Electromagnetic Meson Production in the Nucleon Resonance Region

Recent experimental and theoretical advances in investigating electromagnetic meson production reactions in the nucleon resonance region are reviewed.Comment: 75 pages, 42 figure

First-line latanoprost therapy in ocular hypertension or open-angle glaucoma patients: a 3-month efficacy analysis stratified by initial intraocular pressure

<p>Abstract</p> <p>Background</p> <p>Prospective, multicenter, randomized, double-masked trials have shown latanoprost instilled once daily to be at least as effective as and generally superior to timolol administered twice daily and to be as effective as other frequently prescribed prostaglandin analogues. This study prospectively assessed the efficacy of latanoprost monotherapy in a large cohort of treatment-naive patients with a broad range of baseline intraocular pressure (IOP) levels treated in actual clinical practice settings.</p> <p>Methods</p> <p>This prospective, open-label, multicenter, uncontrolled, phase IV study included treatment-naive ocular hypertension or open-angle glaucoma subjects initiating latanoprost once daily (evening). IOP levels were measured at baseline and after 1 and 3 months. The primary efficacy outcome was mean change in IOP from baseline to month 3. Analyses were stratified by baseline IOP: ≥ 20 and <24 mmHg <it>vs </it>≥ 24 mmHg.</p> <p>Results</p> <p>Efficacy analyses (intent to treat) included 572 subjects: 20 to <24 mmHg group, N = 252; ≥ 24 mmHg group, N = 320. Mean baseline IOP levels were 22.2 ± 0.9 mmHg and 26.7 ± 2.8 mmHg, respectively. At month 3, significant IOP reductions were seen in both groups (p < 0.0001, within-group differences); reductions were smaller in the 20 to <24 mmHg group (-6.3 ± 2.4 <it>vs </it>-9.2 ± 3.7 mmHg, respectively; -28.0 ± 10.6% <it>vs </it>-34.1 ± 11.9%, respectively). An IOP reduction of ≥ 30% from baseline to month 3 was noted in 48.4% and 65.6% of subjects, respectively (p < 0.0001). At month 3, targets IOPs of ≤ 18 mmHg were achieved by ≥ 70% of subjects in both groups. Latanoprost was well tolerated with an adverse event profile similar to that reported in the literature.</p> <p>Conclusions</p> <p>This "real world" study found once-daily latanoprost to be effective and safe in treatment-naive ocular hypertension or open-angle glaucoma patients. Patients with baseline IOP levels of 20 to <24 mmHg as well as ≥ 24 mmHg benefitted from initial latanoprost therapy.</p> <p>Trial Registration</p> <p>Trial Registration Number: NCT00647101</p

Circumstellar disks and planets. Science cases for next-generation optical/infrared long-baseline interferometers

We present a review of the interplay between the evolution of circumstellar disks and the formation of planets, both from the perspective of theoretical models and dedicated observations. Based on this, we identify and discuss fundamental questions concerning the formation and evolution of circumstellar disks and planets which can be addressed in the near future with optical and infrared long-baseline interferometers. Furthermore, the importance of complementary observations with long-baseline (sub)millimeter interferometers and high-sensitivity infrared observatories is outlined.Comment: 83 pages; Accepted for publication in "Astronomy and Astrophysics Review"; The final publication is available at http://www.springerlink.co

Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial

Background We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. Methods EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1–5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030. Findings Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6–76·6); 62·3 months (IQR 46·9–77·1) for the MAP group and 61·1 months (IQR 46·5–75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78–1·23]); hazards were non-proportional (p=0·0003). The most common grade 3–4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. Interpretation EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. Funding UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre

Clinical characteristics and prognosis of osteosarcoma in young children: a retrospective series of 15 cases

<p>Abstract</p> <p>Background</p> <p>Osteosarcoma is the most common primary bone malignancy in childhood and adolescence. However, it is very rare in children under 5 years of age. Although studies in young children are limited in number, they all underline the high rate of amputation in this population, with conflicting results being recently reported regarding their prognosis.</p> <p>Methods</p> <p>To enhance knowledge on the clinical characteristics and prognosis of osteosarcoma in young children, we reviewed the medical records and histology of all children diagnosed with osteosarcoma before the age of five years and treated in SFCE (Société Française des Cancers et leucémies de l'Enfant) centers between 1980 and 2007.</p> <p>Results</p> <p>Fifteen patients from 7 centers were studied. Long bones were involved in 14 cases. Metastases were present at diagnosis in 40% of cases. The histologic type was osteoblastic in 74% of cases. Two patients had a relevant history. One child developed a second malignancy 13 years after osteosarcoma diagnosis.</p> <p>Thirteen children received preoperative chemotherapy including high-dose methotrexate, but only 36% had a good histologic response. Chemotherapy was well tolerated, apart from a case of severe late convulsive encephalopathy in a one-year-old infant. Limb salvage surgery was performed in six cases, with frequent mechanical and infectious complications and variable functional outcomes.</p> <p>Complete remission was obtained in 12 children, six of whom relapsed. With a median follow-up of 5 years, six patients were alive in remission, seven died of their disease (45%), in a broad range of 2 months to 8 years after diagnosis, two were lost to follow-up.</p> <p>Conclusions</p> <p>Osteosarcoma seems to be more aggressive in children under five years of age, and surgical management remains a challange.</p

Genetic Disruption of Both Tryptophan Hydroxylase Genes Dramatically Reduces Serotonin and Affects Behavior in Models Sensitive to Antidepressants

The neurotransmitter serotonin (5-HT) plays an important role in both the peripheral and central nervous systems. The biosynthesis of serotonin is regulated by two rate-limiting enzymes, tryptophan hydroxylase-1 and -2 (TPH1 and TPH2). We used a gene-targeting approach to generate mice with selective and complete elimination of the two known TPH isoforms. This resulted in dramatically reduced central 5-HT levels in Tph2 knockout (TPH2KO) and Tph1/Tph2 double knockout (DKO) mice; and substantially reduced peripheral 5-HT levels in DKO, but not TPH2KO mice. Therefore, differential expression of the two isoforms of TPH was reflected in corresponding depletion of 5-HT content in the brain and periphery. Surprisingly, despite the prominent and evolutionarily ancient role that 5-HT plays in both vertebrate and invertebrate physiology, none of these mutations resulted in an overt phenotype. TPH2KO and DKO mice were viable and normal in appearance. Behavioral alterations in assays with predictive validity for antidepressants were among the very few phenotypes uncovered. These behavioral changes were subtle in the TPH2KO mice; they were enhanced in the DKO mice. Herein, we confirm findings from prior descriptions of TPH1 knockout mice and present the first reported phenotypic evaluations of Tph2 and Tph1/Tph2 knockout mice. The behavioral effects observed in the TPH2 KO and DKO mice strongly confirm the role of 5-HT and its synthetic enzymes in the etiology and treatment of affective disorders

Plasmid pP62BP1 isolated from an Arctic Psychrobacter sp. strain carries two highly homologous type II restriction-modification systems and a putative organic sulfate metabolism operon

The complete nucleotide sequence of plasmid pP62BP1 (34,467 bp), isolated from Arctic Psychrobacter sp. DAB_AL62B, was determined and annotated. The conserved plasmid backbone is composed of several genetic modules, including a replication system (REP) with similarities to the REP region of the iteron-containing plasmid pPS10 of Pseudomonas syringae. The additional genetic load of pP62BP1 includes two highly related type II restriction-modification systems and a set of genes (slfRCHSL) encoding enzymes engaged in the metabolism of organic sulfates, plus a putative transcriptional regulator (SlfR) of the AraC family. The pP62BP1 slflocus has a compact and unique structure. It is predicted that the enzymes SlfC, SlfH, SlfS and SlfL carry out a chain of reactions leading to the transformation of alkyl sulfates into acyl-CoA, with dodecyl sulfate (SDS) as a possible starting substrate. Comparative analysis of the nucleotide sequences of pP62BP1 and other Psychrobacter spp. plasmids revealed their structural diversity. However, the presence of a few highly conserved DNA segments in pP62BP1, plasmid 1 of P. cryohalolentis K5 and pRWF-101 of Psychrobacter sp. PRwf-1 is indicative of recombinational shuffling of genetic information, and is evidence of lateral gene transfer in the Arctic environment

Twenty-four-hour intraocular pressure and ocular perfusion pressure characteristics in newly diagnosed patients with normal tension glaucoma

PurposeTo determine the mean 24-h intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP) characteristics of newly diagnosed, previously untreated, Caucasian, normal tension glaucoma (NTG) patients and to identify relationships between these features and visual field (VF) loss at diagnosis.MethodsConsecutive newly diagnosed NTG patients underwent 24-h habitual IOP and blood pressure (BP) monitoring. Parameters from pooled measurements obtained in the sitting (0800-2200 hours) and supine (1200-0600 hours) positions were compared and associations were sought with VF mean deviation (MD) and pattern standard deviation (PSD).ResultsSixty-two Caucasian NTG patients (24 men and 38 women) successfully completed circadian IOP and BP monitoring. In habitual position, 8 subjects (12.9%) exhibited a diurnal acrophase, 42 subjects (67.7%) demonstrated a nocturnal acrophase, one subject (1.6%) showed a flat rhythm and 11 patients (17.7%) revealed a biphasic/polyphasic rhythm. Nighttime MOPP values (supine position) were significantly greater than diurnal values (sitting position); (P<0.001). No association could be demonstrated between glaucomatous damage, as indicated by VF parameters, and either mean habitual 24-h IOP (P=0.20 and P=0.12 for MD and PSD, respectively), or habitual 24-h MOPP (P=0.96 and 0.29, for MD and PSD, respectively).ConclusionsIn this cohort of Caucasian NTG patients, most patients exhibited a nocturnal IOP acrophase when evaluated in a habitual position. No association was found between 24-h IOP or MOPP and VF damage.Eye advance online publication, 29 July 2016; doi:10.1038/eye.2016.168

Advances in mass spectrometry-based post-column bioaffinity profiling of mixtures

In the screening of complex mixtures, for example combinatorial libraries, natural extracts, and metabolic incubations, different approaches are used for integrated bioaffinity screening. Four major strategies can be used for screening of bioactive mixtures for protein targets—pre-column and post-column off-line, at-line, and on-line strategies. The focus of this review is on recent developments in post-column on-line screening, and the role of mass spectrometry (MS) in these systems. On-line screening systems integrate separation sciences, mass spectrometry, and biochemical methodology, enabling screening for active compounds in complex mixtures. There are three main variants of on-line MS based bioassays: the mass spectrometer is used for ligand identification only; the mass spectrometer is used for both ligand identification and bioassay readout; or MS detection is conducted in parallel with at-line microfractionation with off-line bioaffinity analysis. On the basis of the different fields of application of on-line screening, the principles are explained and their usefulness in the different fields of drug research is critically evaluated. Furthermore, off-line screening is discussed briefly with the on-line and at-line approaches