Strong Absorption of Hadrons with Hidden and Open Strangeness in Nuclear Matter.

We present the first observation of K^{-} and ϕ absorption within nuclear matter by means of π^{-}-induced reactions on C and W targets at an incident beam momentum of 1.7 GeV/c studied with HADES at SIS18/GSI. The double ratio (K^{-}/K^{+})_{W}/(K^{-}/K^{+})_{C} is found to be 0.319±0.009(stat)_{-0.012}^{+0.014}(syst) indicating a larger absorption of K^{-} in heavier targets as compared to lighter ones. The measured ϕ/K^{-} ratios in π^{-}+C and π^{-}+W reactions within the HADES acceptance are found to be equal to 0.55±0.04(stat)_{-0.07}^{+0.06}(syst) and to 0.63±0.06(stat)_{-0.11}^{+0.11}(syst), respectively. The similar ratios measured in the two different reactions demonstrate for the first time experimentally that the dynamics of the ϕ meson in nuclear medium is strongly coupled to the K^{-} dynamics. The large difference in the ϕ production off C and W nuclei is discussed in terms of a strong ϕN in-medium coupling. These results are relevant for the description of heavy-ion collisions and the structure of neutron stars.

Occurrence of occult CSF leaks during standard FESS procedures.

OBJECTIVE: To determine the incidence of occult cerebrospinal fluid leaks (CSF) after functional endoscopic sinus surgery (FESS) and to evaluate the diagnostic performance of beta2-transferrin in blood-contaminated conditions. STUDY DESIGN: Prospective cohort study. METHODS: An analysis of 57 intraoperative samples using hydrogel 6 beta2-transferrin assay after FESS was undertaken. In case of CSF positive samples and continuing rhinorrhea, reanalysis after more than 1 year was conducted. In-vivo analysis of a primary spontaneous CSF leak sample took place to verify difficulties in detecting beta2-transferrin in blood-contaminated settings. Own titrations were performed to evaluate detection limits of CSF by beta2-transferrin and beta-trace protein assays in these settings. RESULTS: An incidence of 13% for occult CSF leaks after FESS was found. In blood-contaminated conditions, routine beta2-transferrin assays showed low sensitivity. In over 1 year follow-up, all samples were negative for CSF and none of them developed clinical relevant CSF leaks or meningitis. CONCLUSION: Occult and clinically irrelevant CSF leaks do occur in a significant proportion of patients during and shortly after FESS. Intra- and postoperatively, routine beta2-transferrin assays show low sensitivity. They should not be used in these settings. The clinical course of patients with occult CSF leaks indicated possibility of an uneventful follow-up.

Reversible and Species-Specific Depigmentation Effects of AZD3293, a BACE Inhibitor for the Treatment of Alzheimer's Disease, Are Related to BACE2 Inhibition and Confined to Epidermis and Hair.

BACKGROUND: AZD3293 (also known as LY3314814) is a novel, potent, non-selective BACE1/BACE2 inhibitor currently in Phase 3 clinical development for the treatment of Alzheimer's disease. OBJECTIVES: The purpose of these studies was to characterize the effects, putative mechanism, and reversibility of hypopigmentation following treatment with AZD3293 in pigmented Long-Evans rats, Beagle dogs, human cell cultures, and humans. DESIGN: Nonclinical studies were conducted in Long-Evans pigmented rats, and both young and older Beagle dogs using a variety of oral dose levels of AZD3293 or AZD3839 (BACE inhibition reference compound; used in older dogs only) for dosing durations of 13 to 26 weeks. In vitro studies of normal human epidermal melanocytes and reconstituted human epidermis were also conducted. Skin biopsy data from a multiple-dose Phase 1 clinical study of AZD3293 (NCT01795339) are also reported. SETTING: Nonclinical in vivo and in vitro studies were conducted in laboratory settings in the US, Canada, and France; the multiple dose clinical study was conducted in a specialized inpatient setting in the US. PARTICIPANTS: Beagle dogs: 13-week study N=36 young (8-10 mo) animals; 39-week study N=64 young animals; and a second 13-week study N=32 older (30-32 mo) animals. Long-Evans rats: N=68 animals. Multiple-dose clinical study: only data for subjects enrolled in Part 2 of this study are included in this report (N=16). INTERVENTIONS: AZD3293 was the primary intervention used in these studies. AZD3839, a relatively BACE1-selective reference inhibitor compound was used in one group in the 13 week study in older Beagle dogs and one in vitro assessment. Finally, AZ1340, another relatively BACE1-selective reference inhibitor compound was used only in one in vitro assessment. MEASUREMENTS: Measurements for the nonclinical studies in dogs and rats included macroscopic observation and assessment of skin biopsies via histopathology, immunochemistry, and electron microscopy. Measurements for the in vitro studies included melanocyte premelanosome protein (PMEL) processing, cytotoxicity, melanin synthesis, Pmel17 labeling, and melanocyte dendricity. Measurements in the clinical study included scoring of melanin content in skin biopsies taken before and after dosing with AZD3293 over 14 days at dose levels up to 150 mg. RESULTS: Depigmentation in rats and dogs was limited to skin, hair, and mucosa with no effects on other pigmented tissues. At a cellular level depigmentation was observed within a week of treatment, whereas the appearance of depigmentation in skin and hair did not become apparent until, at earliest, 4 weeks of treatment. The depigmentation effects were reversible, not associated with degenerative or inflammatory changes, and were dose- and species-dependent in severity. Full recovery of melanization was observed at the microscopic (cellular) level and at least partial recovery was seen in the macroscopic appearance of animals by the end of the 12-week recovery period in both rats and dogs. Interestingly, no changes in melanin production or melanocyte morphology were seen in human primary melanocytes or reconstituted human epidermis in vitro. Finally, there were no changes in melanization level in skin biopsies following 12 days of daily AZD3293 treatment at doses of AZD3293 up to 150 mg/day in human subjects. CONCLUSIONS: AZD3293, a novel, potent, non-selective BACE1/BACE2 inhibitor is in development as a potentially disease-modifying treatment for Alzheimer's disease. Chronic nonclinical studies in Beagle dogs and pigmented rats showed macroscopic and microscopic hypopigmentation effects of AZD3293 that were limited to skin, hair, and mucosa. These effects were shown to be reversible in both species. Analysis of data from nonclinical and in vitro studies suggests that hypopigmentation is caused by BACE2 inhibition resulting in accumulation of a premelanosome protein fragment, which interrupts the normal production of melanin. No macroscopic or microscopic reports of hypopigmentation were observed in a Phase 1 clinical study following 13 doses of AZD3293 over 14 days at dose levels up to 150 mg/day. These data suggest that hypopigmentation is species-specific and humans appear to be least sensitive to the depigmentation effect caused by BACE2 inhibition.

Subthreshold Ξ

Results on the production of the double strange cascade hyperon Ξ^{-} are reported for collisions of p(3.5 GeV)+Nb, studied with the High Acceptance Di-Electron Spectrometer (HADES) at SIS18 at GSI Helmholtzzentrum for Heavy-Ion Research, Darmstadt. For the first time, subthreshold Ξ^{-} production is observed in proton-nucleus interactions. Assuming a Ξ^{-} phase-space distribution similar to that of Λ hyperons, the production probability amounts to P_{Ξ^{-}}=[2.0±0.4(stat)±0.3(norm)±0.6(syst)]×10^{-4} resulting in a Ξ^{-}/(Λ+Σ^{0}) ratio of P_{Ξ^{-}}/P_{Λ+Σ^{0}}=[1.2±0.3(stat)±0.4(syst)]×10^{-2}. Available model predictions are significantly lower than the measured Ξ^{-} yield.

[Adjustable transobturatoric sling system in men : diagnosis and therapy recommendations to persistent pain]. / Adjustierbare transobturatorische Schlingensysteme beim Mann : Diagnostik und Therapieempfehlungen bei persistierenden Schmerzen.

BACKGROUND: In addition to artificial sphincters, male slings are recommended in the current guidelines for the treatment of persistent male stress incontinence. Today, several sling systems are available. Well-known complications of all sling systems are infections, erosion, residual urine/urinary retention, de novo urgency, and postoperative pain. DISCUSSION: Compared to retropubic implanted adjustable sling systems or functional slings, pain is more common after transobturatoric implantation of adjustable sling systems. Early postoperative pain is very common. In contrast, persistent pain is rare. However, the treatment of persistent pain is a large challenge for urologists and patients. There are no recommendations for diagnostic workup or treatment. RESULTS: After pain classification, pain management should be started with nonsteroidal anti-inflammatory drugs and/or tricyclic antidepressive agents, if necessary treatment escalation with a weak opioid and if not effective interventional procedures should be performed. Sling explantation is only necessary in rare cases.

Physiology and biophysics of plant ligand-gated ion channels.

Small molecules and metabolites often act as intra- or extracellular messengers in signal transduction pathways. Ligand-gated ion channels provide a mean to transduce those biochemical signals at the membrane into electrical events and ion fluxes. In plants, cyclic nucleotides and glutamate represent intra- and extracellular signalling ligands, respectively. While the former have been shown to regulate voltage-dependent ion channels and are supposed to activate cyclic nucleotide gated (CNG) channels, the latter are perceived by ionotropic glutamate receptors (GLRs). This review summarises our current knowledge about CNG channels and glutamate receptors in plants and their proposed roles in plant development and adaptation to biotic and abiotic stresses.

Deep subthreshold Xi;{-} production in Ar + KCl reactions at 1.76A GeV.

We report first results on a deep subthreshold production of the doubly strange hyperon Xi;{-} in a heavy-ion reaction. At a beam energy of 1.76A GeV the reaction Ar + KCl was studied with the High Acceptance Di-Electron Spectrometer at SIS18/GSI. A high-statistics and high-purity Lambda sample was collected, allowing for the investigation of the decay channel Xi;{-} --> Lambdapi;{-}. The deduced Xi;{-}/(Lambda + Sigma;{0}) production ratio of (5.6 +/- 1.2_{-1.7};{+1.8}) x 10;{-3} is significantly larger than available model predictions.

Suppression of high-p{T} neutral pion production in central Pb+Pb collisions at sqrt[S{NN}]=17.3 GeV relative to p+C and p+Pb collisions.

Neutral pion transverse momentum spectra were measured in p+C and p+Pb collisions at sqrt[S{NN}]=17.4 GeV at midrapidity (2.3 less than or approximately equal eta{lab} less than or approximately equal 3.0) over the range 0.7 less than or approximately equal p{T} less than or approximately equal 3.5 GeV/c. The spectra are compared to pi{0} spectra measured in Pb+Pb collisions at sqrt[S{NN}]=17.3 GeV in the same experiment. For a wide range of Pb+Pb centralities (N{part} less than or approximately equal 300), the yield of pi{0}'s with p{T} greater than or approximately equal 2 GeV/c is larger than or consistent with the p+C or p+Pb yields scaled with the number of nucleon-nucleon collisions (N{coll}), while for central Pb+Pb collisions with N{part}greater than or approximately equal 350, the pi{0} yield is suppressed.

Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy.

OBJECTIVE: To evaluate the efficacy, tolerability, and safety of two pregabalin regimens administered as adjunctive therapy to that of placebo in patients with medically refractory partial epilepsy. METHODS: A multicenter, double-blind, randomized, parallel-group, placebo-controlled trial was performed. Following a prospective 8-week baseline phase, patients were randomized to 12 weeks of double-blind treatment with placebo or pregabalin 600 mg/day administered twice daily (BID) or three times daily (TID). Primary efficacy was measured as change in seizure frequency from baseline of either pregabalin regimen compared with placebo. Secondary efficacy comparisons included the proportion of patients experiencing > or =50% reduction in seizure frequency (responder rate) and median percentage change from baseline in seizure frequency. Safety/tolerability assessments included adverse events (AEs), physical and neurologic examinations, and clinical laboratory evaluation. Efficacy and safety analyses were performed on the intent-to-treat (ITT) population. RESULTS: Pregabalin treatment resulted in seizure frequency reductions: 53% for pregabalin TID (p < or = 0.0001) and 44% for pregabalin BID (p < or = 0.0001) compared with a 1% increase for placebo. Responder rates were 49% for pregabalin TID and 43% for pregabalin BID compared with 9% for placebo (p < or = 0.001). Both pregabalin regimens were similar in efficacy and tolerability. The most common AEs were dizziness, somnolence, and ataxia. CONCLUSIONS: Pregabalin administered at 600 mg/day is safe, generally well tolerated, and efficacious as adjunctive therapy for the treatment of patients with partial seizures, with or without secondary generalizations. This dose can be administered on a twice daily or three times daily schedule with similar efficacy and tolerability results.

Interferometry of direct photons in central 208Pb + 208Pb collisions at 158A GeV.

Two-particle correlations of direct photons were measured in central 208Pb+208Pb collisions at 158A GeV. The invariant interferometric radii were extracted for 100

Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures.

BACKGROUND: Pregabalin is an alpha(2)-delta ligand that has anxiolytic, analgesic, and anticonvulsant properties. OBJECTIVE: To establish the efficacy, safety, and tolerability of pregabalin administered twice-daily (BID) without dose titration as adjunctive treatment in patients with partial seizures and to confirm the dose-response relationship. METHODS: This 76-center, double-blind, randomized, placebo-controlled, parallel-group study consisted of an 8-week baseline and a 12-week double-blind phase. Patients with refractory partial seizures on one to three antiepileptic drugs were randomly assigned to one of five treatment groups (placebo or 50, 150, 300, and 600 mg/d pregabalin, all administered BID). Efficacy was assessed using seizure frequency reduction and responder rate (> or =50% seizure reduction from baseline). Pharmacokinetic parameters were estimated. RESULTS: A total of 453 patients were included in the intent-to-treat analysis. The median baseline seizure rate was 10 per month. Seizure frequency reductions from baseline were 7% (placebo; n = 100), 12% (50 mg/d; n = 88), 34% (150 mg/d; n = 86), 44% (300 mg/d; n = 90), and 54% (600 mg/d; n = 89). Responder rates (> or =50% seizure reduction) were 14% (placebo), 15% (50 mg/d), 31% (150 mg/d), 40% (300 mg/d), and 51% (600 mg/d). Discontinuation rates due to adverse events were 5% (placebo), 7% (50 mg/d), 1% (150 mg/d), 14% (300 mg/d), and 24% (600 mg/d). The 150-, 300-, and 600-mg/d pregabalin groups were associated with greater reductions in seizures (p < or = 0.0001) and greater responder rates compared with the placebo group (p < or = 0.006). There was a favorable dose-response trend for both seizure reductions (p < or = 0.0001) and responder rate (p < or = 0.001). CONCLUSION: Adjunctive therapy with pregabalin 150, 300, and 600 mg/d, given in twice-daily doses without titration, is significantly effective and well tolerated in the treatment of patients with partial seizures as demonstrated in patients with refractory partial seizures.

[Patient's emotional satisfaction with anaesthetic care]. / Die emotionale Zufriedenheit von Patienten mit der anästhesiologischen Betreuung.

OBJECTIVE: The evaluation of services by patients is an integral part of continuous quality improvement in anaesthesia. Patient satisfaction is affected by various objective and subjective variables. Individual experiences, impressions and needs represent an important part of overall patient satisfaction. METHODS: Data of 519 patients were collected in a standardised anonymous questionnaire independent of the post-anaesthetic visit. RESULTS: Anaesthesia staff appeared to be friendly to 97 % of patients asked, 95 % of patients wanted to be treated by the same staff in case of another anaesthesia, nearly 87 % felt relaxed and satisfied after anaesthesia. Up to 26 % of patients felt tense after pre-anaesthetic visit and 38 % before anaesthesia, 35 % felt that waiting before operation was endless and 20 % complained about loss of humaneness because of technical equipment and monitoring. Significant differences could be found between specific groups of patients: Older and male patients were in all more satisfied compared to younger and female patients, patients after regional anaesthesia were more satisfied compared to ones after general anaesthesia. CONCLUSION: The inquiry of subjective patient impressions can be performed in anaesthesia departments without much effort. The results help to identify and avoid psycho-vegetative stressing situations and to improve patient satisfaction with anaesthesia.

Suppression of soft nuclear bremsstrahlung in proton-nucleus collisions.

Photon energy spectra up to the kinematic limit have been measured in 190 MeV proton reactions with light and heavy nuclei to investigate the influence of the multiple-scattering process on the photon production. Relative to the predictions of models based on a quasifree production mechanism, a strong suppression of bremsstrahlung is observed in the low-energy region of the photon spectrum. We attribute this effect to the interference of photon amplitudes due to multiple scattering of nucleons in the nuclear medium.

Differences in cortical microcirculation in the kidneys of unilaterally congenital hydronephrotic rats.

The surgically induced split hydronephrotic kidney has been generally accepted as a valid model for the assessment of renal microcirculation by means of intravital microscopy. Whereas nearly all previous work on this issue has been done with a transillumination technique, we used an epiillumination model that is suitable for investigation of microvascular perfusion in both normal and hydronephrotic kidneys without surgical manipulation of the ureter. By means of the congenital unilaterally hydronephrotic Tauchi rat, microcirculation of the hydronephrotic and that of the nonhydronephrotic kidney were compared. For that purpose both the hydronephrotic and the nonhydronephrotic kidneys of Tauchi rats were exteriorized on a specially designed microscopy stage. After injection of FITC-dextran and rhodamine 6G, microvascular perfusion was assessed in both kidneys. The new model allowed visualization of arterioles, capillaries, and postcapillary venules in both the hydronephrotic and the nonhydronephrotic kidneys. Glomeruli could only be regularly seen in the hydronephrotic kidney, but also in some normal kidneys. Capillary blood cell velocity was significantly higher in the hydronephrotic kidneys (0.67 +/- 0.03 mm/s) compared to the normal kidney (0.32 +/- 0.05 mm/s; P < 0.05), whereas capillary diameters were smaller (4.2 +/- 0.02 microm vs. 5.7 +/- 0.2 microm; P < 0.05). In addition, the hydronephrotic kidney showed a significantly lower density of perfused microvessels compared to the normal controls. Epiillumination intravital microscopy allows assessment of the cortical microcirculation in both the hydronephrotic and the nonhydronephrotic kidneys without surgical induction of hydronephrosis. The hydronephrotic kidney shows significant microcirculatory differences compared to normal kidneys that should be taken into account when using a hydronephrotic model for pharmacological testing.

Radiative proton capture on (6)He.

Radiative capture of protons is investigated as a probe of clustering in nuclei far from stability. The first such measurement on a halo nucleus is reported here for the reaction 6He(p,gamma) at 40 MeV. Capture into 7Li is observed as the strongest channel. In addition, events have been recorded that may be described by quasifree capture on a halo neutron, the alpha core, and 5He. The possibility of describing such events by capture into the continuum of 7Li is also discussed.

Quantification and in situ localization of MCP-1 mRNA and its relation to the immune response of renal cell carcinoma.

Malignant tumours are usually accompanied by an immune response. Chemokines such as MCP-1 have been claimed to be potent inducers of such tumour-associated reactions. In the present study MCP-1 mRNA was quantified by competitive reverse transcription polymerase reaction and localised by in situ hybridisation in renal cell carcinoma tissue in comparison to tumour-free tissue of the same nephrectomy specimen. MCP-1 mRNA levels were correlated with the immune cell infiltrate, the density of CD31(+)microvessels, and the endothelial expression of ICAM-1, VCAM-1, E-, and P-selectin. In only seven of 19 cases, MCP-1 mRNA levels in carcinoma tissue were increased in comparison to tumour-free tissue. Within tumour tissue, mRNA transcripts could be localised in tumour cells, microvessel endothelia, and in tumour-associated macrophages. A correlation between MCP-1 mRNA levels and the density of immune cells, especially macrophages, the microvessel density, and the expression of adhesion molecules could not be observed. Therefore, MCP-1 seems to be of minor importance for the induction of an immune response in renal cell carcinomas regarding at least the parameters analysed in this study.

Vascular endothelial growth factor expression, angiogenesis, and necrosis in renal cell carcinomas.

Rapidly growing tumors often develop necrosis. In the present study the expression of vascular endothelial growth factor (VEGF) was investigated and compared to microvessel density and necrosis of renal cell carcinomas. In the tumor-host interface the microvessel density was significantly increased compared to central tumor areas. Tumor necrosis was associated with a decrease of microvessel density and an increase of the VEGF protein expression within the perinecrotic rim. VEGF protein was focally upregulated in vital tumor tissue. An increase of the apoptotic rate of endothelia and vital tumor tissue in tumors with necrosis could not be detected. VEGF(121,165) mRNA was decreased in proliferatively active carcinomas compared to less proliferative tumors. Multicellular renal cell cancer spheroids as a model of chronic hypoxia developed central apoptosis but no necrosis. VEGF was upregulated in the spheroid. Tumor microvessels expressed matrix metalloproteinase -2 and -9 and an incomplete pericyte covering in comparison to tumor-free tissue indicating immature active angiogenesis. We conclude that highly proliferative renal cell carcinomas outgrow their vascular supply and develop chronic hypoxia inducing a decrease of proliferation and an increase of VEGF expression. However, chronic hypoxia does not cause significant necrosis or apoptosis. Tumor necrosis is more likely induced by acute hypoxia due to immature microvessels. Furthermore, VEGF expression associated with concomitant tumor necrosis may help identify renal cell carcinomas susceptible to antiangiogenic therapy.