Opportunities to improve antimicrobial use in paediatric intensive care units: a nationwide survey in Spain.

Improving antimicrobial use is a complex process that requires an accurate assessment of ongoing problems and barriers. Paediatric intensive care units (PICU) have seldom been assessed from this perspective. Two Internet-based, self-administered surveys were conducted nationwide in Spain between January and February 2014. The first survey aimed to assess those characteristics of Spanish PICUs that could influence antimicrobial prescribing or antimicrobial stewardship. The second survey targeted Spanish PICU physicians and pursued to assess their attitudes and perceptions regarding antimicrobial resistance and antimicrobial use. Information about 29/39 contacted PICUs was obtained. A total of 114/206 (55.3%) paediatric intensivists responded. PICUs were heterogeneous regarding years since foundation, number of beds, type of patients admitted and staffing. Only 11 (37.9%) PICUs had available e-prescribing systems. Procalcitonin was available in 24 (89.1%) PICUs, but there were no procalcitonin-based protocols in 14 (60.9%) of them. Half of surveyed PICUs had implemented antimicrobial stewardship activities. Ninety-eight of the 114 PICU physicians (86%) who participated considered that antimicrobial resistance was a significantly relevant problem for their daily and that improving antimicrobial use in their PICU should be a priority (103; 90.4%). The main perceived problems regarding antimicrobial use were the excessive use of antimicrobials in patients with nonconfirmed infections and excessive use of broad-spectrum antimicrobials. The most valued antimicrobial stewardship interventions were the implementation of protocols to guide antimicrobial therapy. Spanish PICU doctors are aware of the relevance of the problem of antimicrobial resistance and the need to improve antimicrobial use. Targeted interventions should take into account their difficulties and preferences when feasible.

Metal organic framework synthesis in the presence of surfactants: towards hierarchical MOFs?

The effect of synthesis pH and H2O/EtOH molar ratio on the textural properties of different aluminium trimesate metal organic frameworks (MOFs) prepared in the presence of the well-known cationic surfactant cetyltrimethylammonium bromide (CTAB) at 120 °C was studied with the purpose of obtaining a MOF with hierarchical pore structure. Depending on the pH and the solvent used, different topologies were obtained (namely, MIL-96, MIL-100 and MIL-110). On the one hand, MIL-110 was obtained at lower temperatures than those commonly reported in the literature and without additives to control the pH; on the other hand, MIL-100 with crystallite sizes as small as 30 ± 10 nm could be easily synthesized in a mixture of H2O and EtOH with a H2O/EtOH molar ratio of 3.4 at pH 2.6 in the presence of CTAB. The resulting material displays a hierarchical porosity that combines the microporosity from the MOF and the non-ordered mesopores defined in between the MOF nanoparticles. Interestingly, the maximum of the pore size distribution could be varied between 3 and 33 nm. Finally, at pH 2.5 and using water as a solvent, platelets of MIL-96, a morphology never observed before for this MOF, were synthesized with a (001) preferential crystal orientation, the (001) plane running parallel to the bipyramidal cages of the MIL-96 topology.

Global identification of genes targeted by DNMT3b for epigenetic silencing in lung cancer.

The maintenance cytosine DNA methyltransferase DNMT1 and de novo methyltransferase DNMT3b cooperate to establish aberrant DNA methylation and chromatin complexes to repress gene transcription during cancer development. The expression of DNMT3b was constitutively increased 5-20-fold in hTERT/CDK4-immortalized human bronchial epithelial cells (HBECs) before treatment with low doses of tobacco carcinogens. Overexpression of DNMT3b increased and accelerated carcinogen-induced transformation. Genome-wide profiling of transformed HBECs identified 143 DNMT3b-target genes, many of which were transcriptionally regulated by the polycomb repressive complex 2 (PRC2) complex and silenced through aberrant methylation in non-small-cell lung cancer cell lines. Two genes studied in detail, MAL and OLIG2, were silenced during transformation, initially through enrichment for H3K27me3 and H3K9me2, commonly methylated in lung cancer, and exert tumor suppressor effects in vivo through modulating cancer-related pathways. Re-expression of MAL and OLIG2 to physiological levels dramatically reduced the growth of lung tumor xenografts. Our results identify a key role for DNMT3b in the earliest stages of initiation and provide a comprehensive catalog of genes targeted for silencing by this methyltransferase in non-small-cell lung cancer.

A Review and Framework for Categorizing Current Research and Development in Health Related Geographical Information Systems (GIS) Studies.

OBJECTIVES: The application of GIS in health science has increased over the last decade and new innovative application areas have emerged. This study reviews the literature and builds a framework to provide a conceptual overview of the domain, and to promote strategic planning for further research of GIS in health. METHOD: The framework is based on literature from the library databases Scopus and Web of Science. The articles were identified based on keywords and initially selected for further study based on titles and abstracts. A grounded theory-inspired method was applied to categorize the selected articles in main focus areas. Subsequent frequency analysis was performed on the identified articles in areas of infectious and non-infectious diseases and continent of origin. RESULTS: A total of 865 articles were included. Four conceptual domains within GIS in health sciences comprise the framework: spatial analysis of disease, spatial analysis of health service planning, public health, health technologies and tools. Frequency analysis by disease status and location show that malaria and schistosomiasis are the most commonly analyzed infectious diseases where cancer and asthma are the most frequently analyzed non-infectious diseases. Across categories, articles from North America predominate, and in the category of spatial analysis of diseases an equal number of studies concern Asia. CONCLUSION: Spatial analysis of diseases and health service planning are well-established research areas. The development of future technologies and new application areas for GIS and data-gathering technologies such as GPS, smartphones, remote sensing etc. will be nudging the research in GIS and health.

RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis.

Aerobic glycolysis or the Warburg effect contributes to cancer cell proliferation; however, how this glucose metabolism pathway is precisely regulated remains elusive. Here we show that receptor-interacting protein 1 (RIP1), a cell death and survival signaling factor, regulates mitochondrial oxidative phosphorylation and aerobic glycolysis. Loss of RIP1 in lung cancer cells suppressed peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression, impairing mitochondrial oxidative phosphorylation and accelerating glycolysis, resulting in spontaneous DNA damage and p53-mediated cell proliferation inhibition. Thus, although aerobic glycolysis within a certain range favors cancer cell proliferation, excessive glycolysis causes cytostasis. Our data suggest that maintenance of glycolysis by RIP1 is pivotal to cancer cell energy homeostasis and DNA integrity and may be exploited for use in anticancer therapy.

Aerosolised 5-azacytidine suppresses tumour growth and reprogrammes the epigenome in an orthotopic lung cancer model.

BACKGROUND: Epigenetic silencing by promoter methylation and chromatin remodelling affects hundreds of genes and is a causal event for lung cancer. Treatment of patients with low doses of the demethylating agent 5-azacytidine in combination with the histone deacetylase inhibitor entinostat has yielded clinical responses. The subcutaneous dosing route for consecutive days and reduced bioavailability of 5-azacytidine because of inactivation by cytidine deaminase may limit the expansion of epigenetic therapy into Phase III trials. To mitigate these barriers, an aerosol of 5-azacytidine was generated and characterised. METHODS: The effect of aerosol vs systemic delivery of 5-azacytidine on tumour burden and molecular response of engrafted lung tumours in the nude rat was compared. RESULTS: Pharmacokinetics revealed major improvement in the half-life of 5-azacytidine in lung tissue with aerosol delivery. Aerosolised 5-azacytidine significantly reduced lung tumour burden and induced global demethylation of the epigenome at one-third of the comparable effective systemic dose. High commonality for demethylation of genes was seen in tumours sampled throughout lung lobes and across treated animals receiving the aerosolised drug. CONCLUSION: Collectively, these findings show that aerosolised 5-azacytidine targets the lung, effectively reprogrammes the epigenome of tumours, and is a promising approach to combine with other drugs for treating lung cancer.

Do we need real-time MRI for diagnosis of temporomandibular joint disorders?

INTRODUCTION: Magnetic resonance imaging (MRI) has been approved as an appropriate radiological modality for temporomandibular joint (TMJ) diagnosis, whereas the results of international multicenter studies impressively show the limitations of static three-dimensional MRI. The state of the art for dynamic imaging of the TMJ in real-time are TrueFISP sequences in one sagittal plane. In order to support the diagnostics, a computer-assisted visualization procedure has been developed by the authors for both the static and dynamic MRI. METHODS: A number of validated sequences are available for the static 3D-MRI within the clinical routine. For dynamic MRI in real-time, True-FISP sequences in one sagittal plane with a slice thickness of 5-10 mm and 1.3 mm x 1.3 mm spatial resolution were applied. Both the dynamic and static MRI datasets are animated and visualized using the computer-assisted procedure. RESULTS: The computer-assisted procedure reliably supported the clinical diagnosis, especially the visibility of the articular disc was enhanced. On the basis of the static MRI, a 60-year-old patient was diagnosed with anterior disc displacement without reduction. In contrast, by the dynamic MRI, it was recognized how the articular disc was firstly somehow stretched and flattened before the mandibular condyle again glided under the disc, thus resulting in an anterior disc displacement with reduction. CONCLUSION: These results endorse the relevance of real-time diagnosis for the TMJ. The computer-assisted visualization has been approved as a reliable help for clinical diagnosis.

[Hydatid disease in the Department of Health #2 of the Valencian Community (Spain)]. / Casos de hidatidosis en el Departamento de Salud 2 de la Comunidad Valenciana.

Hydatidosis is one of the most important zoonotic parasitic diseases of Mediterranean and South American countries where they constitute a significant health problem. Its diagnosis is realized essentially by image techniques and its treatment continues being eminently surgical. During the period 2000-2005, we reviewed clinical records of diagnosed and treated cases of hydatidosis carried out at the Department of Health 2 of the Valencia Community, Spain. Thirty three cases were evaluated of which we describe demographic, radiological, clinical, analytic, therapeutical and evolutionary data. We discuss the peculiarities found in them: thirty two cases were of hepatic location, essentially right, 48.5% unique cysts, five casual finding, 88.87% were diagnosed by ultrasonographic technique and in 2/3 of the cases the serology was positive. In addition, 52.17% of the twenty three cases treated surgically cured without recurrence and a 15.15% recurred without subsequent healing. Studies will require long-term monitoring of patients evolution.

[Rare complication after Le Fort I osteotomy]. / Eine seltene Komplikation nach Le-Fort-I-Osteotomie.

Malfunctions of the eustachian tube after Le Fort I osteotomies are rare. A 22-year-old woman was treated by Le Fort I osteotomy for maxillary retrognathism. Postoperatively she developed recurrent tubal malfunction and middle ear effusions on the left side, with no improvement after adenotomy, tonsillectomy, and grommet insertion. In consecutive computed tomography and magnetic resonance imaging scans, a forward dislocation of the left pterygoid hamulus was demonstrated. In addition, damage to the tensor veli palatini muscle was evident. Both postoperative sequelae appear to be responsible for the unilateral tubal dysfunction.

Prospective evaluation of risk of vertebral fractures using quantitative ultrasound measurements and bone mineral density in a population-based sample of postmenopausal women: results of the Basel Osteoporosis Study.

OBJECTIVE: Prospective studies have shown that quantitative ultrasound (QUS) techniques predict the risk of fracture of the proximal femur with similar standardised risk ratios to dual-energy x-ray absorptiometry (DXA). Few studies have investigated these devices for the prediction of vertebral fractures. The Basel Osteoporosis Study (BOS) is a population-based prospective study to assess the performance of QUS devices and DXA in predicting incident vertebral fractures. METHODS: 432 women aged 60-80 years were followed-up for 3 years. Incident vertebral fractures were assessed radiologically. Bone measurements using DXA (spine and hip) and QUS measurements (calcaneus and proximal phalanges) were performed. Measurements were assessed for their value in predicting incident vertebral fractures using logistic regression. RESULTS: QUS measurements at the calcaneus and DXA measurements discriminated between women with and without incident vertebral fracture, (20% height reduction). The relative risks (RRs) for vertebral fracture, adjusted for age, were 2.3 for the Stiffness Index (SI) and 2.8 for the Quantitative Ultrasound Index (QUI) at the calcaneus and 2.0 for bone mineral density at the lumbar spine. The predictive value (AUC (95% CI)) of QUS measurements at the calcaneus remained highly significant (0.70 for SI, 0.72 for the QUI, and 0.67 for DXA at the lumbar spine) even after adjustment for other confounding variables. CONCLUSIONS: QUS of the calcaneus and bone mineral density measurements were shown to be significant predictors of incident vertebral fracture. The RRs for QUS measurements at the calcaneus are of similar magnitude as for DXA measurements.

[Stress-related vertical double vision and ptosis]. / Belastungsabhängige vertikale Doppelbilder und Ptosis. Diagnose: Okuläre Pseudomyasthenie bei Keilbeinmeningeom am Sinus cavernosus links.

A 43-year-old patient presented to our department because her left eyelid had exhibited drooping to varying extents for 2-3 months. Furthermore, in extreme positions or after rapid eye movement, she perceived diplopic images and was sensitive to light. The diagnosis of sphenoid meningioma was reached. Subsequently two rounds of radiopeptide therapy with (90)Y-DOTATOC (somatostatin analog) were administered within 3 months. This treatment approach led to a reduction of tumor volume in our patient as well as clinical improvement followed by stabilization.

[Evaluation of two immunochromatography kits for rapid diagnosis of rotavirus infections]. / Evaluación de dos equipos inmunocromatográficos comerciales para el diagnóstico rápido de la infección por rotavirus.

A prospective study was conducted to evaluate two immunochromatography (ICG) commercial kits for diagnosis of rotavirus infection, VIKIA Rota-Adeno (bioMérieux) and Simple Rota-Adeno (Operon). Reverse transcriptase and polymerase chain reaction (RT-PCR) with specific primers for the VP7 gene of group A rotavirus was used as the reference method. The sensitivity and specificity of the ICG tests compared with those of the reference method were 98.4% and 84.8%, respectively, for Simple Rota-Adeno (Operon), and 100% and 24.2% for VlKIA Rota-Adeno (bioMérieux). It is remarkable the low specificity of the latter method, which yields a high number of false positive results. The predictive value of a positive result by this method was only 71.6%. Most of the detected rotavirus strains corresponded to genotype G9P[8] (65%), followed by G1P[8] (25.4%) and G2P[8] (3.2%).

Determination of asulam by fast stopped-flow chemiluminescence inhibition of luminol/peroxidase.

An efficient, sensitive and fast stopped-flow method has been developed to determine asulam in water, based on its inhibition effect on the horseradish peroxidase-luminol-hydrogen peroxide chemiluminescence reaction, (HRP-luminol-H(2)O(2)). Ultra fast data acquisition (0.20s) facilitates excellent selectivity because no interferences from concomitants in the matrix act in such short time scale. The precision as repeatability (expressed as relative standard deviation, n=10) was 0.4% at a 40 pM level. The detection limit was 1.5 pM (0.35 ng/L) and 7.15 pM in pure and raw water, respectively. The calibration data over the range 5-60 pM present a correlation coefficient of r=0.9993. The proposed method has been applied to determine asulam in water samples by using solid-phase extraction (SPE). Mean recovery value was 98.1+/-2% at 50 pM level.

A novel AKT3 mutation in melanoma tumours and cell lines.

Recently, a rare activating mutation of AKT1 (E17K) has been reported in breast, ovarian, and colorectal cancers. However, analogous activating mutations in AKT2 or AKT3 have not been identified in any cancer lineage. To determine the prevalence of AKT E17K mutations in melanoma, the most aggressive form of skin cancer, we analysed 137 human melanoma specimens and 65 human melanoma cell lines for the previously described activating mutation of AKT1, and for analogous mutations in AKT2 and AKT3. We identified a single AKT1 E17K mutation. Remarkably, a previously unidentified AKT3 E17K mutation was detected in two melanomas (from one patient) as well as two cell lines. The AKT3 E17K mutation results in activation of AKT when expressed in human melanoma cells. This represents the first report of AKT mutations in melanoma, and the initial identification of an AKT3 mutation in any human cancer lineage. We have also identified the first known human cell lines with naturally occurring AKT E17K mutations.

Evaluación de dos equipos inmunocromatográficos comerciales para el diagnóstico rápido de la infección por rotavirus / Evaluation of two immunochromatography kits for rapid diagnosis of rotavirus infections

Se realizó un estudio prospectivo para evaluar dos equipos comerciales inmunocromatográficos para el diagnóstico rápido de infección por rotavirus a partir de muestras fecales: VIKIA® Rota-Adeno, de bioMérieux, y Simple Rota- Adeno, de Operon. Como método de referencia se utilizó la transcripción reversa y reacción en cadena de la polimerasa (RT-PCR) con cebadores específicos del gen de la proteína VP7 de rotavirus del grupo A. La sensibilidad y la especificidad respecto de la RT-PCR fueron del 98,4% y 84,8% para el Simple Rota-Adeno, y del 100% y 24,2% para el VIKIA® Rota-Adeno. Es de destacar la baja especificidad de este último equipo diagnóstico, que presentó un elevado número de falsos positivos, por lo que el valor predictivo de un resultado positivo es sólo del 71,6%. Asimismo, se identificaron los genotipos de las cepas de rotavirus detectadas; la mayoría de ellas correspondieron al genotipo G9P(8) (65%), seguido de los genotipos G1P(8) (25,4%) y G2P(8) (3,2%).

A prospective study was conducted to evaluate two immunochromatography (ICG) commercial kits for diagnosis of rotavirus infection, VIKIA® Rota-Adeno (bioMérieux) and Simple Rota-Adeno (Operon). Reverse transcriptase and polymerase chain reaction (RT-PCR) with specific primers for the VP7 gene of group A rotavirus was used as the reference method. The sensitivity and specificity of the ICG tests compared with those of the reference method were 98.4% and 84.8%, respectively, for Simple Rota-Adeno (Operon), and 100% and 24.2% for VIKIA® Rota-Adeno (bioMérieux). It is remarkable the low specificity of the latter method, which yields a high number of false positive results. The predictive value of a positive result by this method was only 71.6%. Most of the detected rotavirus strains corresponded to genotype G9P(8) (65%), followed by G1P(8) (25.4%) and G2P(8) (3.2%).

A comprehensive classification of mandibular fractures: a preliminary agreement validation study.

This study evaluates a comprehensive classification system for mandibular fractures based on imaging analysis. The AO/ASIF scheme, defining three fracture types (A, B, C), three groups within each type (e.g. A1, A2, A3) and three subgroups within each group (e.g. A1.1, A1.2, A1.3) with increasing severity from A1.1 (lowest) to C3.3 (highest) was used. The mandible is divided into two vertical units (I and V), two lateral horizontal units (II and IV) and one central unit (III) comprising the symphyseal and parasymphyseal region. Type A fractures are non-displaced, type B are displaced and type C are multifragmentary/defect injuries. Groups and subgroups are further defined in the classification system. Two classification sessions using semi-automatic software with 7 and 9 surgeons were performed to evaluate 100 fracture cases in the first session and 50 in the second. Inter-observer reliability and individual rater's accuracy were evaluated by kappa coefficient and latent class analysis, respectively. The analysis of inter-observer agreement for the detailed coding showed kappa coefficients around 0.50 with higher agreement among raters in the vertical units. This system allows standardization of documentation of mandibular fractures, although improvement in the definition of categories and their application is required.

Loss of AP-2alpha results in deregulation of E-cadherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivo.

Activator protein-2 (AP-2) is a transcription factor that regulates proliferation and differentiation in mammalian cells and has been implicated in the acquisition of the metastatic phenotype in several types of cancer. Herein, we examine the role of AP-2alpha in colon cancer progression. We provide evidence for the lack of AP-2alpha expression in the late stages of colon cancer cells. Re-expression of the AP-2alpha gene in the AP-2alpha-negative SW480 colon cancer cells suppressed their tumorigenicity following orthotopic injection into the cecal wall of nude mice. The inhibition of tumor growth could be attributed to the increased expression of E-cadherin and decreased expression and activity of matrix-metalloproteinase-9 (MMP-9) in the transfected cells, as well as a substantial loss of their in vitro invasive properties. Conversely, targeting constitutive expression of AP-2alpha in AP-2-positive KM12C colon cancer cells with small interfering RNA resulted in an increase in their invasive potential, downregulation of E-cadherin and increased expression of MMP-9. In SW480 cells, re-expression of AP-2alpha resulted in a fourfold increase in the activity of E-cadherin promoter, and a 5-14-fold decrease in the activity of MMP-9 promoter, indicating transcriptional regulation of these genes by AP-2alpha. Chromatin immunoprecipitation assay showed that re-expressed AP-2alpha directly binds to the promoter of E-cadherin, where it has been previously reported to act as a transcriptional activator. Furthermore, chromatin immunoprecipitation assay revealed AP-2alpha binding to the MMP-9 promoter, which ensued by decreased binding of transcription factor Sp-1 and changes in the recruitment of transcription factors to a distal AP-1 element, thus, contributing to the overall downregulation of MMP-9 promoter activity. Collectively, our data provide evidence that AP-2alpha acts as a tumor suppressor gene in colon cancer..

Hearing loss after discontinuing secondary prophylaxis for cryptococcal meningitis: relapse or immune reconstitution?

Relapse and immune reconstitution syndrome are difficult to distinguish in HIV-infected patients treated with antiretroviral therapy (ART). We report on a 26-year-old HIV-infected male (CDC C3) with hearing loss on the right side 2 months after discontinuing secondary prophylaxis for cryptococcal meningitis. CD4 cell counts had increased from 32/microl to stable counts > 200/microl for the preceding 6 months on ART but HIV replication was not fully suppressed (7,000 copies/ml). Magnetic resonance imaging identified lesions at the origin of the right cranial nerve VIII. Lumbar puncture revealed monocytic pleocytosis, slightly increased protein, but normal glucose and lactate levels, negative microbiological studies. Fluconazole was restarted and a new ART regimen was started in order to fully suppress HIV replication. Clinical and radiological signs were reversible during follow-up, and secondary prophylaxis was stopped after 6 months without adverse events. We review 26 published cases of cryptococcal infections with immune reconstitution syndrome and highlight the distinguishing features.

Synthesis, molecular structure and vibrational spectra of a dimeric complex formed by cobalt and glycine.

The structure of [Co(gly)(2)(OH)(2)].1.5(H(2)O) was solved by X-ray diffraction. It crystallizes in the space group P-1, with two independent dimmers in the unit cell. The results for the calculated vibrational spectra are in good agreement with the experimental one. The infrared spectrum and ab initio calculations are consistent with the crystallographic results.

Focal myositis of the iliopsoas muscle--a benign pseudotumour: ultrasound appearance in correlation with CT and MRI.

OBJECTIVE: Focal myositis of the iliopsoas muscle is a rare condition. A case is presented, emphasizing the value of ultrasound for detection, localisation, image-guided biopsy and follow-up in correlation with CT and MRI findings. MATERIAL AND METHODS: A 58-year-old woman was referred to our clinic with strong left sided inguinal pain, which radiated to the thigh and had lasted for four days. Ultrasound, CT and MRI were performed. Ultrasound-guided biopsy with histological correlation was obtained and US-follow-ups were available. RESULTS: CT showed an enlarged iliopsoas muscle on the left side without any focal pathology or enhancement. MRI revealed a sharpely delineated lesion, which was hypointense to muscle in fat-suppressed T1 w images with circumferential enhancement and showed a hyperintense appearance in T2 w images. Ultrasound displayed a polylobulated, inhomogeneous and hypoechoic tumour within the iliopsoas muscle. Ultrasound-guided biopsy was found to be compatible with myositis. After oral therapy with steroids, improvement could be documented by serial ultrasound follow-up as the size of the tumour was definitely regressing. CONCLUSION: Focal myositis of the iliopsoas muscle is a rare entity which may mimic a tumoural lesion. Imaging findings may not be conclusive, and US-guided biopsy is recommended to rule out a malignant mass. Ultrasound seems to be the most cost-effective method for diagnosis, image guided biopsy and follow-up.