[Cannabinoids reduce opioid use in older patients with pain : Retrospective three-year analysis of data from a general practice]. / Cannabinoide reduzieren den Opioidverbrauch bei älteren Schmerzpatienten : Eine retrospektive Dreijahresauswertung einer ambulanten kassenärztlichen Praxis.

BACKGROUND: Relevant data for the prescription and therapeutic effects of medical cannabinoids (CAM) are still missing in everyday medicine especially for elderly and geriatric patients. AIM OF THE STUDY: Documentation of prescription (duration, age) of CAM (dronabinol, nabiximols, cannabinoid extracts) and co-medicated opioids in a doctor's office specializing in pain. METHODS: Analysis of the consumption of opioids (morphine equivalent) and CAM (THC equivalent) for age and gender. RESULTS: In all, 178 patients with chronic pain were treated for a period of 366 days (median; range 31-2590 days). Median age was 72 years (26-96 years); 115 were women (64.8%). Of these, 34 were younger than 65 years, 42 were 65-80 years and 40 were more than 80 years old. Of the 63 men, 29 were younger than 65 years, 24 were 65-80 years and 10 were older than 80 years. Indications for CAM were chronic pain and the limitations for opioids because of side effects and worsening of quality of life. To total of 1001 CAM were prescribed, 557 (55.6%) dronabinol as liquid, 328 (32.7%) as full spectrum extracts and 66 (6.6%) as oro-mucosal nabiximols spray. 50 prescriptions (5%) contained more than one CAM simultaneously. The daily consumption of dronabinol liquor and extracts were 9.6 mg/day (median), and of spray 13.6 mg. The dosage over time did not change in patients older than 64; in younger patients, there was a non-significant increasing trend. Women requested lower THC dosages compared to men (8.1 mg vs. 14.8 mg). Furthermore, 10 patients (5.6%) stopped CAM because of failing effectivity, 7 (3.9%) because of failing cost coverage and only 5 because of adverse side effects. 115 patients (65%) with CAM also received opioids a median 65 mg/day morphine equivalents. This opioid dosage was significantly reduced in course of time by 24 mg/day morphine equivalents or 50%. This reduction was independent on CAM dosage, age and gender. DISCUSSION: Patients with chronic pain profit from long-term CAM which safely and significantly lower the consumption of comedicated opioids, even at low dosages (< 7.5 mg/day). For women, low-dose THC may be sufficient. Older patients benefit from CAM, and adverse effects do not limit the (chronic) use and prescription of CAM in the elderly.

Cellular events of acute, resolving or progressive COVID-19 in SARS-CoV-2 infected non-human primates.

Understanding SARS-CoV-2 associated immune pathology is crucial to develop pan-effective vaccines and treatments. Here we investigate the immune events from the acute state up to four weeks post SARS-CoV-2 infection, in non-human primates (NHP) with heterogeneous pulmonary pathology. We show a robust migration of CD16 expressing monocytes to the lungs occurring during the acute phase, and we describe two subsets of interstitial macrophages (HLA-DR+CD206-): a transitional CD11c+CD16+ cell population directly associated with IL-6 levels in plasma, and a long-lasting CD11b+CD16+ cell population. Trafficking of monocytes is mediated by TARC (CCL17) and associates with viral load measured in bronchial brushes. We also describe associations between disease outcomes and high levels of cell infiltration in lungs including CD11b+CD16hi macrophages and CD11b+ neutrophils. Accumulation of macrophages is long-lasting and detectable even in animals with mild or no signs of disease. Interestingly, animals with anti-inflammatory responses including high IL-10:IL-6 and kynurenine to tryptophan ratios show less severe illness. Our results unravel cellular mechanisms of COVID-19 and suggest that NHP may be appropriate models to test immune therapies.

New Insight in the Q

Virtual Compton scattering on the proton has been investigated at three yet unexplored values of the four-momentum transfer Q^{2}: 0.10, 0.20, and 0.45 GeV^{2}, at the Mainz Microtron. Fits performed using either the low-energy theorem or dispersion relations allowed the extraction of the structure functions P_{LL}-P_{TT}/ε and P_{LT}, as well as the electric and magnetic generalized polarizabilities α_{E1}(Q^{2}) and ß_{M1}(Q^{2}). These new results show a smooth and rapid falloff of α_{E1}(Q^{2}), in contrast to previous measurements at Q^{2}=0.33 GeV^{2}, and provide for the first time a precise mapping of ß_{M1}(Q^{2}) in the low-Q^{2} region.

Beam-Recoil Polarization Measurement of π

The helicity-dependent recoil proton polarizations P_{x}^{'} and P_{z}^{'} as well as the helicity-independent component P_{y} have been measured in the p(e[over →],e^{'}p[over →])π^{0} reaction at four-momentum transfer Q^{2}≃0.1 GeV^{2}, center-of-mass proton emission angle θ_{p}^{*}≃90°, and invariant mass W≃1440 MeV. This first precise measurement of double-polarization observables in the energy domain of the Roper resonance P_{11}(1440) by exploiting recoil polarimetry has allowed for the extraction of its scalar electroexcitation amplitude at an unprecedentedly low value of Q^{2}, establishing a powerful instrument for probing the interplay of quark and meson degrees of freedom in the nucleon.

Observation of Λ(4)H Hyperhydrogen by Decay-Pion Spectroscopy in Electron Scattering.

At the Mainz Microtron MAMI, the first high-resolution pion spectroscopy from decays of strange systems was performed by electron scattering off a (9)Be target in order to study the Λ binding energy of light hypernuclei. Positively charged kaons were detected by a short-orbit spectrometer with a broad momentum acceptance at 0° forward angles with respect to the beam, efficiently tagging the production of strangeness in the target nucleus. Coincidentally, negatively charged decay pions were detected by two independent high-resolution spectrometers. About 10(3) pionic weak decays of hyperfragments and hyperons were observed. The pion momentum distribution shows a monochromatic peak at pπ≈133 MeV/c, corresponding to the unique signature for the two-body decay of hyperhydrogen Λ(4)H→(4)He+π(-), stopped inside the target. Its Λ binding energy was determined to be BΛ=2.12±0.01 (stat)±0.09 (syst)MeV with respect to the (3)H+Λ mass.

Cyclic di-GMP acts as a cell cycle oscillator to drive chromosome replication.

Fundamental to all living organisms is the capacity to coordinate cell division and cell differentiation to generate appropriate numbers of specialized cells. Whereas eukaryotes use cyclins and cyclin-dependent kinases to balance division with cell fate decisions, equivalent regulatory systems have not been described in bacteria. Moreover, the mechanisms used by bacteria to tune division in line with developmental programs are poorly understood. Here we show that Caulobacter crescentus, a bacterium with an asymmetric division cycle, uses oscillating levels of the second messenger cyclic diguanylate (c-di-GMP) to drive its cell cycle. We demonstrate that c-di-GMP directly binds to the essential cell cycle kinase CckA to inhibit kinase activity and stimulate phosphatase activity. An upshift of c-di-GMP during the G1-S transition switches CckA from the kinase to the phosphatase mode, thereby allowing replication initiation and cell cycle progression. Finally, we show that during division, c-di-GMP imposes spatial control on CckA to install the replication asymmetry of future daughter cells. These studies reveal c-di-GMP to be a cyclin-like molecule in bacteria that coordinates chromosome replication with cell morphogenesis in Caulobacter. The observation that c-di-GMP-mediated control is conserved in the plant pathogen Agrobacterium tumefaciens suggests a general mechanism through which this global regulator of bacterial virulence and persistence coordinates behaviour and cell proliferation.

[Propranolol therapy for periocular and orbital infantile haemangiomas]. / Propranolol-Therapie bei infantilen Hämangiomen im Lid- und Orbitabereich.

In spite of the self-limiting natural course of infantile haemangiomas of the eyelids and orbit, the effects of amblyopia, compression of the optic nerve, and impairment of the aesthetic appearance may develop. Since the serendipitous discovery of the effects of propranolol, a non-selective beta-blocker, on infantile haemangioma in 2008, it has largely replaced the former standard treatments with corticosteroids, laser or surgical procedures. This review discusses the pathogenesis, classification, indication for treatment, and treatment options for infantile haemangiomas. In addition, the results of patients with infantile haemangiomas of the eyelids and orbit treated with systemic propranolol are shown. With additional confirmation of data, including a positive effect-risk-analysis, propranolol will potentially replace high-dose corticosteroids and surgery in the treatment of infantile haemangiomas in the eyelids and orbit. Further clinical studies are necessary to optimise the dosage, treatment period, and application modalities (oral or topical). In the future, propranolol accompanied with paediatric-cardiological monitoring should emerge as the first-line therapy for problematic infantile haemangiomas.

Search at the Mainz Microtron for light massive gauge bosons relevant for the muon g-2 anomaly.

A massive, but light, Abelian U(1) gauge boson is a well-motivated possible signature of physics beyond the standard model of particle physics. In this Letter, the search for the signal of such a U(1) gauge boson in electron-positron pair production at the spectrometer setup of the A1 Collaboration at the Mainz Microtron is described. Exclusion limits in the mass range of 40 MeV/c^{2} to 300 MeV/c^{2}, with a sensitivity in the squared mixing parameter of as little as ε^{2}=8×10^{-7} are presented. A large fraction of the parameter space has been excluded where the discrepancy of the measured anomalous magnetic moment of the muon with theory might be explained by an additional U(1) gauge boson.

Use of threshold-specific energy model for the prediction of effects of smoking and radon exposure on the risk of lung cancer.

Lung cancer is the leading cause of cancer death in both men and women. Smoking causes 80-90% of cases of lung cancer. In this study, an attempt was made to assess the impact of cigarette smoking on the risk of lung cancer by the so-called threshold-specific energy model. This model allows to analyse the biological effects of radon daughter products on the lung tissue, and is based on the assumption that the biological effect (i.e. cell inactivation) will manifest itself after the threshold-specific energy z0 deposited in the sensitive volume of the cell is exceeded. Cigarette smoking causes, among others, an increase in the synthesis of the survivin protein that protects cells from apoptosis and thereby reduces their radiosensitivity. Based on these facts, an attempt was made to estimate the shape of the curves describing the increase in the oncological effect of radiation as a function of daily cigarette consumption.

Measurement of the neutron electric to magnetic form factor ratio at Q2=1.58 GeV2 using the reaction 3He[over →](e[over →],e'n)pp.

A measurement of beam helicity asymmetries in the reaction 3He[over →](e[over →],e'n)pp is performed at the Mainz Microtron in quasielastic kinematics to determine the electric to magnetic form factor ratio of the neutron GEn/GMn at a four-momentum transfer Q2=1.58 GeV2. Longitudinally polarized electrons are scattered on a highly polarized 3He gas target. The scattered electrons are detected with a high-resolution magnetic spectrometer, and the ejected neutrons are detected with a dedicated neutron detector composed of scintillator bars. To reduce systematic errors, data are taken for four different target polarization orientations allowing the determination of GEn/GMn from a double ratio. We find µnGEn/GMn=0.250±0.058(stat)±0.017(syst).

The shaker potassium channel is no target for xenon anesthesia in short-sleeping Drosophila melanogaster mutants.

BACKGROUND: Xenon seems to be an ideal anesthetic drug. To explore if next to the antagonism at the NMDA-receptor other molecular targets are involved, we tested the xenon requirement in short sleeping Drosophila shaker mutants and in na[har(38)]. METHODS: The Drosophila melanogaster strains wildtype Canton-S, na[har(38)], sh(102) and sh(mns), were raised and sleep was measured. Based on the response of the flies at different xenon concentrations, logEC50 values were calculated. RESULTS: The logEC50-values for WT Canton-S were 1.671 (1.601-1.742 95%-confidence intervall; n = 238; P versus sh(102) > 0,05), for sh(mns) 1.711 (1.650-1.773; n = 242; P versus WT Canton-S > 0,05). The logEC50-value for sh(102) was 1.594 (1.493-1.694; n = 261; P versus sh(mns) > 0.05). The logEC-value of na[har(38)] was 2.076 (1.619-2.532; n = 207; P versus sh(mns) < 0.05, versus sh(102) < 0.05, versus WT Canton-S < 0.05). P values for all shaker mutants were P > 0.05, while na[har(38)] was found to be hyposensitive compared to wildtype (P < 0.05). CONCLUSIONS: The xenon requirement in Drosophila melanogaster is not influenced by a single gene mutation at the shaker locus, whereas a reduced expression of a nonselective cation channel leads to an increased xenon requirement. This supports the thesis that xenon mediates its effects not only via an antagonism at the NMDA-receptor.

The effect of short time periods of pre-operative warming in the prevention of peri-operative hypothermia.

The aim of our study was to evaluate the performance of different durations of active pre-operative skin-surface warming (pre-warming) to prevent peri-operative hypothermia and postoperative shivering. We randomly assigned 200 patients, scheduled for surgery of 30-90 min under general anaesthesia, to receive passive insulation or forced-air skin surface warming for 10, 20 or 30 min. Body temperature was measured at the tympanic membrane. Shivering was graded by visual inspection. There were significant differences in changes of core temperature between the non-pre-warmed group and all the pre-warmed groups (p < 0.00001), but none between the three pre-warmed groups (p = 0.54). Without pre-warming, 38/55 (69%) patients became hypothermic (< 36 °C) at the end of anaesthesia, whereas only 7/52 (13%), 3/43 (7%) and 3/50 (6%) patients following 10, 20 or 30 min pre-warming, respectively, became hypothermic (p < 0.001 vs no pre-warming). Shivering was observed in 10 patients without, and in three, three and one patients with pre-warming in the respective groups (p = 0.02). Pre-warming of patients for only 10 or 20 min before general anaesthesia mostly prevents hypothermia and reduces shivering.

A rhesus macaque model of Streptococcus pneumoniae carriage.

BACKGROUND: Nasopharyngeal colonization by Streptococcus pneumoniae precedes pneumococcal disease. Elucidation of procedures to prevent or eradicate nasopharyngeal carriage in a model akin to the human would help to diminish the incidence of both pneumonia and invasive pneumococcal disease. METHODS: We conducted a survey of the nasopharynx of infant rhesus macaques from our breeding colony, in search of natural carriers of S. pneumoniae. We also attempted experimental induction of colonization, by nasopharyngeal instillation of a human S. pneumoniae strain (19F). RESULTS: None of 158 colony animals surveyed carried S. pneumoniae in the nasopharynx. Colonization was induced in eight of eight infant rhesus by nasopharyngeal instillation and lasted 2weeks in 100% of the animals and 7weeks in more than 60%. CONCLUSION: Rhesus macaques are probably not natural carriers of S. pneumoniae. The high rate and duration of colonization obtained in our experiments indicates that the rhesus macaque will serve as a human-like carriage model.

Normal values of quantitative T2' in a spontaneously hypertensive stroke prone rat stem at 3T.

INTRODUCTION: Regarding therapy and prognosis of acute ischemic stroke the identification of ischemic penumbra is pivotal. A promising candidate is BOLD-imaging using qT2'-maps. For valid interpretation of experimental studies in animals normal values for qT2' are needed. Normal values in humans at 1.5T already exist. Normal values for cortical and subcortical structures in a spontaneously hypertensive stroke prone rat stem (SHR-SP) at a fieldstrength of 3T are reported. MATERIALS AND METHODS: 39 (20 males and 19 females) spontaneously hypertensive stroke prone (SHRSP) rats were examined in a 3T scanner using a dedicated small animal coil. Mean weight was 144.1 ± 8.2g and mean age was 60.2 ± 2.7 days. For the calculation of qT2' multiple echo T2w and T2 w images were acquired. ROIs were placed into deep and cortical grey matter in five different brain regions to obtain values for qT2', qT2 and qT2. RESULTS: Mean qT2' for cortical grey matter was 74.76 ± 33.27 ms and 67.73 ± 17.86 ms for deep grey matter. The 99% confidence interval for cortical grey matter was 69.91-79.61 ms. For qT2 it was 79.02 ± 2.9 ms and 70.45 ± 1.89 ms, respectively. For qT2 it was 34.65 ± 5.25 ms and 31.9 ± 2.9 ms. CONCLUSION: The values for qT2' presented here can serve as reference values for further studies examining the ischemic penumbra in a rat model.

Search for light gauge bosons of the dark sector at the Mainz Microtron.

A new exclusion limit for the electromagnetic production of a light U(1) gauge boson γ' decaying to e + e- was determined by the A1 Collaboration at the Mainz Microtron. Such light gauge bosons appear in several extensions of the standard model and are also discussed as candidates for the interaction of dark matter with standard model matter. In electron scattering from a heavy nucleus, the existing limits for a narrow state coupling to e + e- were reduced by nearly an order of magnitude in the range of the lepton pair mass of 210 MeV/c2}

High-precision determination of the electric and magnetic form factors of the proton.

New precise results of a measurement of the elastic electron-proton scattering cross section performed at the Mainz Microtron MAMI are presented. About 1400 cross sections were measured with negative four-momentum transfers squared up to Q² = 1 (GeV/c)² with statistical errors below 0.2%. The electric and magnetic form factors of the proton were extracted by fits of a large variety of form factor models directly to the cross sections. The form factors show some features at the scale of the pion cloud. The charge and magnetic radii are determined to be ½ = 0.879(5)stat(4)syst(2)model(4)group fm and ½ = 0.777(13)stat(9)syst(5)model(2)group fm.

Investigation of the exclusive 3He(e,e' pn)1H reaction.

Cross sections for the 3He(e,e' pn)1H reaction were measured for the first time at energy transfers of 220 and 270 MeV for several momentum transfers ranging from 300 to 450 MeV/c. Cross sections are presented as a function of the momentum of the recoil proton and the momentum transfer. Continuum Faddeev calculations using the Argonne V18 and Bonn-B nucleon-nucleon potentials overestimate the measured cross sections by a factor 5 at low recoil proton momentum with the discrepancy becoming smaller at higher recoil proton momentum.

Overview of the ability of different treatment methods for liquid and solid manure to inactivate pathogens.

The use of manure as a fertilizer in agriculture includes the risk of spreading pathogenic infectious agents to the environment, to animals and humans. The treatment of manure can help avoid or reduce these risks. Even if the treatment is dominated by economic considerations such as biogas production, ammonia stripping or phosphorous precipitation, the hygienic aspect should be kept in mind. Otherwise, new infection chains may be established by the use of insufficiently treated manure by-products such as fertilizers still containing infective pathogens. Treatment plants should use a concept according to HACCP principles that includes hazard analysis, risk assessment, the determination of process relevant CCPs and the validation of the process by determining the hygienizing efficiency using representative test organisms as well as microbial end product supervision. Treatment methods can be divided into physical, chemical and microbiological treatment, sometimes used in combination. For economical reasons, only composting or anaerobic treatment (biogas) or, to a minor extent, aerobic thermophilic stabilization (ATS) are used as routine preventive measures on a farm level. In cases of outbreaks of notifiable diseases both physical and chemical treatment of manure can lead to reliable disinfected/pasteurised end products which can be used in agriculture without long-lasting risks for soil fertility or the environment.

[Long-term results with the Wagner metal-on-metal resurfacing prosthesis]. / Langzeitergebnisse mit der Wagner-Metall/Metall-Schalenprothese.

INTRODUCTION: Former failures of hip resurfacing arthroplasties in the 1980s were attributed to articulating materials and malpositioning of the implants. To solve these problems in the 1990s metal-on-metal articulations were developed. The purpose of this study was to depict the long-term results of the Wagner resurfacing prosthesis utilising a metal-on-metal surface articulation. PATIENTS AND METHOD: Between January 1991 and December 1995 40 Wagner resurfacing prostheses were implanted. All operations were performed via an anterior approach. 37 patients were able to be followed up after an average period of 13.1 years. For clinical evaluation the score according to Merle d'Aubigné was used. For radiological assessment X-rays in two planes were evaluated. RESULTS: On average, 1.45 (1 to 9) preliminary operations were performed on each patient prior to the implantation of the actual surface replacement prosthesis. In 32 cases a cementless femoral component was used, in the remaining 8 cases a cemented one. The score according to Merle d'Aubigné improved from a pre-operative average of 8.3 to a post-operative average of 17.3 points (p < 0.001). 17 of 40 (42.5 %) hip resurfacing arthroplasties have been revised. DISCUSSION: Taking all aspects into account, the high rate of revisions in this series was attributed to extreme indications for hip resurfacing which would not be considered as standard nowadays. Combined with a stricter indication and an exact, careful operative technique, the metal-on-metal surface replacement of the hip joint may offer an alternative replacement option.