Total Synthesis of Prostaglandin 15d-PGJ(2) and Investigation of its Effect on the Secretion of IL-6 and IL-12.

An efficient synthesis of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, 1) is reported. The route described allows for diversification of the parent structure to prepare seven analogues of 1 in which the positioning of electrophilic sites is varied. These analogues were tested in SAR studies for their ability to reduce the secretion of proinflammatory cytokines. It was shown that the endocyclic enone is crucial for the bioactivity investigated and that the conjugated ω-side chain serves in a reinforcing manner.

A field study on characteristics and diversity of gene expression in the liver of dairy cows during the transition period

Metabolic and endocrine adaptations to support milk production during the transition period vary between individual cows. This variation between cows to adapt to lactation may have a genetic basis. The present field study was carried out to determine hepatic adaptations occurring from late pregnancy through early lactation by measuring mRNA abundance of candidate genes in dairy cows on-farm. Additionally, the objective was to observe the diversity in inter-individual variation for the candidate genes that may give indications where individual adaptations at a molecular level can be found. This study was carried out on-farm including 232 dairy cows (parity >3) from 64 farms in Switzerland. Blood and liver samples were collected on d 20+/-7 before parturition, on d 24+/-2, and on d 89+/-4 after parturition. Blood plasma was assayed for concentrations of glucose, nonesterified fatty acids, beta-hydroxybutyrate, cholesterol, triglycerides, urea, albumin, protein, insulin, insulin-like growth factor-1, leptin, 3,5,3'-triiodothyronine, and thyroxine. Liver samples were obtained at the same time points and were measured for mRNA abundance of 26 candidate genes encoding enzymes and nuclear receptors involved in gluconeogenesis, fatty acid beta-oxidation, fatty acid and triglyceride synthesis, ketogenesis, citric acid cycle, cholesterol synthesis, and the urea cycle. The cows in the present study experienced a marked metabolic load in early lactation, as presented by changes in plasma metabolites and hormones, and responded accordingly with upregulation and downregulation of almost all candidate genes involved in metabolic processes in the liver. The observed inter-individual variation for the candidate genes, which was highest for acetyl-CoA-carboxylase and glycerol-3-phosphate dehydrogenase 2, should be further investigated to unravel the regulation at molecular level for optimal adaptive performance in dairy cows.

Continuous or repeated prolonged cisplatin infusions in children: a prospective study on ototoxicity, platinum concentrations, and standard serum parameters

BACKGROUND: To overcome the ototoxicity of cisplatin, single bolus infusions were replaced by repeated prolonged infusions of lower doses or by continuous infusions at still lower infusion rates. However, considering ototoxicity little is, in fact, known about the tolerance of repeated prolonged or continuous infusion in children. PROCEDURE: Auditory function was monitored along with plasma concentrations of free and total platinum (Pt), and with standard serum parameters (sodium, potassium, calcium, magnesium, phosphate, chloride, and creatinine) in 24 children receiving cisplatin by continuous infusion for the treatment of neuroblastoma and osteosarcoma or by repeated 1 or 6 hr infusions for the treatment of germ cell tumors. RESULTS: Hearing deteriorated in 10/15 osteosarcoma patients, 2/3 neuroblastoma patients, and 1/6 patients with germ cell tumors. Ototoxicity occurred after cumulative doses between 120 and 360 mg/m(2) cisplatin. In osteosarcoma patients, ototoxicity was associated with a comparatively higher mean plasma concentration of free Pt. However, Pt plasma concentrations did not discriminate between patients with or without ototoxicity. In patients experiencing ototoxicity serum creatinine increased by 45% compared to pre-treatment levels (mean). Serum creatinine increased by 26% in patients without ototoxicity (P < 0.05, Mann-Whitney Rank sum test). Despite standardized hydration, discrete but significant changes of potassium, sodium, magnesium, and phosphate were observed during and/or after cisplatin infusion, which, however, did not discriminate between patients with and without ototoxicity. CONCLUSIONS: While continuous cisplatin infusions are less nephrotoxic than repeated prolonged infusions, we observed considerable ototoxicity in patients treated with continuous cisplatin infusions, which necessitates further evaluations on the tolerance of continuous cisplatin infusions in children.

[Mason vertical gastroplasty in treatment of morbid obesity. Results of a prospective clinical study]

Morbid obesity (body mass index > 40 kg/m2) is a risk factor for cardiovascular, pulmonary, metabolic, neoplastic, and psychologic sequelae. In the present prospective clinical study 65 patients (11 men, 54 women) underwent vertical banded gastroplasty (Mason procedure) from June 1994 to October 1997. The median age was 41 +/- 5.3 years (range 18-69; n = 65). Preoperative body weight was 135 +/- 23 kg (96-229; n = 65), excess body weight in kg was 75 +/- 6.9 (44-155; n = 65) or in % 126 +/- 10 (78-223; n = 65) and BMI was 49 +/- 7.4 kg/m2 (39-69; n = 65). Mean hospital stay was 9.7 +/- 2.4 days (6-18; n = 65). Hospital mortality was 0% (0/65). Early complications were vomiting (30%) and problems in wound healing (15%; n = 65). Late complications (> 30 days) were incisional hernias (13.8%) and staple-line disruptions (12.3%; n = 65) with a reoperation rate of 23% (15/65). Median follow-up was 15.0 +/- 5.2 months (2-42) with a follow up rate of 100%. Mean weight loss after 12 months was 38.5 +/- 17 kg (30-98; n = 34) (P < 0.0001) and loss of excessive body weight 65 +/- 10% (57-86; n = 34), respectively (P < 0.0001). Cardiovascular risk factors (hypertension, diabetes, hyperlipidemia) were significantly improved within 12 months (n = 34). Vertical banded gastroplasty (Mason procedure)--well established for 20 years--is a good, safe therapy for morbid obesity if strict indications for operation are observed and if there is multidisciplinary long-term follow-up. Comorbid risk factors are considerably reduced and a long-term weight loss of more than 50% can be achieved without the risk of pathological metabolic changes.

Marginal fit of cemented and screw-retained crowns incorporated on the Straumann (ITI) Dental Implant System: an in vitro study

AIM: The aim of this study was to assess the marginal fit of crowns on the Straumann (ITI) Dental Implant System with special consideration of different casting dental materials. MATERIAL AND METHODS: Sixty porcelain-fused-to-metal crowns were fabricated: 18 crowns on standard cone abutments with an impression cylinder, partially prefabricated analogs, no coping and screw-retained (A); 18 crowns on solid abutments without an impression device, no analogs, no coping and cemented (B); and 18 crowns on solid abutments using an impression transfer cap, an analog with a shoulder, no coping and cemented (C). In each group, six crowns were made on epoxy mastercasts (Bluestar), six on synthetic plaster (Moldasynt) and six on super hard stone (Fujirock). Six additional crowns were fabricated with the transversal screw retention system onto the Octa system with impression transfer caps, metal analogs, gold copings and screw-retained (D). Impregum was used as impression material. Crowns of B and C were cemented with KetacCem. Crowns of A and D were fixed with an occlusal screw torqued at 15 N cm. Crowns were embedded, cut and polished. Under a light microscope using a magnification of x 100, the distance between the crown margin (CM) and the shoulder (marginal gap, MG) and the distance between the CM and the end of the shoulder (crown length, CL) was measured. RESULTS: MGs were 15.4+/-13.2 microm (A), 21.2+/-23.1 microm (B), 11+/-12.1 microm (C) and 10.4+/-9.3 microm (D). No statistically significantly differences using either of the casting materials were observed. CLs were -21.3+/-24.8 microm (A), 3+/-28.9 microm (B), 0.5+/-22 microm (C) and 0.1+/-15.8 microm (D). Crowns were shorter on synthetic casting materials compared with stone casts (P<0.005). CONCLUSIONS: CMs fit precisely with both cemented and screw-retained versions as well as when using no, partial or full analogs.

Effect of synthetic agonists of toll-like receptor 9 on canine lymphocyte proliferation and cytokine production in vitro.

Synthetic agonists of TLR9 containing novel DNA structures and R'pG (wherein R=1-(2'-deoxy-beta-d-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine) motifs, referred to as immune modulatory oligonucleotides (IMOs), have been shown to stimulate T(H)-1-type-immune responses and potently reverse allergen-induced T(H)-2 responses to T(H)-1 responses in vitro and in vivo in mice. In order to investigate the immunomodulatory potential of IMOs in dogs, canine peripheral blood mononuclear cells (PBMC) from healthy dogs were stimulated with three different IMOs and a control IMO, alone or in combination with concanavalin A (ConA). Lipopolysaccharide (LPS) was used as a positive control for B lymphocyte activation. Carboxyfluorescein diacetate succinimidyl ester and phenotype staining was used to tag proliferating T and B lymphocytes (CD5(+) and CD21(+)) by flow cytometry. Real-time PCR and ELISA were processed to assay cytokine production of IFN-gamma, IL-10, TGF-beta, IL-6 and IL-10. Like LPS, IMOs alone induced neither proliferation of CD5(+) T cells nor CD21(+) B cells, but both LPS and IMO had the capacity to co-stimulate ConA and induced proliferation of B cells. In combination with ConA, one of the IMOs (IMO1) also induced proliferation of T cells. IMO1 also significantly enhanced the expression of IFN-gamma on the mRNA and protein level in canine PBMC, whereas expression of IL-10, TGF-beta and IL-4 mRNAs was not induced by any of the IMOs. These results indicate that in canine PBMC from healthy dogs, IMO1 was able to induce a T(H)-1 immune response including T- and B-cell proliferation.

Acute muscular sarcocystosis: an international investigation among ill travelers returning from tioman island, malaysia, 2011-2012.

BACKGROUND Through 2 international traveler-focused surveillance networks (GeoSentinel and TropNet), we identified and investigated a large outbreak of acute muscular sarcocystosis (AMS), a rarely reported zoonosis caused by a protozoan parasite of the genus Sarcocystis, associated with travel to Tioman Island, Malaysia, during 2011-2012. METHODS Clinicians reporting patients with suspected AMS to GeoSentinel submitted demographic, clinical, itinerary, and exposure data. We defined a probable case as travel to Tioman Island after 1 March 2011, eosinophilia (>5%), clinical or laboratory-supported myositis, and negative trichinellosis serology. Case confirmation required histologic observation of sarcocysts or isolation of Sarcocystis species DNA from muscle biopsy. RESULTS Sixty-eight patients met the case definition (62 probable and 6 confirmed). All but 2 resided in Europe; all were tourists and traveled mostly during the summer months. The most frequent symptoms reported were myalgia (100%), fatigue (91%), fever (82%), headache (59%), and arthralgia (29%); onset clustered during 2 distinct periods: "early" during the second and "late" during the sixth week after departure from the island. Blood eosinophilia and elevated serum creatinine phosphokinase (CPK) levels were observed beginning during the fifth week after departure. Sarcocystis nesbitti DNA was recovered from 1 muscle biopsy. CONCLUSIONS Clinicians evaluating travelers returning ill from Malaysia with myalgia, with or without fever, should consider AMS, noting the apparent biphasic aspect of the disease, the later onset of elevated CPK and eosinophilia, and the possibility for relapses. The exact source of infection among travelers to Tioman Island remains unclear but needs to be determined to prevent future illnesses.

Behindertenpolitik – Positionen der Parteien nach der 6. IV-Revision

Für Menschen mit Behinderungen und ihr Umfeld ist es entscheidend zu wissen, welche Parteien sie mit ihrer Arbeit im Parlament unterstützen. In den Fragen rund um Behinderungen zeigt sich unter der Bundeshauskuppel tendenziell ein Rechts-Links-Graben. Die Mitte-Parteien, insbesondere die CVP, scheinen diese Tatsache allerdings in Frage zu stellen.

Changes in Scleral Architecture in Chronic Vogt-Koyanagi-Harada Disease.

PURPOSE: To describe scleral changes in chronic VKH. METHODS: Medical records of patients with chronic VKH were retrospectively reviewed. Change of scleral architecture was defined as progressive posterior bowing on OCT, axial length elongation, and/or increased myopia more than -1.0 D, not explicable by other etiologies. RESULTS: In total, 28 eyes (16 patients) with mean age of disease onset 32.5 ± 14.0 years were included in the study. Disease duration was 15.1 ± 10.2 years. Eight eyes (28.6%) showed progressive scleral architectural changes. Five eyes (18%) developed scleral changes on OCT, not seen on prior imaging (2-12 years earlier). One eye had posterior bowing on OCT with increased axial length, both eyes of a bilateral pseudophake developed increased myopia with increased axial length. Well-circumscribed chorioretinal atrophy within the arcade was associated with progressive scleral change. CONCLUSIONS: Progressive scleral change may develop as a late complication of VKH. The association with well-circumscribed chorioretinal atrophy suggests that chronic choroidal inflammation may be responsible.

Measurement of the muon neutrino inclusive charged-current cross section in the energy range of 1–3 GeV with the T2K INGRID detector

We report a measurement of the νµ-nucleus inclusive charged current cross section (=σ cc) on ironusing data from exposed to the J-PARC neutrino beam. The detector consists of 14 modules in total, which are spread over a range of off-axis angles from 0◦ to 1.1◦. The variation in the neutrino energy spectrum as a function of the off-axis angle, combined with event topology information, is used to calculate this cross section as a function of neutrino energy. The cross section is measured to be σcc(1.1 GeV) = 1.10±0.15 (10^−38cm^2/nucleon), σcc(2.0 GeV) = 2.07±0.27 (10^−38cm^2/nucleon), and σcc(3.3 GeV) = 2.29 ± 0.45 (10^−38cm^2/nucleon), at energies of 1.1, 2.0, and 3.3 GeV, respectively. These results are consistent with the cross section calculated by the neutrino interaction generators currently used by T2K. More importantly, the method described here opens up a new way to determine the energy dependence of neutrino-nucleus cross sections.