Baseline characteristics and patient reported outcome data of patients prescribed etanercept: web-based and telephone evaluation.
The anti-TNF inhibitor, etanercept is administered as a once or twice weekly subcutaneous injection for the treatment of rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis (JIA). Limited data from the patients' perspective are available on the use of biologics in the treatment of these chronic conditions and this evaluation was designed to collect data from patients who had been prescribed etanercept for the first time. This manuscript describes the self-reported baseline characteristics and health-related quality of life of patients prior to treatment. Follow-up data will be reported separately. Patients throughout the United Kingdom prescribed etanercept were invited to participate in an evaluation of their condition and treatment using a data collection tool consisting of a web-based system supplemented by telephone reporting (PROBE). Outcome measures reported at baseline included demographic data, the condition being treated, previous treatment with biologic agents and current and previous medications. Questions modified from standard, validated quality of life questionnaires such as EQ-5D were incorporated and patients made a global assessment of the severity of their own illness using the CGI-S scale. A total of 344 patients/carers/parents participated in the evaluation at baseline, 290 (84%) by online questionnaire and 54 (16%) by telephone. Overall, the study population had a mean age of 53 years, was predominantly female (62%) and 20% had been previously treated with a biologic agent. A total of 191 (56%) patients were receiving treatment with etanercept for rheumatoid arthritis, 44 (13%) for psoriatic arthritis, 43 (13%) for ankylosing spondylitis, 35 (10%) for psoriasis, 9 (3%) for known juvenile idiopathic arthritis (JIA) and 22 (6%) for another condition/patient unsure/missing response. All patients were prescribed the 50 mg weekly dose of etanercept except for 1 patient with JIA (40 mg) dose and 2 patients with psoriasis (100 mg). Thirty-eight percent of patients with rheumatoid arthritis were not receiving treatment with methotrexate. The baseline characteristics and health-related quality of life of first time users of etanercept can be adequately described using self-reported patient data collected using an online questionnaire with a telephone option (PROBE).


Nanofluidic analytical system integrated with nanochannel open/close valves for enzyme-linked immunosorbent assay.
There have been significant advances in the field of nanofluidics, and novel technologies such as single-cell analysis have been demonstrated. Despite the evident advantages of nanofluidics, fluid control in nanochannels for complicated analyses is extremely difficult because the fluids are currently manipulated by maintaining the balance of driving pressure. To address this issue, the use of valves will be essential. Our group previously developed a nanochannel open/close valve utilizing glass deformation, but this has not yet been integrated into nanofluidic devices for analytical applications. In the present study, a nanofluidic analytical system integrated with multiple nanochannel open/close valves was developed. This system consists of eight pneumatic pumps, seven nanochannel open/close valves combined with piezoelectric actuators, and an ultra-high sensitivity detector for non-fluorescent molecules. For simultaneous actuation of multiple valves, a device holder was designed that prevented deformation of the entire device caused by operating the valves. A system was subsequently devised to align each valve and actuator with a precision of better than 20 μm to permit the operation of valves. The developed analytical system was verified by analyzing IL-6 molecules using an enzyme-linked immunosorbent assay. Fluid operations such as sample injection, pL-level aliquot sampling and flow switching were accomplished in this device simply by opening/closing specific valves, and a sample consisting of approximately 1500 IL-6 molecules was successfully detected. This study is expected to significantly improve the usability of nanofluidic analytical devices and lead to the realization of sophisticated analytical techniques such as single-cell proteomics.


Unconventional dc Transport in Rashba Electron Gases.
We discuss the transport properties of a disordered two-dimensional electron gas with strong Rashba spin-orbit coupling. We show that in the high-density regime where the Fermi energy overcomes the energy associated with spin-orbit coupling, dc transport is accurately described by a standard Drude's law, due to a nontrivial compensation between the suppression of backscattering and the relativistic correction to the quasiparticle velocity. On the contrary, when the system enters the opposite dominant spin-orbit regime, Drude's paradigm breaks down and the dc conductivity becomes strongly sensitive to the spin-orbit coupling strength, providing a suitable tool to test the entanglement between spin and charge degrees of freedom in these systems.


Regulatory Science and Innovation Programme for Europe (ReScIPE): A proposed model.
Regulatory science underpins the objective evaluation of medicinal products. It is therefore imperative that regulatory science and expertise remain at the cutting edge so that innovations of ever-increasing complexity are translated safely and swiftly into effective, high-quality therapies. We undertook a comprehensive examination of the evolution of science and technology impacting on medicinal product evaluation over the next 5-10 years and this horizon-scanning activity was complemented by extensive stakeholder interviews, resulting in a number of significant recommendations. Highlighted in particular was the need for expertise and regulatory science research to fill knowledge gaps in both more fundamental, longer-term research, with respect to technological and product-specific challenges. A model is proposed to realise these objectives in Europe, comprising a synergistic relationship between the European Medicines Agency, the European Medicines Regulatory Network and academic research centres to establish a novel regulatory science and innovation platform.


New and continuing developments at PROSITE.
PROSITE (http://prosite.expasy.org/) consists of documentation entries describing protein domains, families and functional sites, as well as associated patterns and profiles to identify them. It is complemented by ProRule a collection of rules, which increases the discriminatory power of these profiles and patterns by providing additional information about functionally and/or structurally critical amino acids. PROSITE signatures, together with ProRule, are used for the annotation of domains and features of UniProtKB/Swiss-Prot entries. Here, we describe recent developments that allow users to perform whole-proteome annotation as well as a number of filtering options that can be combined to perform powerful targeted searches for biological discovery. The latest version of PROSITE (release 20.85, of 30 August 2012) contains 1308 patterns, 1039 profiles and 1041 ProRules.


Attention-deficit/hyperactivity disorder with obstructive sleep apnea: a treatment outcome study.
Children diagnosed with attention-deficit/hyperactivity disorder (ADHD), based on Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM-IV) criteria, may also have obstructive sleep apnea (OSA), but it is unclear whether treating OSA has similar results as methylphenidate (MPH), a commonly used treatment for ADHD. This study enrolled 66 school-age children, referred for and diagnosed with ADHD, and 20 healthy controls. Polysomnography (PSG) performed after ADHD diagnosis showed the presence of mild OSA. After otolaryngological evaluation, parents and referring physicians of the children could select treatment of ADHD with MPH, treatment of OSA with adenotonsillectomy or no treatment. Systematic follow-up was performed six months after initiation of treatment, or diagnosis if no treatment. All children had pre- and post-clinical interviews; pediatric, neurologic, psychiatric and neurocognitive evaluation; PSG; ADHD rating scale, child behavior checklist (CBCL) filled out by parents and teacher; test of variables of attention (TOVA); and the quality of life in children with obstructive sleep disorder questionnaire (OSA-18). ADHD children had an apnea-hypopnea index (AHI)>1<5 event/hour; 27 were treated with MPH, 25 had adenotonsillectomy, and 14 had no treatment. The surgical and MPH groups improved more than the non-treatment group. When comparing MPH to post-surgery, the PSG and questionnaire sleep variables, some daytime symptoms (including attention span) and TOVA subscales (impulse control, response time and total ADHD score) improved more in the surgical group than the MPH group. The surgical group had an ADHD total score of 21.16+/-7.13 on the ADHD rating scale (ADHD-RS) post-surgery compared to 31.52+/-7.01 pre-surgery (p=0.0001), and the inattention and hyperactivity subscales were also significantly lower (p=0.0001). Finally, the results were significantly different between surgically and MPH-treated groups (ADHD-RS p=0.007). The surgical group also had a TOVA ADHD score lower than -1.8 and close to those obtained in normal controls. A low AHI score of >1 considered abnormal is detrimental to children with ADHD. Recognition and surgical treatment of underlying mild sleep-disordered breathing (SDB) in children with ADHD may prevent unnecessary long-term MPH usage and the potential side effects associated with drug intake.


Tumefactive multiple sclerosis in Taiwan.
Multiple sclerosis (MS) is less common in Asia, including Taiwan, and some characteristics of MS in Asians differ from those of Caucasians. Tumefactive brain lesion is even rarer in MS patients. To review patients with tumefactive MS and compare them with those in other studies investigating tumefactive demyelinating lesions and our Taiwanese typical MS patients. Twelve patients (6.3%) from the 190 MS patients visiting Taipei Veterans General Hospital from 1985 to 2010 were enrolled. They all fulfilled the McDonald or Poser criteria for MS and had at least one brain lesion larger than 2 centimeters with or without a mass effect. Eleven patients (91.7%) were female and presented tumefactive brain lesions during the first attack. The clinical course of all patients was relapsing-remitting with a second attack within 2 years. Their initial extended disability status score was higher, but the prognosis was better after more than 2 years of follow-up, than in other studies. Moreover, our patients did not have optic or spinal involvement as well as positive neuromyelitis optica immunoglobulin or aquaporin-4 antibody, which is very common in Taiwanese MS patients. Tumefactive MS is not common in Taiwan. Although the tumefactive demyelinating lesions seem to be terrible initially, their prognosis is relatively more favorable than expected.


Choroidal Thickness in Children with Beta Thalassemia Major.
The purpose of this study was to determine whether there are differences in choroidal thickness in children with beta thalassemia major (β-TM). Thirty-five patients with β-TM and 38 healthy children aged between 3 and 16 years participated in the study. After complete eye examinations were conducted on the participants, choroidal thickness measurements were performed using optical coherence tomography. Correlations between choroidal thickness and laboratory and clinical parameters, such as age, sex, hemoglobin and ferritin levels, duration of disease, type and duration of chelating therapy, visual acuity, intraocular pressure, central corneal thickness, and axial length were also evaluated. The mean ages for the study group and for the control group were 8.2 ± 2.7 and 7.9 ± 2.4 years, respectively. There were no statistical differences between groups in terms of visual acuity, intraocular pressure, central corneal thickness, or axial length (p > 0.05). Choroidal thicknesses at the foveal center were 286 ± 33 μm in β-TM patients and 335 ± 423 μm in the healthy control children. Choroidal thicknesses at each point within the horizontal nasal and temporal quadrants were thinner in the β-TM group. There was a positive correlation between choroidal thickness and hemoglobin levels and a negative correlation between choroidal thickness and ferritin levels (r = 0.924, p < 0.001 and r = -0.947, p < 0.001, respectively). There was no correlation between clinical or ocular characteristics and choroidal thickness. Choroidal thickness was significantly thinner in all quadrants in children with β-TM. This thinning of the choroid may be the reason for the development of eye disorders in older patients with β-TM.


The interactive effect of occupational noise on attention and short-term memory: A pilot study.
Human performance is influenced by several job-related factors and workplace conditions, including occupational noise. This influence can occur at sound pressure levels lower than the ones that cause physiological damage, such as hearing loss, being mediated by the noise characteristics. However, studies concerning this issue are still scarce. Study. The aim of this study was to investigate the effects of three noise conditions on attention and short-term memory: standard condition (C1), environmental noise without alarm sounds (C2), and environmental noise with alarm sounds (C3). First, noise levels were measured during a normal workweek in a fast food establishment. Second, an experiment was designed to simulate the noise normally prevailing in the workplace. The noise levels were fixed at 45 ± 0.3 dB(A) (C1), 60 ± 0.4 dB(A) (C2), and 68 ± 0.4 dB(A) (C3). The influence of noise on participants' attention and short-term memory was assessed with the following test battery: serial recall, response inhibition, and Stroop interference. Because annoyance, stress, and discomfort perceptions during the tests can influence results, visual analog scales to assess these variables were applied in the end of each trial. Fifteen undergraduate students were included in this pilot study (20-23 years; M = 21.6; SD = 0.8; all female). The results demonstrated that participants' performance during the tests was lower in C3, that is, the number of errors was higher and the reaction time longer. Participants also experienced higher levels of discomfort, stress, and annoyance perceptions in this condition. However, task performance was not found to be influenced by these perceptions. This study provided important insights about the different noise conditions that workers are exposed in a fast food restaurant, and how they influence participants' performance. Further research should involve workers, exploring how these conditions are implicated in their performance in the field.


Prevention of type 2 diabetes: data from recent trials.
All four main studies of lifestyle intervention on diabetes incidence found a clear benefit for diet and exercise intervention compared with usual care. Although the study populations differed by race and ethnicity, the mean BMI, and the intensity of the lifestyle intervention provided, all investigators found substantial diabetes risk reduction with modest weight loss and increased physical activity. Results of these trials give health care providers useful and heartening information to share with patients at risk for diabetes. The challenge remains to find feasible and cost-efficient methods to identify people at risk and to deliver effective lifestyle interventions. Findings from trials of pharmacologic agents such as metformin, acarbose, and troglitazone are encouraging; however, the ADA recommends that drug therapy should not be used routinely to prevent diabetes until more information regarding the cost-effectiveness of such intervention is known [20]. Results from trials that found a lower incidence of diabetes among those randomly assigned to angiotensin-converting enzyme inhibitors, statins, or hormone therapy are intriguing but must be viewed with caution because they are based on post hoc analyses. Because it is difficult to conduct randomized controlled trials of major operative procedures such as bariatric surgery, observational studies that compare surgical interventions for weight loss with traditional weight-loss management may be the best evidence available. These studies have the potential for healthy-person bias in that people who choose bariatric surgery may have other healthy behaviors that are often difficult to measure and control for; such behaviors could account for their lower incidence of diabetes. Undeniably, the best test to diagnose those at high risk for diabetes is not yet known. New strategies that identify those with pre-diabetes and that overcome the limitations of the current tests, particularly the 2-hour post-challenge glucose test, are needed.


Secreted Klotho and FGF23 in chronic kidney disease Stage 1 to 5: a sequence suggested from a cross-sectional study.
Klotho and fibroblast growth factor 23 (FGF23) are key regulators of mineral metabolism in renal insufficiency. FGF23 levels have been shown to increase early in chronic kidney disease (CKD); however, the corresponding soluble Klotho levels at the different CKD stages are not known. Soluble Klotho, FGF23, parathyroid hormone (PTH), 1,25-dihydroxy vitamin D(3) (1,25D) and other parameters of mineral metabolism were measured in an observational cross-sectional study in 87 patients. Locally weighted scatter plot smoothing function of these parameters were plotted versus estimated glomerular filtration rate (eGFR) to illustrate the pattern of the relationship. Linear and non-linear regression analyses were performed to estimate changes in mineral metabolism parameters per 1mL/min/1.73 m(2) decline. In CKD 1-5, Klotho and 1,25D linearly decreased, whereas both FGF23 and PTH showed a baseline at early CKD stages and then a curvilinear increase. Crude mean Klotho level declined by 4.8 pg/mL (95% CI 3.5-6.2 pg/mL, P < 0.0001) and 1,25D levels by 0.30 ng/L (95% CI 0.18-0.41 ng/L, P < 0.0001) as GFR declined by 1 mL/min/1.73 m(2). After adjustment for age, gender, serum 25-hydroxyvitamin D levels and concomitant medications (calcium, supplemental vitamin D and calcitriol), we estimated that the mean Klotho change was 3.2 pg/mL (95% CI 1.2-5.2 pg/mL, P = 0.0019) for each 1 mL/min/1.73 m(2) GFR change. FGF23 departed from the baseline at an eGFR of 47 mL/min/1.73 m(2) (95% CI 39-56 mL/min/1.73 m(2)), whereas PTH departed at an eGFR of 34 mL/min/1.73 m(2) (95% CI 19-50 mL/min/1.73 m(2)). Soluble Klotho and 1,25D levels decrease and FGF23 levels increase at early CKD stages, whereas PTH levels increase at more advanced CKD stages.


Working with 'hands-off' support: a qualitative study of multidisciplinary teams' experiences of home rehabilitation for older people.
There is a move towards the provision of rehabilitation for older people in their homes. It is essential to ensure that rehabilitation services promote independence of older people. The aim of the study was to explore multidisciplinary teams' experiences of home rehabilitation for older people. Five focus groups were conducted with multidisciplinary teams based in a municipality in Sweden, covering seven different professions. In total, 28 participants volunteered to participate in these interviews. Interviews were transcribed verbatim and analysed according to content analysis. Two main categories, as well as four subcategories, emerged. The first main category, having a rehabilitative approach in everyday life, consisted of the subcategories: 'giving 'hands-off' support' and 'being in a home environment'. The second main category, working across professional boundaries, consisted of the subcategories: 'coordinating resources' and 'learning from each other'. Common goals, communication skills and role understanding contributed to facilitating the teams' performances of rehabilitation. A potential benefit of home rehabilitation, because the older person is in a familiar environment, is to work a rehabilitative approach into each individual's activity in their everyday life in order to meet their specific needs. At an organisational level, there is a need for developing services to further support older people's psychosocial needs during rehabilitation. Team performance towards an individual's rehabilitation should come from an emerged whole and not only from the performance of a specific professional approach depending on the traditional role of each profession. A rehabilitative approach is based on 'hands-off' support in order to incorporate an individual's everyday activities as a part of their rehabilitation.


Asthma control test via text messaging: could it be a tool for evaluating asthma control?
Originally, the Asthma Control Test (ACT) was designed for English-speaking patients using a paper-and-pencil format. The Turkish version of the ACT was recently validated. This article compares the paper-and-pencil and web-based texting formats of the Turkish version of the ACT and evaluates the compatibility of these ACT scores with GINA-based physician assessments of asthma control. This multicentre prospective study included 431 asthma patients from outpatient clinics in Turkey. The patients were randomized into a paper-and-pencil group (n = 220) and a text messaging group (n = 211). Patients completed the ACT at Visit 1, after 10 ± 2 days, and at 5 ± 1 week to demonstrate the reliability and responsiveness of the test. At each visit, physicians assessed patients' asthma control levels. The ACT administered via texting showed an internal consistency of 0.82. For the texting group, we found a significant correlation between the ACT and physician assessments at Visit 1 (r = 0.60, p < 0.001). The AUC was 0.87, with a sensitivity of 78.0% and a specificity of 77.5% for a score of ≤19 for screening "uncontrolled" asthma in the texting group. When the Turkish version of the ACT was administered via either the paper-and-pencil or text messaging test, scores were closely associated with physician assessments of asthma control.


In Vitro Global Gene Expression Analyses Support the Ethnopharmacological Use of Achyranthes aspera.
Achyranthes aspera (family Amaranthaceae) is known for its anticancer properties. We have systematically validated the in vitro and in vivo anticancer properties of this plant. However, we do not know its mode of action. Global gene expression analyses may help decipher its mode of action. In the absence of identified active molecules, we believe this is the best approach to discover the mode of action of natural products with known medicinal properties. We exposed human pancreatic cancer cell line MiaPaCa-2 (CRL-1420) to 34 μ g/mL of LE for 24, 48, and 72 hours. Gene expression analyses were performed using whole human genome microarrays (Agilent Technologies, USA). In our analyses, 82 (54/28) genes passed the quality control parameter, set at FDR ≤ 0.01 and FC of ≥±2. LE predominantly affected pathways of immune response, metabolism, development, gene expression regulation, cell adhesion, cystic fibrosis transmembrane conductance regulation (CFTR), and chemotaxis (MetaCore tool (Thomson Reuters, NY)). Disease biomarker enrichment analysis identified LE regulated genes involved in Vasculitis-inflammation of blood vessels. Arthritis and pancreatitis are two of many etiologies for vasculitis. The outcome of disease network analysis supports the medicinal use of A. aspera, viz, to stop bleeding, as a cure for pancreatic cancer, as an antiarthritic medication, and so forth.


Tris(1,10-phenanthroline-κ(2) N,N')ruthenium(II) bis-(perchlorate).
The asymmetric unit of the title compound, [Ru(C12H8N2)3](ClO4)2, contains one octahedrally coordinated Ru(II) cation of the ruthenium-phenanthroline complex and three differently occupied perchlorate anions: two, denoted A and B, are located on the twofold axis while another, denoted C, is positioned in the proximity of the twofold screw axis. Perchlorate anions B and C are severely disordered. The occupancies of the two major conformers of anion B refined to 0.302 (6) and 0.198 (6). Perchlorate ion C was modeled in two alternate conformations which refined to occupancies of 0.552 (10) and 0.448 (10).


Assessing trade-offs to inform ecosystem-based fisheries management of forage fish.
Twenty-first century conservation is centered on negotiating trade-offs between the diverse needs of people and the needs of the other species constituting coupled human-natural ecosystems. Marine forage fishes, such as sardines, anchovies, and herring, are a nexus for such trade-offs because they are both central nodes in marine food webs and targeted by fisheries. An important example is Pacific herring, Clupea pallisii in the Northeast Pacific. Herring populations are subject to two distinct fisheries: one that harvests adults and one that harvests spawned eggs. We develop stochastic, age-structured models to assess the interaction between fisheries, herring populations, and the persistence of predators reliant on herring populations. We show that egg- and adult-fishing have asymmetric effects on herring population dynamics--herring stocks can withstand higher levels of egg harvest before becoming depleted. Second, ecosystem thresholds proposed to ensure the persistence of herring predators do not necessarily pose more stringent constraints on fisheries than conventional, fishery driven harvest guidelines. Our approach provides a general template to evaluate ecosystem trade-offs between stage-specific harvest practices in relation to environmental variability, the risk of fishery closures, and the risk of exceeding ecosystem thresholds intended to ensure conservation goals are met.


Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma.
Whether the brain tumor medulloblastoma originates from stem cells or restricted progenitor cells is unclear. To investigate this, we activated oncogenic Hedgehog (Hh) signaling in multipotent and lineage-restricted central nervous system (CNS) progenitors. We observed that normal unipotent cerebellar granule neuron precursors (CGNPs) derive from hGFAP(+) and Olig2(+) rhombic lip progenitors. Hh activation in a spectrum of early- and late-stage CNS progenitors generated similar medulloblastomas, but not other brain cancers, indicating that acquisition of CGNP identity is essential for tumorigenesis. We show in human and mouse medulloblastoma that cells expressing the glia-associated markers Gfap and Olig2 are neoplastic and retain features of embryonic-type granule lineage progenitors. Thus, oncogenic Hh signaling promotes medulloblastoma from lineage-restricted granule cell progenitors.


Identification, structure, and function of a novel type VI secretion peptidoglycan glycoside hydrolase effector-immunity pair.
Bacteria employ type VI secretion systems (T6SSs) to facilitate interactions with prokaryotic and eukaryotic cells. Despite the widespread identification of T6SSs among Gram-negative bacteria, the number of experimentally validated substrate effector proteins mediating these interactions remains small. Here, employing an informatics approach, we define novel families of T6S peptidoglycan glycoside hydrolase effectors. Consistent with the known intercellular self-intoxication exhibited by the T6S pathway, we observe that each effector gene is located adjacent to a hypothetical open reading frame encoding a putative periplasmically localized immunity determinant. To validate our sequence-based approach, we functionally investigate a representative family member from the soil-dwelling bacterium Pseudomonas protegens. We demonstrate that this protein is secreted in a T6SS-dependent manner and that it confers a fitness advantage in growth competition assays with Pseudomonas putida. In addition, we determined the 1.4 Å x-ray crystal structure of this effector in complex with its cognate immunity protein. The structure reveals the effector shares highest overall structural similarity to a glycoside hydrolase family associated with peptidoglycan N-acetylglucosaminidase activity, suggesting that T6S peptidoglycan glycoside hydrolase effector families may comprise significant enzymatic diversity. Our structural analyses also demonstrate that self-intoxication is prevented by the immunity protein through direct occlusion of the effector active site. This work significantly expands our current understanding of T6S effector diversity.


Setting up an outpatient parenteral antimicrobial therapy (OPAT) unit in Switzerland: review of the first 18 months of activity.
Outpatient parenteral antimicrobial therapy (OPAT) has been recognised as a useful, cost-effective and safe alternative to inpatient treatment, but no formal OPAT unit existed in Switzerland until recently. In December 2013 an OPAT unit was established at Lausanne University Hospital. We review here the experience of this new OPAT unit after 18 months of activity. Patient characteristics, clinical activities and outcomes were recorded prospectively. Need and acceptance was evaluated as number of OPAT courses administered and number of patients refusing OPAT. Safety and efficacy were evaluated as: (1) adverse events linked to antimicrobials and catheters, (2) re-admission to hospital, (3) rate of treatment failures and (4) mortality. Over 18 months, 179 courses of OPAT were administered. Acceptance was high with only four patients refusing OPAT. Urinary tract infections with resistant bacteria and musculoskeletal infections were the most common diagnoses. Self-administration of antibiotics using elastomeric pumps became rapidly the most frequently used approach. Sixteen patients presented with adverse events linked to antimicrobials and catheters. OPAT-related readmissions occurred in nine patients. The overall cure rate was 94 %. This study shows that OPAT is very well accepted by patients and medical staff, even in a setting which has not used this type of treatment approach until now. Self-administration using elastomeric pumps proved to be particularly useful, safe and efficient. OPAT offers a good alternative to hospitalisation for patients presenting with infections due to resistant bacteria that cannot be treated orally anymore and for difficult to treat infections.


Comparison of computational methods for identifying translation initiation sites in EST data.
Expressed Sequence Tag (EST) sequences are generally single-strand, single-pass sequences, only 200-600 nucleotides long, contain errors resulting in frame shifts, and represent different parts of their parent cDNA. If the cDNAs contain translation initiation sites, they may be suitable for functional genomics studies. We have compared five methods to predict translation initiation sites in EST data: first-ATG, ESTScan, Diogenes, Netstart, and ATGpr. A dataset of 100 EST sequences, 50 with and 50 without, translation initiation sites, was created. Based on analysis of this dataset, ATGpr is found to be the most accurate for predicting the presence versus absence of translation initiation sites. With a maximum accuracy of 76%, ATGpr more accurately predicts the position or absence of translation initiation sites than NetStart (57%) or Diogenes (50%). ATGpr similarly excels when start sites are known to be present (90%), whereas NetStart achieves only 60% overall accuracy. As a baseline for comparison, choosing the first ATG correctly identifies the translation initiation site in 74% of the sequences. ESTScan and Diogenes, consistent with their intended use, are able to identify open reading frames, but are unable to determine the precise position of translation initiation sites. ATGpr demonstrates high sensitivity, specificity, and overall accuracy in identifying start sites while also rejecting incomplete sequences. A database of EST sequences suitable for validating programs for translation initiation site prediction is now available. These tools and materials may open an avenue for future improvements in start site prediction and EST analysis.


Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes.
Epidemiologic studies suggest that type 2 diabetes (T2D) increases breast cancer risk and mortality, but there is limited experimental evidence supporting this association. Moreover, there has not been any definition of a pathophysiological pathway that diabetes may use to promote tumorigenesis. In the present study, we used the MKR mouse model of T2D to investigate molecular mechanisms that link T2D to breast cancer development and progression. MKR mice harbor a transgene encoding a dominant-negative, kinase-dead human insulin-like growth factor-I receptor (IGF-IR) that is expressed exclusively in skeletal muscle, where it acts to inactivate endogenous insulin receptor (IR) and IGF-IR. Although lean female MKR mice are insulin resistant and glucose intolerant, displaying accelerated mammary gland development and enhanced phosphorylation of IR/IGF-IR and Akt in mammary tissue, in the context of three different mouse models of breast cancer, these metabolic abnormalities were found to accelerate the development of hyperplastic precancerous lesions. Normal or malignant mammary tissue isolated from these mice exhibited increased phosphorylation of IR/IGF-IR and Akt, whereas extracellular signal-regulated kinase 1/2 phosphorylation was largely unaffected. Tumor-promoting effects of T2D in the models were reversed by pharmacological blockade of IR/IGF-IR signaling by the small-molecule tyrosine kinase inhibitor BMS-536924. Our findings offer compelling experimental evidence that T2D accelerates mammary gland development and carcinogenesis,and that the IR and/or the IGF-IR are major mediators of these effects.


Fourier modeling of the BOLD response to a breath-hold task: Optimization and reproducibility.
Cerebrovascular reactivity (CVR) reflects the capacity of blood vessels to adjust their caliber in order to maintain a steady supply of brain perfusion, and it may provide a sensitive disease biomarker. Measurement of the blood oxygen level dependent (BOLD) response to a hypercapnia-inducing breath-hold (BH) task has been frequently used to map CVR noninvasively using functional magnetic resonance imaging (fMRI). However, the best modeling approach for the accurate quantification of CVR maps remains an open issue. Here, we compare and optimize Fourier models of the BOLD response to a BH task with a preparatory inspiration, and assess the test-retest reproducibility of the associated CVR measurements, in a group of 10 healthy volunteers studied over two fMRI sessions. Linear combinations of sine-cosine pairs at the BH task frequency and its successive harmonics were added sequentially in a nested models approach, and were compared in terms of the adjusted coefficient of determination and corresponding variance explained (VE) of the BOLD signal, as well as the number of voxels exhibiting significant BOLD responses, the estimated CVR values, and their test-retest reproducibility. The brain average VE increased significantly with the Fourier model order, up to the 3rd order. However, the number of responsive voxels increased significantly only up to the 2nd order, and started to decrease from the 3rd order onwards. Moreover, no significant relative underestimation of CVR values was observed beyond the 2nd order. Hence, the 2nd order model was concluded to be the optimal choice for the studied paradigm. This model also yielded the best test-retest reproducibility results, with intra-subject coefficients of variation of 12 and 16% and an intra-class correlation coefficient of 0.74. In conclusion, our results indicate that a Fourier series set consisting of a sine-cosine pair at the BH task frequency and its two harmonics is a suitable model for BOLD-fMRI CVR measurements based on a BH task with preparatory inspiration, yielding robust estimates of this important physiological parameter.


European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma.
Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).


Decoupling of Early V5 Motion Processing from Visual Awareness: A Matter of Velocity as Revealed by Transcranial Magnetic Stimulation.
Motion information can reach V5/MT through two parallel routes: one conveying information at early latencies through a direct subcortical route and the other reaching V5 later via recurrent projections through V1. Here, we tested the hypothesis that input via the faster direct pathway depends on motion characteristics. To this end, we presented motion stimuli to healthy human observers at different velocities (4.4°/sec vs. 23°/sec) with static stimuli as controls while applying transcranial magnetic stimulation (TMS) pulses over V5 or V1. We probed for TMS interference with objective (two-alternative forced choice [2AFC]) and subjective (awareness) measures of motion processing at six TMS delays from stimulus onset (poststimulus window covered: ∼27-160 msec). Our results for V5-TMS showed earlier interference with objective performance for fast motion (53.3 msec) than slow motion (80 msec) stimuli. Importantly, TMS-induced decreases in objective measures of motion processing did correlate with decreases in subjective measures for slow but not fast motion stimuli. Moreover, V1-TMS induced a temporally unspecific interference with visual processing as it impaired the processing of both motion and static stimuli at the same delays. These results are in accordance with fast moving stimuli reaching V5 through a different route than slow moving stimuli. The differential latencies and coupling to awareness suggest distinct involvement of a direct (i.e., colliculo-extrastriate) connection bypassing V1 depending on stimulus velocity (fast vs. slow). Implication of a direct pathway in the early processing of fast motion may have evolved through its behavioral relevance.


Heparin-induced thrombocytopenia and cardiac surgery.
Unfractionated heparin given during cardiopulmonary bypass is remarkably immunogenic, as 25% to 50% of postcardiac surgery patients develop heparin-dependent antibodies during the next 5 to 10 days. Sometimes, these antibodies strongly activate platelets and coagulation, thereby causing the prothrombotic disorder, heparin-induced thrombocytopenia. The risk of heparin-induced thrombocytopenia is 1% to 3% if unfractionated heparin is continued beyond the first postoperative week. When cardiac surgery is urgently needed for a patient with acute or subacute heparin-induced thrombocytopenia, options include an alternative anticoagulant (bivalirudin, lepirudin, or danaparoid) or combining unfractionated heparin with a platelet antagonist (epoprostenol or tirofiban). As heparin-induced thrombocytopenia antibodies are transient, unfractionated heparin alone is appropriate in a patient with previous heparin-induced thrombocytopenia whose antibodies have disappeared.


Arthritogenic self-reactive CD4+ T cells acquire an FR4hiCD73hi anergic state in the presence of Foxp3+ regulatory T cells.
Rheumatoid arthritis develops in association with a defect in peripheral CD4(+) T cell homeostasis. T cell lymphopenia has also been shown to be a barrier to CD4(+) T cell clonal anergy induction. We therefore explored the relationship between clonal anergy induction and the avoidance of autoimmune arthritis by tracking the fate of glucose-6-phosphate isomerase (GPI)-reactive CD4(+) T cells in the setting of selective T cell lymphopenia. CD4(+) T cell recognition of self-GPI peptide/MHC class II complexes in normal murine hosts did not lead to arthritis and instead caused those T cells to develop a Folate receptor 4(hi)CD73(hi) anergic phenotype. In contrast, hosts selectively depleted of polyclonal Foxp3(+)CD4(+) regulatory T cells could not make GPI-specific CD4(+) T cells anergic and failed to control arthritis. This suggests that autoimmune arthritis develops in the setting of lymphopenia when Foxp3(+)CD4(+) regulatory T cells are insufficient to functionally inactivate all autoreactive CD4(+) T cells that encounter self-Ag.


Cost-effectiveness of magnetic resonance guided focused ultrasound for the treatment of uterine fibroids.
The aim of this study is to evaluate the cost-effectiveness of Magnetic Resonance Guided Focused Ultrasound (MRgFUS) compared with alternative treatments for uterine fibroids in the United States. We used techniques of decision analysis and data from secondary sources to develop and estimate an economic model of the management of uterine fibroids among premenopausal women. Patients in the model receive treatment with MRgFUS, uterine artery embolization (UAE), abdominal myomectomy, hysterectomy, or pharmacotherapy. The model predicts total costs (including subsequent procedures) and quality-adjusted life-years (QALYs) for each treatment strategy over a lifetime horizon, discounted at 3 percent, from a societal perspective. Data on treatment efficacy and safety were obtained from published and unpublished studies. Costs (2005 US$) were obtained from an analysis of a large administrative database and other secondary sources. Lost productivity costs were included in the base-case analysis, but excluded in a sensitivity analysis. UAE was associated with the most QALYs (17.39), followed by MRgFUS (17.36), myomectomy (17.31), hysterectomy (17.18), and pharmacotherapy (16.70). Pharmacotherapy was the least costly strategy ($9,200 per patient), followed by hysterectomy ($19,800), MRgFUS ($27,300), UAE ($28,900), and myomectomy ($35,100). Incremental cost-effectiveness ratios (cost per QALY gained) were $21,800 for hysterectomy, $41,400 for MRgFUS, and $54,200 for UAE; myomectomy was more costly and less effective than both MRgFUS and UAE. Results were sensitive to MRgFUS recurrence rates, MRgFUS procedure costs, and assumptions about quality of life following hysterectomy. Our findings suggest that MRgFUS is in the range of currently accepted criteria for cost-effectiveness, along with hysterectomy and UAE.


Incoherent wavefront reconstruction by a retroemission device.
This Letter addresses wavefront reconstruction by a retroemission device (REM). REM represents a lenslet array mounted on a substrate made of photoluminescent optical material, such as a polymer film impregnated with upconversion nanoparticles. An excitation light wavefront incident on the REM was sampled by the lenslet array piece-wise. Each wavelet at the lenslet aperture was converged into a voxel in the substrate, with its coordinates encoding the angle of incidence and curvature of the wavelet. Photoluminescence excited in the voxel was radiated isotropically, its back-propagating fraction was captured by the lenslet and transformed into a back-propagating wavelet, which contributed to reproduction of the entire incident wavefront with some fidelity. We experimentally proved the wavefront reconstruction based on REM, and present its theoretical model based on a Fresnel-Kirchhoff approximation.


Phenylacetylene polymerisation mediated by cationic cyclometallated palladium(ii) complexes bearing benzylidene 2,6-diisopropylphenylamine and its derivatives as ligands.
A series of novel cationic palladacycle complexes bearing benzylidene-2,6-diisopropylphenylamine derivatives as ligands and with the general formula [Pd(MeCN)(L)(R-C6H3)CH[double bond, length as m-dash]N{2,6-iPr2-C6H3}][B(3,5-(CF3)2-C6H3)] (R = H, Cl, Br, F, OMe and L = 1,3,5-triaza-7-phosphaadamantane (PTA), tricyclohexylphosphine (PCy3) and triphenylphosphine (PPh3)) were prepared and characterized by a range of analytical techniques. These cationic palladacycle complexes were found to be active precatalysts for the polymerisation of phenylacetylene. The meta-substituent on the cyclometallated ring was found to have a marked effect on the catalyst performance in that complexes, which contained electron-withdrawing substituents, were found to be the most active in the polymerisation process. Furthermore, increasing the steric bulk of the phosphine ligand led to the production of higher molecular weight polyphenylacetylenes (PPA). Polymerisation reactions performed at 25 °C gave a mixture of both cis-transoidal and trans-cisoidal PPA while trans-cisoidal PPA was selectively produced at elevated temperatures (60 °C). Preliminary mechanistic studies demonstrated that polymerisation proceeds via dissociation of the C,N-chelating ligand, and involves the formation of an iminium cationic fragment.


Comparative transcriptomic profiling of hydrogen peroxide signaling networks in zebrafish and human keratinocytes: Implications toward conservation, migration and wound healing.
Skin wounds need to be repaired rapidly after injury to restore proper skin barrier function. Hydrogen peroxide (H2O2) is a conserved signaling factor that has been shown to promote a variety of skin wound repair processes, including immune cell migration, angiogenesis and sensory axon repair. Despite growing research on H2O2 functions in wound repair, the downstream signaling pathways activated by this reactive oxygen species in the context of injury remain largely unknown. The goal of this study was to provide a comprehensive analysis of gene expression changes in the epidermis upon exposure to H2O2 concentrations known to promote wound repair. Comparative transcriptome analysis using RNA-seq data from larval zebrafish and previously reported microarray data from a human epidermal keratinocyte line shows that H2O2 activates conserved cell migration, adhesion, cytoprotective and anti-apoptotic programs in both zebrafish and human keratinocytes. Further assessment of expression characteristics and signaling pathways revealed the activation of three major H2O2-dependent pathways, EGF, FOXO1, and IKKα. This study expands on our current understanding of the clinical potential of low-level H2O2 for the promotion of epidermal wound repair and provides potential candidates in the treatment of wound healing deficits.


The induction of proliferative vascular smooth muscle cell phenotypes by benzo(a)pyrene is characterized by up-regulation of inositol phospholipid metabolism and c-Ha-ras gene expression.
Polycyclic aromatic hydrocarbons, such as benzo(a)pyrene (BaP), have been implicated in the initiation and progression of vascular lesions of atherosclerotic morphology in laboratory animals. In the present study, experiments were conducted to define the impact of repeated cycles of BaP challenge in vivo on the phenotypic expression of rat vascular (aortic) smooth muscle cells (SMCs). After eight weekly injections of male Sprague-Dawley rats with BaP (10 mg/kg) or vehicle, SMCs were isolated from the thoracic aorta and established in culture to define patterns of phenotypic expression. The mitogenic responsiveness of five independent strains of BaP cells was markedly enhanced relative to control counterparts. Increased proliferation rates in BaP cells correlated with increased synthesis and secretion of proline-containing proteins. Upregulation of mitogenicity in BaP cells did not involve autocrine factors since conditioned media from growth-arrested, as well as cycling cultures of, BaP cells stimulated DNA synthesis to a lesser extent than conditioned media from control counterparts. Levels of inositol phosphate metabolites, primarily products of phosphatidylinositol (PtdIns)-3-kinase activity, were increased relative to controls in cultures of BaP cells under constitutive and serum-stimulated conditions. LY294002, an inhibitor of PtdIns-3-kinase, inhibited DNA synthesis and cell proliferation in control cells to a greater extent than in BaP counterparts. The proliferative phenotype of BaP cells was also characterized by marked up-regulation of c-Ha-ras protooncogene expression. Based on these data we conclude that repeated cycles of BaP challenge in vivo induce highly proliferative vascular smooth muscle cell phenotypes characterized by up-regulation of PtdIns metabolism and c-Ha-ras gene expression.


Effect of moderate static electric field on the growth and metabolism of Chlorella vulgaris.
An electric field (EF) generator device was fabricated and applied to the treatment of Chlorella vulgaris ISC33 at three distinct concentrations before cultivation. The EF of moderate intensity (2.7kVcm(-1)) has a hormetic effect on algal growth. The highest growth stimulation of 51% was observed after 50min treatment of 0.4gL(-1) algal suspension. The influence of EF on the system was then studied from both theoretical and experimental perspectives. The growth rate increased with treatment time up to a maximum because of improved membrane permeability, and then declined afterwards due to peroxide accumulation in the medium. The contents of chlorophylls, carotenoids, soluble carbohydrates, lipids, and proteins were also measured to understand possible changes on algal metabolism. The EF treatment of algal suspension has no observable effect on the cell metabolism while both algal growth and metabolism was significantly affected by the inoculum size.


Utility of tissue residues for predicting effects of metals on aquatic organisms.
As part of a SETAC Pellston Workshop, we evaluated the potential use of metal tissue residues for predicting effects in aquatic organisms. This evaluation included consideration of different conceptual models and then development of several case studies on how tissue residues might be applied for metals, assessing the strengths and weaknesses of these different approaches. We further developed a new conceptual model in which metal tissue concentrations from metal-accumulating organisms (principally invertebrates) that are relatively insensitive to metal toxicity could be used as predictors of effects in metal-sensitive taxa that typically do not accumulate metals to a significant degree. Overall, we conclude that the use of tissue residue assessment for metals other than organometals has not led to the development of a generalized approach as in the case of organic substances. Species-specific and site-specific approaches have been developed for one or more metals (e.g., Ni). The use of gill tissue residues within the biotic ligand model is another successful application. Aquatic organisms contain a diverse array of homeostatic mechanisms that are both metal- and species-specific. As a result, use of whole-body measurements (and often specific organs) for metals does not lead to a defensible position regarding risk to the organism. Rather, we suggest that in the short term, with sufficient validation, species- and site-specific approaches for metals can be developed. In the longer term it may be possible to use metal-accumulating species to predict toxicity to metal-sensitive species with appropriate field validation.


An evaluation of recent federal spending on comparative effectiveness research: priorities, gaps, and next steps.
The American Recovery and Reinvestment Act of 2009 included new funding for developing better evidence about health interventions, with a down payment of $1.1 billion for comparative effectiveness research. Our analysis of funds allocated in the legislation found that nearly 90 percent of the $1.1 billion will eventually be spent on two main types of activity: developing and synthesizing comparative effectiveness evidence, and improving the capacity to conduct comparative effectiveness research. Based on our analysis, priorities for the new funding should include greater emphasis on experimental research; evaluation of reforms at the health system level; identification of effects on subgroups of patients; inclusion of understudied groups of patients; and dissemination of results.


Hospital care for children and young adults in the last year of life: a population-based study.
To help design population-based pediatric palliative care services, we sought to describe the hospital care received in the last year of life by children and young adults who died. We also determined the proportion with complex chronic conditions (CCCs) and tested whether the use of hospital services increased as the date of death drew nearer. For all deaths occurring under 25 years of age from 1990 to 1996 in Washington State, USA, we linked death certificate information to hospital utilization records and analyzed the timing and duration of hospitalizations and the nature of hospital procedures during the year prior to death. Of the 8 893 deaths, 25 % had CCCs. Among infants with CCCs, 84 % were hospitalized at the time of death and 50 % had been mechanically ventilated during their terminal admission. Among the 458 CCC neonates dying under a week of age, 92% of all days of life were spent in the hospital; among the 172 CCC neonates dying during the second to fourth weeks of life, 85 % of all days of life were spent hospitalized; among the 286 CCC infants dying during the second to twelfth month of life, 41 % of all days of life were spent hospitalized. Among children and young adults with CCCs, 55 % were hospitalized at the time of death, and 19 % had been mechanically ventilated during their terminal admission. For these older patients, the median number of days spent in the hospital during the year preceding death was 18, yet less than a third of this group was hospitalized at any point in time until the last week of their lives. The rate of hospital use increased as death drew near. For subjects who had received hospital care, 44 % had governmental insurance as the source of primary payment. Infants who died spent a substantial proportion of their lives in hospitals, whereas children and adolescents who died from CCCs predominantly lived outside of the hospital during the last year of life. To serve these patients, pediatric palliative and end-of-life care will have to be provided in an integrated, coordinated manner both in hospitals and home communities.


A new oil/membrane approach for integrated sweat sampling and sensing: sample volumes reduced from μL's to nL's and reduction of analyte contamination from skin.
Wearable sweat biosensensing technology has dominantly relied on techniques which place planar-sensors or fluid-capture materials directly onto the skin surface. This 'on-skin' approach can result in sample volumes in the μL regime, due to the roughness of skin and/or due to the presence of hair. Not only does this increase the required sampling time to 10's of minutes or more, but it also increases the time that sweat spends on skin and therefore increases the amount of analyte contamination coming from the skin surface. Reported here is a first demonstration of a new paradigm in sweat sampling and sensing, where sample volumes are reduced from the μL's to nL's regime, and where analyte contamination from skin is reduced or even eliminated. A micro-porous membrane is constructed such that it is porous to sweat only. To complete a working device, first placed onto skin is a cosmetic-grade oil, secondly this membrane, and thirdly the sensors. As a result, spreading of sweat is isolated to only regions above the sweat glands before it reaches the sensors. Best case sampling intervals are on the order of several minutes, and the majority of hydrophilic (low oil solubility) contaminants from the skin surface are blocked. In vitro validation of this new approach is performed with an improved artificial skin including human hair. In vivo tests show strikingly consistent results, and reveal that the oil/membrane is robust enough to even allow horizontal sliding of a sensor.


Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy.
Amyloid transthyretin (ATTR) amyloidosis with polyneuropathy (PN) is a progressive, debilitating, systemic disease wherein transthyretin protein misfolds to form amyloid, which is deposited in the endoneurium. ATTR amyloidosis with PN is the most serious hereditary polyneuropathy of adult onset. It arises from a hereditary mutation in the TTR gene and may involve the heart as well as other organs. It is critical to identify and diagnose the disease earlier because treatments are available to help slow the progression of neuropathy. Early diagnosis is complicated, however, because presentation may vary and family history is not always known. Symptoms may be mistakenly attributed to other diseases such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), idiopathic axonal polyneuropathy, lumbar spinal stenosis, and, more rarely, diabetic neuropathy and AL amyloidosis. In endemic countries (e.g., Portugal, Japan, Sweden, Brazil), ATTR amyloidosis with PN should be suspected in any patient who has length-dependent small-fiber PN with autonomic dysfunction and a family history of ATTR amyloidosis, unexplained weight loss, heart rhythm disorders, vitreous opacities, or renal abnormalities. In nonendemic countries, the disease may present as idiopathic rapidly progressive sensory motor axonal neuropathy or atypical CIDP with any of the above symptoms or with bilateral carpal tunnel syndrome, gait disorders, or cardiac hypertrophy. Diagnosis should include DNA testing, biopsy, and amyloid typing. Patients should be followed up every 6-12 months, depending on the severity of the disease and response to therapy. This review outlines detailed recommendations to improve the diagnosis of ATTR amyloidosis with PN.


Resistant hypertension: comparing hemodynamic management to specialist care.
Although resistant hypertension affects a minority of all hypertensives, this group continues to experience disproportionately high cardiovascular event rates despite newer antihypertensive agents. Hypertension represents an imbalance of hemodynamic forces within the circulation, usually characterized by elevated systemic vascular resistance. We studied the utility of serial hemodynamic parameters in the selection and titration of antihypertensive medication in resistant hypertensive patients using highly reproducible noninvasive measurements by thoracic bioimpedance. Resistant hypertension patients (n=104) were randomized to drug selection based either on serial hemodynamic (HD) measurements and a predefined algorithm or on drug selection directed by a hypertension specialist (SC) in a 3-month intensive treatment program. Blood pressure was lowered by intensified drug therapy in both treatment groups (169+/-3/87+/-2 to 139+/-2/72+/-1 mm Hg HD versus 173+/-3/91+/-2 to 147+/-2/79+/-1 mm Hg SC, P<0.01 for systolic and diastolic BP), using similar numbers and intensity of antihypertensive medications. Blood pressures were reduced further for those treated according to hemodynamic measurements, resulting in improved control rates (56% HD versus 33% SC controlled to </=140/90 mm Hg, P<0.05) and incremental reduction in systemic vascular resistance measurements. Although the number of patients taking diuretics did not differ between groups, final diuretic dosage was higher in the hemodynamic cohort. Our results demonstrate superior blood pressure control using a treatment algorithm and serial hemodynamic measurements compared with clinical judgment alone in a randomized prospective study. Our measurements of thoracic fluid volume support occult volume expansion as a mediator of antihypertensive drug resistance and use of impedance measurements to guide advancing diuretic dose and adjustment of multidrug antihypertensive treatment.


The persistence of infectious adenovirus (type 35) in mussels (Mytilus edulis) and oysters (Ostrea edulis).
The aim of this study was to provide information for improving risk assessment of viral contaminants in bivalves. The persistence of viable adenovirus type 35 (Ad35) after controlled contaminations of blue mussels, Mytilus edulis, and oysters, Ostrea edulis, was studied. Bivalves, kept in running seawater at two different temperatures (4 and 18 degrees C) were sampled after 1, 3, 7, 14, 21, 35, 42, 49, 56, and 70 days. Virus particles were separated from the gills and the digestive gland through ultra high-speed centrifugation. Qualitative PCR analyses of DNA in the virus extracts showed that Ad35 was detectable for 6-10 weeks and quantitative real-time PCR verified a gradual but not linear decrease in copy numbers, within this time interval. The virus genome was detectable to the same degree on the gills as in the digestive gland. When viral extractions were inoculated on A549 cells to investigate the cytopathic effect (CPE) it was shown that Ad35 stayed infectious in oysters, kept at 4 degrees C, for about six weeks, which was double the time compared to that for mussels. The detection of the viral genome exceeded the persistence of their infectivity, in most cases with 4-6 weeks. The data were highly variable and the sporadic occurrence of high numbers of accumulated viruses and their remaining infectivity is seemingly a significant factor regarding food safety.


Exposure to fogger trucks and breast cancer incidence in the Long Island Breast Cancer Study Project: a case-control study.
Few studies have supported an association between breast cancer and DDT, usually assessed with biomarkers that cannot discern timing of exposure, or differentiate between the accumulation of chronic low-dose versus acute high-dose exposures in the past. Previous studies suggest that an association may be evident only among women exposed to DDT during biologically susceptible windows, or among those diagnosed with estrogen receptor/progesterone receptor-positive (ER+PR+) breast cancer subtypes. Self-reported acute exposure to a fogger truck, which sprayed DDT prior to 1972, was hypothesized to increase the risk of breast cancer, particularly among women exposed at a young age or diagnosed with ER+PR+ breast cancer. We examined these possibilities in the Long Island Breast Cancer Study Project (LIBCSP) (1,508 cases, 1,556 controls), which included exposure assessment by structured questionnaire and serum samples collected between 1996-1998, using adjusted logistic and polytomous regression to estimate ORs and 95% CIs. Women with ER+PR+ breast cancer had a 44% increased odds of ever seeing a pre-1972 fogger truck compared to other subtypes (OR = 1.44; 95% CI 1.08-1.93). However, there was little variation in the observed increase in breast cancer risk when considering all women who reported seeing a pre-1972 fogger truck at their residence (OR = 1.16; 95% CI 0.98, 1.37), or during hypothesized susceptible windows. Self-reported acute exposure was not correlated with serum concentrations, a biomarker of long-term exposure. These findings support the hypothesis that seeing a fogger truck, a proxy measure for acute DDT exposure, may be associated with ER+PR+ tumors, the most commonly diagnosed breast cancer subtype among American women.


Three new members of the serine-aspartate repeat protein multigene family of Staphylococcus aureus.
Three new genes encoding the serine-aspartate (SD) repeat-containing proteins SdrC, SdrD and SdrE were found in Staphylococcus aureus strain Newman. The SD repeats had earlier been found in the S. aureus fibrinogen-binding clumping factors ClfA and ClfB. The clfA and clfB genes encode high-molecular-mass fibrinogen-binding proteins that are anchored to the cell surface of S. aureus. The sdr genes now reported are closely linked and tandemly arrayed. The putative Sdr proteins have both organizational and sequence similarity to ClfA and ClfB. At the N-terminus, putative secretory signal sequences precede approximately 500 residue A regions. The A regions of the Sdr and Clf proteins exhibit only 20-30% residue identity when aligned with any other member of the family. The only conserved sequence is the consensus motif TYTFTDYVD. The Sdr proteins differ from ClfA and ClfB by having two to five additional 110-113 residue repeated sequences (B-motifs) located between region A and the R-region. Each B-motif contains a consensus Ca2+-binding EF-hand loop normally found in eukaryotic proteins. The structural integrity of recombinant SdrD(B1-B5) protein comprising the five B-repeats of SdrD was shown by bisANS fluorescence analysis to be Ca2+-dependent, suggesting that the EF-hands are functional. When Ca2+ was removed the structure collapsed to an unfolded conformation. The original structure was restored by addition of Ca2+. The C-terminal R-domains of the Sdr proteins contain 132-170 SD residues. These are followed by conserved wall-anchoring regions characteristic of many surface proteins of Gram-positive bacteria. The sdr locus was present in all 31 S. aureus strains from human and bovine sources tested by Southern hybridization, although in a few strains it contained two rather than three genes.


A QSAR study for modeling of 8-azaadenine analogues proposed as A1 adenosine receptor antagonists using genetic algorithm coupling adaptive neuro-fuzzy inference system (ANFIS).
A quantitative structure activity relationship (QSAR) study of 8-azaadenine, as antagonists for the A1 receptor, is described. A genetic algorithm (GA) method was used as the feature selection tool, and an adaptive neuro-fuzzy inference system (ANFIS) was employed for feature mapping. The best descriptors (GATS4v and BELv7) were applied to train the ANFIS model. The optimum number and shape of related functions were obtained through a subtractive clustering algorithm. The ability and robustness of the GA-ANFIS model in predicting the affinity of 8-azaadenine derivatives (pK(i)) are illustrated by validation techniques of Leave One Out, heuristic and randomized methods. The results have indicated that the proposed model of ANFIS in this work is superior over two other methods, radial basis function (RBF) and multiple linear regression (MLR).


Socio-economic factors influencing control of vector-borne diseases in the pastoralist system of south western Uganda.
Research in control of tick-borne diseases and trypanosomosis, and their vectors, namely, ticks and tsetse flies respectively, has been on going for decades. However, very little attention has been paid to the socio-economic factors that are likely to influence the outcome of the interventions in the control of these diseases. Thus, this study was designed to investigate these factors, mainly the intra-household factors influencing decision-making in the control of Vector-borne diseases in the pastoralist areas of Uganda. These factors included: indigenous technical knowledge, household economic factors, and gender. Both qualitative and quantitative methods were used in the collection and analysis of data. The tools used for data collection included among others, participatory learning and action (PLA), and Case studies. The findings included the following: In pastoralist households, a big proportion of the household budget was allocated to vector-borne diseases control. In the male-headed households, men dominated decision-making on vector-borne diseases control, although the goals and priorities of men and women in these households were not the same. Also, vector-borne disease control was predominantly by use of modern veterinary drugs, and pastoralists treated sick cattle by themselves even in situations where there were veterinary personnel.


Activation of neutrophils by nanoparticles.
The use of nanoparticles (NPs) has increased in the past few years in various fields, including defence, aerospace, electronics, biology, medicine, and so forth. and in applications such as diagnostic technology, bioimaging, and drug/gene delivery. Thus, human exposure to NPs and nanomaterials is unavoidable and will certainly expand in the future resulting in a growing interest in nanotoxicology, the study of toxicity of nanomaterials. A number of studies have reported the effects of NPs in respect to pulmonary inflammation by investigating in vitro activation of pulmonary cells with NPs and in vivo in a variety of models in which neutrophils appear to be the predominant leukocyte cell type in lungs and in bronchoalveolar lavages following inhalation or intratracheal instillation of NPs. Despite the fact that several studies have reported an increased number of neutrophils, the literature dealing with the direct activation of neutrophils by a given NP is poorly documented. This paper will summarize the current literature in this latter area of research and will end with a perspective view in which our laboratory will be involved in the following years.


Fear, but not fear-relevance, modulates reaction times in visual search with animal distractors.
The research aimed at examining attentional selectivity in a visual search paradigm using pictures of animals that have provided a recurrent threat in an evolutionary perspective (i.e., snakes and spiders) and pictures of animals that have supposedly posed no such threat (i.e., cats and fish). Experiment 1 showed no advantage of fear-relevant stimuli over non-fear-relevant animal stimuli. However, an attentional capture seemed to emerge as a delay in the disengagement of attention, specifically when there was a massive presentation of fear-relevant stimuli in the array. The results from Experiment 2, where participants were selected based specifically on their fear of either snakes or spiders (but not both), showed a preferential processing of the congruent feared stimulus, when compared with non-fearful participants, which strengthens the notion that fear significance may be an important factor drawing attention to a particular spatial location.


Changes in radiographic and clinical outcomes with primary treatment adult spinal deformity surgeries from two years to three- to five-years follow-up.
Retrospective analysis of data entered prospectively into a multicenter database-clinical and radiographic outcomes assessment. Our hypothesis is that between the 2-year and the 3- to 5-year points surgically treated adult spinal deformity patients will show significant reduction in outcomes by Scoliosis Research Society (SRS), Oswestry Disability Index (ODI), and numerical rating scale back and leg pain scores and will show increasing thoracic kyphosis, loss of lumbar lordosis, and loss of coronal and sagittal balance. Most analyses of primary presentation adult spinal deformity surgery assess 2-year follow-up. However, it is established that in some patients unfavorable events occur between the 2-year and 5-year points. The cohort of 113 patients entered into a multicenter database with complete preoperative, 2-year, and 3- to 5-year data. All patients who had adult spinal deformity and surgical treatment represented their first reconstruction. Diagnoses were scoliosis (82.5%), kyphosis (10%), and scoliosis and kyphosis combined (7.5%). Outcome measures and basic radiographic parameters (curve size, thoracic and lumbar sagittal plane, coronal and sagittal balance) were assessed at those 3 time intervals. Complications (pseudarthrosis/implant failure, infection, and junctional deformities) were assessed at the 2-year and the 3- to 5-year (mean, 3.76 years) points. RESULTS.: The mean major curve Cobb angle (preoperative, 57°; 2-year, 29°; 3-5 year, 26°); thoracic kyphosis T5 to T12 (30°, 31°, 32°) and lumbar lordosis T12 to sacrum (48°, 49°, 51°) did not change from the 2-year to ultimate follow-up. Likewise, coronal and sagittal balance parameters were the same at 2-year and ultimate follow-up. SRS total scores and modified ODI were similar at the 2 year and final follow-up (SRS: 3.89-3.88; ODI: 19-18). Preoperative SRS total score was 3.17. Six patients demonstrated complications at the 2-year point and additional 9 patients demonstrated complications at the 3- to 5-year point. Those 9 patients with complications at ultimate follow-up demonstrated significant deterioration in their ODI and SRS scores when compared with the patients who did not have complications at ultimate follow-up. Contrary to our hypothesis, we could not establish deterioration in mean radiographic or clinical outcomes between the 2-year and 3- to 5-year follow-up points when analyzing the group as a whole. However, for the 9 patients who experienced complications between 3- and 5-year follow-up, their outcomes were significantly worse than for the other 104 patients.One should not anticipate an overall radiographic and clinical deterioration of the outcomes of surgically treated primary presentation adult spinal deformity patients in this studied time interval. However, close to 10% of patients will experience a new complication at the 3- to 5-year point, most commonly implant failure/nonunion and/or junctional kyphosis, which will negatively effect the patient-reported outcome.


ICMR's tryst with HIV epidemic in India: 1986-1991.
The Indian Council of Medical Research (ICMR) undertook screening of asymptomatic persons from high risk group with the ELISA test for HIV infection in 1986 and found that HIV infection has reached India. ICMR in collaboration with the central and State health services initiated the national sero-surveillance programme for HIV infection in 43 surveillance and five reference centres to determine the major modes of transmission and magnitude of infection. Data from the sero-surveillance showed that HIV infection was present in all the known high risk groups and in the general population in all the States both in urban and rural areas. HIV was getting transmitted through all the known modes of transmission. In most States heterosexual transmission was predominant but in Manipur intravenous (iv) drug use was the most common mode of transmission. Prevalence of HIV infection in high risk groups was not high and that in low risk groups was quite low. ICMR initiated hospital based sentinel surveillance in high risk groups and general population to obtain time trends in seroprevalence. Between 1986 and 1991, National AIDS Programme was carried out as a collaborative effort of ICMR, and central and State health services. As the dimensions of the epidemic unfolded, rational evidence based interventions which could be implemented within the existing health system, were initiated. National AIDS Control Programme (NACP) continued and upscaled all these interventions. Effective implementation of a multi-pronged, rational strategy for HIV infection containment and control right from the initial stages, and dedicated work done by committed professionals belonging to government and voluntary sectors, cultural ethos of the country, responsible behaviour of the population and relatively low iv drug use have resulted in rapid decline in new infection and in prevalence of infection within a quarter of a century after the initial detection of HIV.


A novel, reproducible, and objective method for volumetric magnetic resonance imaging assessment of enhancing glioblastoma.
Robust methodology that allows objective, automated, and observer-independent measurements of brain tumor volume, especially after resection, is lacking. Thus, determination of tumor response and progression in neurooncology is unreliable. The objective of this study was to determine if a semi-automated volumetric method for quantifying enhancing tissue would perform with high reproducibility and low interobserver variability. Fifty-seven MR images from 13 patients with glioblastoma were assessed using our method, by 2 neuroradiologists, 1 neurosurgeon, 1 neurosurgical resident, 1 nurse practitioner, and 1 medical student. The 2 neuroradiologists also performed traditional 1-dimensional (1D) and 2-dimensional (2D) measurements. Intraclass correlation coefficients (ICCs) assessed interobserver variability between measurements. Radiological response was determined using Response Evaluation Criteria In Solid Tumors (RECIST) guidelines and Macdonald criteria. Kappa statistics described interobserver variability of volumetric radiological response determinations. There was strong agreement for 1D (RECIST) and 2D (Macdonald) measurements between neuroradiologists (ICC = 0.42 and 0.61, respectively), but the agreement using the authors' novel automated approach was significantly stronger (ICC = 0.97). The volumetric method had the strongest agreement with regard to radiological response (κ = 0.96) when compared with 2D (κ = 0.54) or 1D (κ = 0.46) methods. Despite diverse levels of experience of the users of the volumetric method, measurements using the volumetric program remained remarkably consistent in all users (0.94). Interobserver variability using this new semi-automated method is less than the variability with traditional methods of tumor measurement. This new method is objective, quick, and highly reproducible among operators with varying levels of expertise. This approach should be further evaluated as a potential standard for response assessment based on contrast enhancement in brain tumors.


Lewis acid-base interactions between platinum(ii) diaryl complexes and bis(perfluorophenyl)zinc: strongly accelerated reductive elimination induced by a Z-type ligand.
Z-type interactions between bis(perfluorophenyl)zinc and platinum(ii) diaryl complexes supported by 1,10-phenanthroline (phen), 2,2'-bipyridine (bpy), and bis(dimethylphosphino)ethane (dmpe) ligands are reported. In the solid state, the nature of the Pt-Zn interaction depends on the bidentate ligand; the phen-supported complex exhibits an unsupported Pt-Zn bond, while the dmpe derivative features additional bridging aryl interactions. A strongly accelerated rate of reductive elimination is observed for phen- and bpy-supported complexes, while aryl exchange between Pt and Zn is observed for the dmpe complex.


Travelling waves in a tissue interaction model for skin pattern formation.
Tissue interaction plays a major role in many morphogenetic processes, particularly those associated with skin organ primordia. We examine travelling wave solutions in a tissue interaction model for skin pattern formation which is firmly based on the known biology. From a phase space analysis we conjecture the existence of travelling waves with specific wave speeds. Subsequently, analytical approximations to the wave profiles are derived using perturbation methods. We then show numerically that such travelling wave solutions do exist and that they are in good agreement with out analytical results. Finally, the biological implications of our analysis are discussed.


Economic evaluation of a worksite obesity prevention and intervention trial among hotel workers in Hawaii.
Economic evaluation of Work, Weight, and Wellness (3W), a 2-year randomized trial of a weight loss program delivered through Hawaii hotel worksites. Business case analysis from hotel perspective. Program resources were micro-costed (2008 dollars). Program benefits were reduced medical costs, fewer absences, and higher productivity. Primary outcome was discounted 24-month net present value (NPV). Control program cost $222K to implement over 24 months ($61 per participant), intervention program cost $1.12M ($334). Including overweight participants (body mass index >25), discounted control NPV was -$217K; -$1.1M for intervention program. Presenteeism improvement of 50% combined with baseline 10% productivity shortfall required to generate positive 24-month intervention NPV. 3W's positive clinical outcomes did not translate into immediate economic benefit for participating hotels, although modest cost savings were observed in the trial's second year.


High-intensity intermittent exercise attenuates ad-libitum energy intake.
To examine the acute effects of high-intensity intermittent exercise (HIIE) on energy intake, perceptions of appetite and appetite-related hormones in sedentary, overweight men. Seventeen overweight men (body mass index: 27.7±1.6 kg m(-2); body mass: 89.8±10.1 kg; body fat: 30.0±4.3%; VO(2peak): 39.2±4.8 ml kg(-1) min(-1)) completed four 30-min experimental conditions using a randomised counterbalanced design. CON: resting control, MC: continuous moderate-intensity exercise (60% VO(2peak)), HI: high-intensity intermittent exercise (alternating 60 s at 100% VO(2peak) and 240 s at 50% VO(2peak)), VHI: very-high-intensity intermittent exercise (alternating 15 s at 170% VO(2peak) and 60 s at 32% VO(2peak)). Participants consumed a standard caloric meal following exercise/CON and an ad-libitum meal 70 min later. Capillary blood was sampled and perceived appetite assessed at regular time intervals throughout the session. Free-living energy intake and physical activity levels for the experimental day and the day after were also assessed. Ad-libitum energy intake was lower after HI and VHI compared with CON (P=0.038 and P=0.004, respectively), and VHI was also lower than MC (P=0.028). Free-living energy intake in the subsequent 38 h remained less after VHI compared with CON and MC (P≤0.050). These observations were associated with lower active ghrelin (P≤0.050), higher blood lactate (P≤0.014) and higher blood glucose (P≤0.020) after VHI compared with all other trials. Despite higher heart rate and ratings of perceived exertion (RPE) during HI and VHI compared with MC (P≤0.004), ratings of physical activity enjoyment were similar between all the exercise trials (P=0.593). No differences were found in perceived appetite between trials. High-intensity intermittent exercise suppresses subsequent ad-libitum energy intake in overweight inactive men. This format of exercise was found to be well tolerated in an overweight population.


Analysis of the Basidiomycete Coprinopsis cinerea reveals conservation of the core meiotic expression program over half a billion years of evolution.
Coprinopsis cinerea (also known as Coprinus cinereus) is a multicellular basidiomycete mushroom particularly suited to the study of meiosis due to its synchronous meiotic development and prolonged prophase. We examined the 15-hour meiotic transcriptional program of C. cinerea, encompassing time points prior to haploid nuclear fusion though tetrad formation, using a 70-mer oligonucleotide microarray. As with other organisms, a large proportion (∼20%) of genes are differentially regulated during this developmental process, with successive waves of transcription apparent in nine transcriptional clusters, including one enriched for meiotic functions. C. cinerea and the fungi Saccharomyces cerevisiae and Schizosaccharomyces pombe diverged ∼500-900 million years ago, permitting a comparison of transcriptional programs across a broad evolutionary time scale. Previous studies of S. cerevisiae and S. pombe compared genes that were induced upon entry into meiosis; inclusion of C. cinerea data indicates that meiotic genes are more conserved in their patterns of induction across species than genes not known to be meiotic. In addition, we found that meiotic genes are significantly more conserved in their transcript profiles than genes not known to be meiotic, which indicates a remarkable conservation of the meiotic process across evolutionarily distant organisms. Overall, meiotic function genes are more conserved in both induction and transcript profile than genes not known to be meiotic. However, of 50 meiotic function genes that were co-induced in all three species, 41 transcript profiles were well-correlated in at least two of the three species, but only a single gene (rad50) exhibited coordinated induction and well-correlated transcript profiles in all three species, indicating that co-induction does not necessarily predict correlated expression or vice versa. Differences may reflect differences in meiotic mechanisms or new roles for paralogs. Similarities in induction, transcript profiles, or both, should contribute to gene discovery for orthologs without currently characterized meiotic roles.


DJ-1 and alpha-synuclein in human cerebrospinal fluid as biomarkers of Parkinson's disease.
Biomarkers are urgently needed for the diagnosis and monitoring of disease progression in Parkinson's disease. Both DJ-1 and alpha-synuclein, two proteins critically involved in Parkinson's disease pathogenesis, have been tested as disease biomarkers in several recent studies with inconsistent results. These have been largely due to variation in the protein species detected by different antibodies, limited numbers of patients in some studies, or inadequate control of several important variables. In this study, the nature of DJ-1 and alpha-synuclein in human cerebrospinal fluid was studied by a combination of western blotting, gel filtration and mass spectrometry. Sensitive and quantitative Luminex assays detecting most, if not all, species of DJ-1 and alpha-synuclein in human cerebrospinal fluid were established. Cerebrospinal fluid concentrations of DJ-1 and alpha-synuclein from 117 patients with Parkinson's disease, 132 healthy individuals and 50 patients with Alzheimer's disease were analysed using newly developed, highly sensitive Luminex technology while controlling for several major confounders. A total of 299 individuals and 389 samples were analysed. The results showed that cerebrospinal fluid DJ-1 and alpha-synuclein levels were dependent on age and influenced by the extent of blood contamination in cerebrospinal fluid. Both DJ-1 and alpha-synuclein levels were decreased in Parkinson's patients versus controls or Alzheimer's patients when blood contamination was controlled for. In the population aged > or = 65 years, when cut-off values of 40 and 0.5 ng/ml were chosen for DJ-1 and alpha-synuclein, respectively, the sensitivity and specificity for patients with Parkinson's disease versus controls were 90 and 70% for DJ-1, and 92 and 58% for alpha-synuclein. A combination of the two markers did not enhance the test performance. There was no association between DJ-1 or alpha-synuclein and the severity of Parkinson's disease. Taken together, this represents the largest scale study for DJ-1 or alpha-synuclein in human cerebrospinal fluid so far, while using newly established sensitive Luminex assays, with controls for multiple variables. We have demonstrated that total DJ-1 and alpha-synuclein in human cerebrospinal fluid are helpful diagnostic markers for Parkinson's disease, if variables such as blood contamination and age are taken into consideration.


Early-onset and late-onset Alzheimer's disease are associated with distinct patterns of memory impairment.
The goal of this study was to investigate the specific patterns of memory breakdown in patients suffering from early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD). Twenty EOAD patients, twenty LOAD patients, twenty matched younger controls, and twenty matched older controls participated in this study. All participants underwent a detailed neuropsychological assessment, an MRI scan, an FDG-PET scan, and AD patients had biomarkers as supporting evidence of both amyloïdopathy and neuronal injury. Results of the neuropsychological assessment showed that both EOAD and LOAD groups were impaired in the domains of memory, executive functions, language, praxis, and visuoconstructional abilities, when compared to their respective control groups. EOAD and LOAD groups, however, showed distinct patterns of memory impairment. Even though both groups were similarly affected on measures of episodic, short term and working memory, in contrast semantic memory was significantly more impaired in LOAD than in EOAD patients. The EOAD group was not more affected than the LOAD group in any memory domain. EOAD patients, however, showed significantly poorer performance in other cognitive domains including executive functions and visuoconstructional abilities. A more detailed analysis of the pattern of semantic memory performance among patient groups revealed that the LOAD was more profoundly impaired, in tasks of both spontaneous recall and semantic recognition. Voxel-Based Morphometry (VBM) analyses showed that impaired semantic performance in patients was associated with reduced gray matter volume in the anterior temporal lobe (ATL) region, while PET-FDG analyses revealed that poorer semantic performance was associated with greater hypometabolism in the left temporoparietal region, both areas reflecting key regions of the semantic network. Results of this study indicate that EOAD and LOAD patients present with distinct patterns of memory impairment, and that a genuine semantic impairment may represent one of the clinical hallmarks of LOAD.


Differential growth and yield by canola (Brassica napus L.) and wheat (Triticum aestivum L.) arising from alterations in chemical properties of sandy soils due to additions of fly ash.
There is a need for field trials on testing agronomic potential of coal fly ash to engender routine use of this technology. Two field trials were undertaken with alkaline and acidic fly ashes supplied at between 3 and 6 Mg ha⁻¹ to acidic soils and sown to wheat and canola at Richmond (Eastern Australia) and to wheat only at Merredin (Western Australia). Ash addition marginally (P< 0.10) raised the pH in the top soil layers at both sites. The exceptionally dry season at both sites constrained yields and thwarted any likelihood of gaining yield benefits from ash-induced improvements in soil conditions. Yield improvements due to ash addition were absent at Merredin and only marginal at Richmond, where no elevated accumulation of B, Mo, Se, P or S in either the straw or seeds of wheat was observed; canola increased accumulation of Mo and Se in its shoot with acidic fly ash, but it was well below phyto toxic levels. Simulations of wheat using APSIM at Richmond over a 100-year period (1909-2008) predicted yield increases in 52% of years with addition of ash at 3.0 Mg ha⁻¹ compared with 24% of years with addition of ash at 6.0 Mg ha⁻¹. The simulated yield increases did not exceed 40% over the control with addition of 6 Mg ha⁻¹ ash, but was between 40% and 50% with an addition rate of 3 Mg ha⁻¹. We found no evidence of phytotoxicity in either crop in this unusually dry year and there is still a need for further field assessment in years with favourable rainfall to enable development of clear recommendations on fly ash rates for optimum yield benefits.


A Mapping Study on the Internet and Suicide.
Since the mid-1990s concerns have been raised regarding the possible links between suicide and the Internet, especially among adolescents and young adults. To identify the nature and extent of the scientific publications, especially original research studies, on suicide and the Internet, and to investigate how the field has developed over time. In particular, this mapping study looks at types of publications, topic areas, focus of original research papers, and suicide-related variables of interest in publications. A search of three major databases (PubMED, PsycINFO, and Sociological Abstracts) was conducted to identify papers published until the end of January 2015. The study identified 237 publications on suicide and the Internet published from 1997 to the end of January 2015. These included 122 original research papers. The three most frequent topic areas covered in publications were searching for information on suicide, online interventions, and online suicide-related behaviors. The online mediums most frequently studied were online forums/message boards, search engines, intervention and information websites, and social media. The mapping study did not include an analysis of results of research studies and did not assess their quality. The field is rapidly evolving, as seen in the recent increase in the number of publications. However, there are gaps in terms of the countries where research is conducted and the coverage of topics.


Molecular Events Linking Oxidative Stress and Inflammation to Insulin Resistance and β-Cell Dysfunction.
The prevalence of diabetes mellitus (DM) is increasing worldwide, a consequence of the alarming rise in obesity and metabolic syndrome (MetS). Oxidative stress and inflammation are key physiological and pathological events linking obesity, insulin resistance, and the progression of type 2 DM (T2DM). Unresolved inflammation alongside a "glucolipotoxic" environment of the pancreatic islets, in insulin resistant pathologies, enhances the infiltration of immune cells which through secretory activity cause dysfunction of insulin-secreting β-cells and ultimately cell death. Recent molecular investigations have revealed that mechanisms responsible for insulin resistance associated with T2DM are detected in conditions such as obesity and MetS, including impaired insulin receptor (IR) signalling in insulin responsive tissues, oxidative stress, and endoplasmic reticulum (ER) stress. The aim of the present review is to describe the evidence linking oxidative stress and inflammation with impairment of insulin secretion and action, which result in the progression of T2DM and other conditions associated with metabolic dysregulation.


Comparative effectiveness of different oral antibiotics regimens for treatment of urinary tract infection in outpatients: an analysis of national representative claims database.
There are very limited data on the postmarketing outcome comparison of different guideline antibiotic regimens for patients with urinary tract infections (UTIs). We carried out a population-based comparative effectiveness study from year 2000 through 2009, using the administrative data of 2 million patients from the National Health Informatics Project of Taiwan. Treatment failure was defined as either hospitalization or emergency department visits for UTI. Odd ratios were computed using conditional logistic regression models matched on propensity score. We identified 73,675 individuals with UTI, of whom 54,796 (74.4%) received trimethoprim-sulfamethoxazole (TMP-SMX), 4184 (5.7%) received ciprofloxacin, 3142 (4.3%) received levofloxacin, 5984 (8.1%) received ofloxacin, and 5569 (7.6%) received norfloxacin. Compared with TMP-SMX, the composite treatment failure was significantly lowered for norfloxacin in propensity score (PS) matching analyses (OR, 0.73; 95% CI, 0.54-0.99). Both norfloxacin (PS-matched OR, 0.68; 95% CI, 0.47-0.98) and ofloxacin (PS-matched OR, 0.70; 95% CI, 0.49-0.99) had significantly lowered composite treatment failure rate when compared with ciprofloxacin. Subgroup analysis suggested that both norfloxacin and ofloxacin were more effective in female patients without complications (W/O indwelling catheters, W/O bedridden status and W/O spinal cord injury), when compared with either TMP-SMX or ciprofloxacin. Among outpatients receiving oral fluoroquinolone therapy for UTIs, there was evidence of superiority of norfloxacin or ofloxacin over ciprofloxacin or TMP-SMX in terms of treatment failure. Given the observational nature of this study and regional difference in antibiotic resistance patterns, more studies are required to validate our results.


Clinical features and outcome of 6 new patients carrying de novo KCNB1 gene mutations.
To describe electroclinical features and outcome of 6 patients harboring KCNB1 mutations. Clinical, EEG, neuropsychological, and brain MRI data analysis. Targeted next-generation sequencing of a 95 epilepsy gene panel. The mean age at seizure onset was 11 months. The mean follow-up of 11.3 years documented that 4 patients following an infantile phase of frequent seizures became seizure free; the mean age at seizure offset was 4.25 years. Epilepsy phenotypes comprised West syndrome in 2 patients, infantile-onset unspecified generalized epilepsy, myoclonic and photosensitive eyelid myoclonia epilepsy resembling Jeavons syndrome, Lennox-Gastaut syndrome, and focal epilepsy with prolonged occipital or clonic seizures in each and every one. Five patients had developmental delay prior to seizure onset evolving into severe intellectual disability with absent speech and autistic traits in one and stereotypic hand movements with impulse control disorder in another. The patient with Jeavons syndrome evolved into moderate intellectual disability. Mutations were de novo, 4 missense and 2 nonsense, 5 were novel, and 1 resulted from somatic mosaicism. KCNB1-related manifestations include a spectrum of infantile-onset generalized or focal seizures whose combination leads to early infantile epileptic encephalopathy including West, Lennox-Gastaut, and Jeavons syndromes. Long-term follow-up highlights that following a stormy phase, seizures subside or cease and treatment may be eased or withdrawn. Cognitive and motor functions are almost always delayed prior to seizure onset and evolve into severe, persistent impairment. Thus, KCNB1 mutations are associated with diffuse brain dysfunction combining seizures, motor, and cognitive impairment.