter
Published: November 2013

Introduction

The transforming growth factor beta (TGF-β) signalling pathway is known to control human breast cancer invasion and metastasis. We demonstrate that the zebrafish xenograft assay is a robust and dependable animal model for examining the role of pharmacological modulators and genetic perturbation of TGF-β signalling in human breast tumour cells.

Methods

We injected cancer cells into the embryonic circulation (duct of cuvier) and examined their invasion and metastasis into the avascular collagenous tail. Various aspects of the TGF-β signalling pathway were blocked by chemical inhibition, small interfering RNA (siRNA), or small hairpin RNA (shRNA). Analysis was conducted using fluorescent microscopy.

Results

Breast cancer cells with different levels of malignancy, according to in vitro and in vivo mouse studies, demonstrated invasive and metastatic properties within the embryonic zebrafish model that nicely correlated with their differential tumourigenicity in mouse models. Interestingly, MCF10A M2 and M4 cells invaded into the caudal hematopoietic tissue and were visible as a cluster of cells, whereas MDA MB 231 cells invaded into the tail fin and were visible as individual cells. Pharmacological inhibition with TGF-β receptor kinase inhibitors or tumour specific Smad4 knockdown disturbed invasion and metastasis in the zebrafish xenograft model and closely mimicked the results we obtained with these cells in a mouse metastasis model. Inhibition of matrix metallo proteinases, which are induced by TGF-β in breast cancer cells, blocked invasion and metastasis of breast cancer cells.

Conclusions

The zebrafish-embryonic breast cancer xenograft model is applicable for the mechanistic understanding, screening and development of anti-TGF-β drugs for the treatment of metastatic breast cancer in a timely and cost-effective manner.
Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy
Authors: Fugate Jennifer E , Kalimullah Ejaaz A , Hocker Sara E , Clark Sarah L , Wijdicks Eelco FM , Rabinstein Alejandro A
Published: November 2013

Introduction

Cefepime, a broad spectrum antibiotic, is commonly prescribed in intensive care units (ICU) and may be an overlooked cause of neurologic symptoms such as encephalopathy, myoclonus, seizures, and coma. We aimed to characterize cefepime neurotoxicity in the ICU.

Methods

We performed a retrospective study of adult ICU patients treated with intravenous cefepime for at least 3 days between January 1, 2009 and December 31, 2011. The primary outcome was the development of cefepime neurotoxicity, with the likelihood of causality ascribed via a modified Delphi method.

Results

This study included 100 patients. The mean age was 65.8 years (± 12.7 years). The median daily average dose of cefepime was 2.5 (IQR 2.0 to 3.5) grams. The median treatment duration was 6 (IQR 4 to 10) days. Renal failure in any form was present in 84 patients. Chronic kidney disease affected 40 patients, and 77 had acute kidney injury. Cefepime neurotoxicity occurred in 15 patients. Of these, seven were considered definite cases, three probable, and five possible. Neurotoxic symptoms included impaired consciousness (n = 13), myoclonus (n = 11), disorientation (n = 6), and nonconvulsive status epilepticus (n = 1). The dose of cefepime was appropriately adjusted for renal clearance in 64 patients (75.3%) without cefepime neurotoxicity and four patients (28.6%) with neurotoxicity (P = 0.001). Chronic kidney disease was present in 30 patients (35.3%) without neurotoxicity and in 10 (66.7%) of those with neurotoxicity (P = 0.04).

Conclusions

Critically ill patients with chronic kidney disease are particularly susceptible to cefepime neurotoxicity. Myoclonus and impaired consciousness are the predominant clinical manifestations. Neurotoxic symptoms occur more often when the cefepime dose is not adjusted for renal function, but can still occur despite those modifications.
Initial use of one or two antibiotics for critically ill patients with community-acquired pneumonia: impact on survival and bacterial resistance
Authors: Adrie Christophe , Schwebel Carole , Garrouste-Orgeas Maïté , Vignoud Lucile , Planquette Benjamin , Azoulay Elie , Kallel Hatem , Darmon Michael , Souweine Bertrand , Dinh-Xuan Anh-Tuan , Jamali Samir , Zahar Jean-Ralph , Timsit Jean-François ,   This article was written on behalf of the Outcomerea Study Group
Published: November 2013

Introduction

Several guidelines recommend initial empirical treatment with two antibiotics instead of one to decrease mortality in community-acquired pneumonia (CAP) requiring intensive-care-unit (ICU) admission. We compared the impact on 60-day mortality of using one or two antibiotics. We also compared the rates of nosocomial pneumonia and multidrug-resistant bacteria.

Methods

This is an observational cohort study of 956 immunocompetent patients with CAP admitted to ICUs in France and entered into a prospective database between 1997 and 2010.

Patients with chronic obstructive pulmonary disease were excluded. Multivariate analysis adjusted for disease severity, gender, and co-morbidities was used to compare the impact on 60-day mortality of receiving adequate initial antibiotics and of receiving one versus two initial antibiotics.

Results

Initial adequate antibiotic therapy was significantly associated with better survival (subdistribution hazard ratio (sHR), 0.63; 95% confidence interval (95% CI), 0.42 to 0.94; P = 0.02); this effect was strongest in patients with Streptococcus pneumonia CAP (sHR, 0.05; 95% CI, 0.005 to 0.46; p = 0.001) or septic shock (sHR: 0.62; 95% CI 0.38 to 1.00; p = 0.05). Dual therapy was associated with a higher frequency of initial adequate antibiotic therapy. However, no difference in 60-day mortality was found between monotherapy (β-lactam) and either of the two dual-therapy groups (β-lactam plus macrolide or fluoroquinolone). The rates of nosocomial pneumonia and multidrug-resistant bacteria were not significantly different across these three groups.

Conclusions

Initial adequate antibiotic therapy markedly decreased 60-day mortality. Dual therapy improved the likelihood of initial adequate therapy but did not predict decreased 60-day mortality. Dual therapy did not increase the risk of nosocomial pneumonia or multidrug-resistant bacteria.
VDR Attenuates Acute Lung Injury by Blocking Ang-2-Tie-2 Pathway and Renin-Angiotensin System
Authors: Kong Juan , Zhu Xiangdong , Shi Yongyan , Liu Tianjing , Chen Yunzi , Bhan Ishir , Zhao Qun , Thadhani Ravi , Li Yan Chun
Published: November 2013

Acute lung injury (ALI) is a hallmark of systemic inflammation associated with high mortality. Although the vitamin D receptor (VDR) is highly expressed in the lung, its role in lung physiology remains unclear. We investigated the effect of VDR deletion on ALI using a lipopolysaccharide (LPS)-induced sepsis model. After LPS challenge VDR-null mice exhibited more severe ALI and higher mortality compared with wild-type (WT) counterparts, manifested by increased pulmonary vascular leakiness, pulmonary edema, apoptosis, neutrophil infiltration, and pulmonary inflammation, which was accompanied by excessive induction of angiopoietin (Ang)-2 and myosin light chain (MLC) phosphorylation in the lung. 1,25-Dihydroxyvitamin D blocked LPS-induced Ang-2 expression by blocking nuclear factor-κB activation in human pulmonary artery endothelial cells. The severity of lung injury seen in VDR-null mice was ameliorated by pretreatment with L1–10, an antagonist of Ang-2, suggesting that VDR signaling protects the pulmonary vascular barrier by targeting the Ang-2-Tie-2-MLC kinase cascade. Severe ALI in VDR-null mice was also accompanied by an increase in pulmonary renin and angiotensin II levels, and pretreatment of VDR-null mice with angiotensin II type 1 receptor blocker losartan partially ameliorated the severity of LPS-induced lung injury. Taken together, these observations provide evidence that the vitamin D-VDR signaling prevents lung injury by blocking the Ang-2-Tie-2-MLC kinase cascade and the renin-angiotensin system.
The Type II Deiodinase Is Retrotranslocated to the Cytoplasm and Proteasomes via p97/Atx3 Complex
Authors: Arrojo e Drigo Rafael , Egri Péter , Jo Sungro , Gereben Balázs , Bianco Antonio C.
Published: November 2013

The type II iodothyronine deiodinase (D2) is a type I endoplasmic reticulum (ER)-resident thioredoxin fold-containing selenoprotein that activates thyroid hormone. D2 is inactivated by ER-associated ubiquitination and can be reactivated by two ubiquitin-specific peptidase-class D2-interacting deubiquitinases (DUBs). Here, we used D2-expressing cell models to define that D2 ubiquitination (UbD2) occurs via K48-linked ubiquitin chains and that exposure to its natural substrate, T4, accelerates UbD2 formation and retrotranslocation to the cytoplasm via interaction with the p97-ATPase complex. D2 retrotranslocation also includes deubiquitination by the p97-associated DUB Ataxin-3 (Atx3). Inhibiting Atx3 with eeyarestatin-I did not affect D2:p97 binding but decreased UbD2 retrotranslocation and caused ER accumulation of high-molecular weight UbD2 bands possibly by interfering with the D2-ubiquitin-specific peptidases binding. Once in the cytosol, D2 is delivered to the proteasomes as evidenced by coprecipitation with 19S proteasome subunit S5a and increased colocalization with the 20S proteasome. We conclude that interaction between UbD2 and p97/Atx3 mediates retranslocation of UbD2 to the cytoplasm for terminal degradation in the proteasomes, a pathway that is accelerated by exposure to T4.
Cell delamination in the mesencephalic neural fold and its implication for the origin of ectomesenchyme
Authors: Lee Raymond Teck Ho , Nagai Hiroki , Nakaya Yukiko , Sheng Guojun , Trainor Paul A. , Weston James A. , Thiery Jean Paul
Published: November 2013

The neural crest is a transient structure unique to vertebrate embryos that gives rise to multiple lineages along the rostrocaudal axis. In cranial regions, neural crest cells are thought to differentiate into chondrocytes, osteocytes, pericytes and stromal cells, which are collectively termed ectomesenchyme derivatives, as well as pigment and neuronal derivatives. There is still no consensus as to whether the neural crest can be classified as a homogenous multipotent population of cells. This unresolved controversy has important implications for the formation of ectomesenchyme and for confirmation of whether the neural fold is compartmentalized into distinct domains, each with a different repertoire of derivatives. Here we report in mouse and chicken that cells in the neural fold delaminate over an extended period from different regions of the cranial neural fold to give rise to cells with distinct fates. Importantly, cells that give rise to ectomesenchyme undergo epithelial-mesenchymal transition from a lateral neural fold domain that does not express definitive neural markers, such as Sox1 and N-cadherin. Additionally, the inference that cells originating from the cranial neural ectoderm have a common origin and cell fate with trunk neural crest cells prompted us to revisit the issue of what defines the neural crest and the origin of the ectomesenchyme.
Guidance receptor promotes the asymmetric distribution of exocyst and recycling endosome during collective cell migration
Authors: Wan Ping , Wang Dou , Luo Jun , Chu Dandan , Wang Heng , Zhang Lijun , Chen Jiong
Published: November 2013

During collective migration, guidance receptors signal downstream to result in a polarized distribution of molecules, including cytoskeletal regulators and guidance receptors themselves, in response to an extracellular gradient of chemotactic factors. However, the underlying mechanism of asymmetry generation in the context of the migration of a group of cells is not well understood. Using border cells in the Drosophila ovary as a model system for collective migration, we found that the receptor tyrosine kinase (RTK) PDGF/VEGF receptor (PVR) is required for a polarized distribution of recycling endosome and exocyst in the leading cells of the border cell cluster. Interestingly, PVR signaled through the small GTPase Rac to positively affect the levels of Rab11-labeled recycling endosomes, probably in an F-actin-dependent manner. Conversely, the exocyst complex component Sec3 was required for the asymmetric localization of RTK activity and F-actin, similar to that previously reported for the function of Rab11. Together, these results suggested a positive-feedback loop in border cells, in which RTKs such as PVR act to induce a higher level of vesicle recycling and tethering activity in the leading cells, which in turn enables RTK activity to be distributed in a more polarized fashion at the front. We also provided evidence that E-cadherin, the major adhesion molecule for border cell migration, is a specific cargo in the Rab11-labeled recycling endosomes and that Sec3 is required for the delivery of the E-cadherin-containing vesicles to the membrane.
Pebble/ECT2 RhoGEF negatively regulates the Wingless/Wnt signaling pathway
Authors: Greer Elisabeth R. , Chao Anna T. , Bejsovec Amy
Published: November 2013

Wingless (Wg)/Wnt signaling is essential for patterning invertebrate and vertebrate embryos, and inappropriate Wnt activity is associated with a variety of human cancers. Despite intensive study, Wnt pathway mechanisms are not fully understood. We have discovered a new mechanism for regulating the Wnt pathway: activity of a Rho guanine nucleotide exchange factor (GEF) encoded by pebble (pbl) in Drosophila and ECT2 in humans. This RhoGEF has an essential role in cytokinesis, but also plays an unexpected, conserved role in inhibiting Wg/Wnt activity. Loss and gain of pbl function in Drosophila embryos cause pattern defects that indicate altered Wg activity. Both Pbl and ECT2 repress Wg/Wnt target gene expression in cultured Drosophila and human cells. The GEF activity is required for Wnt regulation, whereas other protein domains important for cytokinesis are not. Unlike most negative regulators of Wnt activity, Pbl/ECT2 functions downstream of Armadillo (Arm)/beta-catenin stabilization. Our results indicate GTPase regulation at a novel point in Wg/Wnt signal transduction, and provide new insight into the categorization of ECT2 as a human proto-oncogene.
Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development
Authors: Baenke Franziska , Peck Barrie , Miess Heike , Schulze Almut
Published: November 2013

An increased rate of lipid synthesis in cancerous tissues has long been recognised as an important aspect of the rewired metabolism of transformed cells. However, the contribution of lipids to cellular transformation, tumour development and tumour progression, as well as their potential role in facilitating the spread of cancerous cells to secondary sites, are not yet fully understood. In this article, we review the recent findings that support the importance of lipid synthesis and metabolism in tumorigenesis. Specifically, we explore the role of aberrant lipid biosynthesis in cancer cell migration and invasion, and in the induction of tumour angiogenesis. These processes are crucial for the dissemination of tumour cells and formation of metastases, which constitute the main cause of cancer mortality.
Apart from its basic function the plasma membrane Ca2+ATPase regulates Ca2+ signaling by controlling phosphatidylinositol-4,5-bisphosphate levels
Authors: Penniston John T. , Padányi Rita , Pászty Katalin , Varga Karolina , Hegedűs Luca , Enyedi Agnes
Published: November 2013

Plasma membrane Ca2+ ATPases (PMCAs) are known targets of phosphatidylinositol-4,5-bisphosphate (PIP2), but if and how they control the PIP2 pool has not been considered. We demonstrate here that PMCAs protect PIP2 in the plasma membrane. Comparison of active and inactive PMCAs indicates that the protection operates by 2 mechanisms; one requiring active PMCA, the other not. It appears that the mechanism requiring activity is the removal of the Ca2+ required for sustained phospholipase C (PLC) activity, while the mechanism not requiring activity is PIP2 binding. We show that in PMCA overexpressing cells, PIP2 binding can lead to less IP3 and diminished Ca2+ release from intracellular Ca2+ pools. Inspection of a homology model of PMCA suggests that PMCAs have a conserved cluster of basic residues forming a “blue collar” at the interface between the membrane core and the cytoplasmic domains. By molecular dynamics simulation we found that the blue collar forms four binding pockets for the phosphorylated inositol head group of PIP2; these pockets bound PIP2 strongly and frequently. Our studies suggest that by having the ability to bind PIP2, PMCAs can control the accessibility of PIP2 for PLC and other PIP2 mediated processes.
Light-harvesting chlorophyll pigments enable mammalian mitochondria to capture photonic energy and produce ATP
Authors: Xu Chen , Zhang Junhua , Mihai Doina M. , Washington Ilyas
Published: November 2013

Sunlight is the most abundant energy source on this planet. However, the ability to convert sunlight into biological energy as adenosine-5′-triphosphate (ATP) is thought to be limited to chloroplasts in photosynthetic organisms. Here we show that mammalian mitochondria can also capture light and synthesize ATP when mixed with a light-capturing metabolite of chlorophyll. The same metabolite fed to the worm Caenorhabditis elegans leads to increase in ATP synthesis upon light exposure, along with an increase in life span. We further demonstrate the same potential to convert light into energy exists in mammals, as chlorophyll metabolites accumulate in rodents when fed a chlorophyll-rich diet. Results suggest chlorophyll type molecules modulate mitochondrial ATP by catalyzing the reduction of coenzyme Q, a slow step in mitochondrial ATP synthesis. We propose that through consumption of plant chlorophyll pigments, animals, too, are able to derive energy directly from sunlight.
Landmarks and ant search strategies after interrupted tandem runs
Authors: Basari Norasmah , Bruendl Aisha C. , Hemingway Charlotte E. , Roberts Nicholas W. , Sendova-Franks Ana B. , Franks Nigel R.
Published: November 2013

During a tandem run, a single leading ant recruits a single follower to an important resource such as a new nest. Here, for the first time, we used a motorized gantry to track tandem running ants accurately in a large arena and we compared their performance in the presence of different types of landmark. We interrupted tandem runs by taking away the leader and moved a large distant landmark behind the new nest just at the time of this separation. Our aim was to determine what information followers may have obtained from the incomplete tandem run they had followed and how they behave after the tandem run had been interrupted. Our results show that former followers search by using composite random strategies with elements of sub-diffusive and diffusive movements. Furthermore, when we provided more landmarks former followers searched for longer. However, when all landmarks were removed completely from the arena, the ants' search duration lasted up to four times longer. Hence, their search strategy changes in the presence or absence of landmarks. Even after extensive search of this kind, former followers headed back to their old nest but did not return along the path of the tandem run they had followed. The combination of the position to which the large distant landmark behind the new nest was moved and the presence or absence of additional landmarks influenced the orientation of the former followers' paths back to the old nest. We also found that these ants exhibit behavioural lateralization in which they may use their right eye more than their left eye to recognize landmarks for navigation. Our results suggest that former follower ants learn landmarks during tandem running and use this information to make strategic decisions.