Atmospheric observations suggest methane emissions in north-eastern China growing with natural gas use.

The dramatic increase of natural gas use in China, as a substitute for coal, helps to reduce CO2 emissions and air pollution, but the climate mitigation benefit can be offset by methane leakage into the atmosphere. We estimate methane emissions from 2010 to 2018 in four regions of China using the GOSAT satellite data and in-situ observations with a high-resolution (0.1° × 0.1°) inverse model and analyze interannual changes of emissions by source sectors. We find that estimated methane emission over the north-eastern China region contributes the largest part (0.77 Tg CH4 yr-1) of the methane emission growth rate of China (0.87 Tg CH4 yr-1) and is largely attributable to the growth in natural gas use. The results provide evidence of a detectable impact on atmospheric methane observations by the increasing natural gas use in China and call for methane emission reductions throughout the gas supply chain and promotion of low emission end-use facilities.

Deposition chamber technology as building blocks for a standardized brain-on-chip framework.

The in vitro modeling of human brain connectomes is key to exploring the structure-function relationship of the central nervous system. Elucidating this intricate relationship will allow better studying of the pathological mechanisms of neurodegeneration and hence result in improved drug screenings for complex neurological disorders, such as Alzheimer's and Parkinson diseases. However, currently used in vitro modeling technologies lack the potential to mimic physiologically relevant neural structures. Herein, we present an innovative microfluidic design that overcomes one of the current limitations of in vitro brain models: their inability to recapitulate the heterogeneity of brain regions in terms of cellular density and number. This device allows the controlled and uniform deposition of any cellular population within unique plating chambers of variable size and shape. Through the fine tuning of the hydrodynamic resistance and cell deposition rate, the number of neurons seeded in each plating chamber can be tailored from a thousand up to a million. By applying our design to so-called neurofluidic devices, we offer novel neuro-engineered microfluidic platforms that can be strategically used as organ-on-a-chip platforms for neuroscience research. These advances provide essential enhancements to in vitro platforms in the quest to provide structural architectures that support models for investigating human neurodegenerative diseases.

[Mission (im)possible : Setting up a neurological center 12,000 km away with telemedicine]. / "Mission (im)possible" : Aufbau eines neurologischen Zentrums 12.000 km entfernt mittels Telemedizin.

BACKGROUND: Specialized neurological treatment decreases the mortality and morbidity of stroke patients. In many regions of the world an extensive coverage is not available. The cooperation between the Krankenhaus Nordwest (KHNW, Frankfurt, Germany) and the Government of Brunei Darussalam describes the set-up process of a specialized neurological center, including stroke unit, science and rehabilitation center. AIM: The aim of this project called to teach to treat - to treat to teach was to set up a center of excellence in neurology in Brunei Darussalam over a distance of 12,000 km. Treatment options were elucidated by teaching and taught by case examples. MATERIAL AND METHODS: The construction of the Brunei Neuroscience Stroke and Rehabilitation Center (BNSRC) began in July 2010. To overcome the large distance between the department of neurology and neuroradiology at the KHNW and the BNSRC, a telemedical network was established. We provided daily teleteaching for all professions involved in patient care as well as 24/7 availability of teleneurological services from Germany to support the local team on site. RESULTS: In the BNSRC unit over 1000 patients with ischemic and hemorrhagic stroke and all the various acute neurological conditions were treated from July 2010 until July 2016 as inpatients and over 5000 were treated as outpatients. Since 2010, a total of 52 patients with stroke were treated by thrombolysis within the thrombolytic window and 81 hemicraniectomies were performed. CONCLUSION: The project has shown that it is possible to convey specialized neurological knowledge over large distances to provide significant benefits for patients and caregivers.

Sulfur isotope analysis of cinnabar from Roman wall paintings by elemental analysis/isotope ratio mass spectrometry--tracking the origin of archaeological red pigments and their authenticity.

The most valuable pigment of the Roman wall paintings was the red color obtained from powdered cinnabar (Minium Cinnabaris pigment), the red mercury sulfide (HgS), which was brought from mercury (Hg) deposits in the Roman Empire. To address the question of whether sulfur isotope signatures can serve as a rapid method to establish the provenance of the red pigment in Roman frescoes, we have measured the sulfur isotope composition (δ(34)S value in ‰ VCDT) in samples of wall painting from the Roman city Aventicum (Avenches, Vaud, Switzerland) and compared them with values from cinnabar from European mercury deposits (Almadén in Spain, Idria in Slovenia, Monte Amiata in Italy, Moschellandsberg in Germany, and Genepy in France). Our study shows that the δ(34)S values of cinnabar from the studied Roman wall paintings fall within or near to the composition of Almadén cinnabar; thus, the provenance of the raw material may be deduced. This approach may provide information on provenance and authenticity in archaeological, restoration and forensic studies of Roman and Greek frescoes.

Intravenous immunoglobulins in the therapy of paraneoplastic neurological disorders.

The treatment of paraneoplastic neurological syndromes (e.g., tumor therapy, immunosuppressive therapy, plasmapheresis) rarely leads to an improvement in the neurological symptoms. We treated four patients suffering from paraneoplastic neurological syndromes with intravenous immunoglobulins. All four had high titers of antineuronal antibodies in serum and CSF. Two of the patients, one suffering from paraneoplastic cerebellar degeneration and the other from paraneoplastic brain stem encephalitis and polyneuropathy, received intravenous immunoglobulin treatment within 3 weeks of the onset of neurological symptoms. Both patients showed clinical improvement within 2 weeks after the initiation of therapy. They also showed a decline in the intrathecal antibody synthesis of the antineuronal antibody. Two other patients, who had suffered from paraneoplastic neuropathy for 3 and 6 months showed no improvement with the intravenous immunoglobulin therapy. In these cases there was no effect on intrathecal antibody synthesis. When started early, intravenous immunoglobulins may be of therapeutical value in treating paraneoplastic neurological syndromes. Specific intrathecal antibody synthesis may be a better measure of clinical course that autoantibody serum titers.

Changes of cerebral perfusion after osmotherapy in acute cerebral edema assessed with perfusion weighted MRI.

Perfusion is thought to be impaired in brain edema due to reduced perfusion pressure. Brain edema therapy is assumed to improve perfusion. We assessed regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV) and mean transit time of blood (MTT) using perfusion-weighted magnetic resonance imaging (MRI) in 15 patients showing acute local brain edema due to infarction or intracerebral hematoma. Patients were treated by intravenous infusion of 125 ml 40% sorbitol over 10 min. rCBF, rCBV and MTT in the edematous region were measured before and 30 min after treatment. Before treatment rCBF (46.5 +/- 12.1 vs. 42.9 +/- 10.5 ml 100 g-1 min-1), MTT (4.7 +/- 1.9 vs. 4.0 +/- 1.7 s) and rCBV (5.4 +/- 1.7 vs. 4.7 +/- 1.1 ml 100 g-1) were significantly (p < 0.05) increased in the edematous region compared to the contralateral side. After treatment no significant differences could be found. We interpret the elevation of MTT and rCBV in the edema as signs of an autoregulative compensation of an impaired perfusion. rCBF is even over-compensated. After brain edema therapy perfusion seems normalised. This new MRI method appears as useful for measuring therapeutic effects on cerebral perfusion.

Femoral injection of echo contrast medium may increase the sensitivity of testing for a patent foramen ovale.

OBJECTIVE: The diagnosis of a patent foramen ovale (PFO) as a cause of stroke is of increasing interest especially in young (<45 years) patients. METHODS: We studied potential right-to-left shunting using transesophageal echocardiography (TEE) and bilateral transcranial Doppler sonography (TCD) of the middle cerebral artery (MCA) simultaneously in 44 patients. All patients were younger than age 45 years and suffered from an acute ischemic stroke or transient ischemic attack. Other possible etiologies were excluded. Echo contrast medium was injected in an alternating mode via antecubital or femoral veins. Tests were performed with and without the Valsalva maneuver. The criteria for a PFO were that the contrast pass from the right to the left atrium (TEE) and early detection (<10 seconds) of more than 10 micro air bubbles in at least one MCA by TCD. RESULTS: A PFO was diagnosed in 22 patients (50%). The detection rate with TEE/TCD was 11.4%/4.5% via antecubital injection, 18%/13.6% via antecubital injection plus the Valsalva maneuver, 38.6%/36% via femoral injection alone, and 50%/50% via femoral injection plus the Valsalva maneuver. The difference between femoral and antecubital injections was significant with and without the Valsalva maneuver (p < 0.01, chi2 test). There were no differences between TEE and TCD after femoral injection with the Valsalva maneuver. The brain transit time was 4.6 +/- 2.1 seconds for femoral injection and 6.3 +/- 4.1 seconds for antecubital injection. CONCLUSIONS: The sensitivity in detecting a PFO was markedly increased by femoral injection. This may be caused by different inflow patterns to the right atrium: inferior vena caval flow is directed to the right atrial septum, whereas superior vena caval flow is directed to the tricuspid valve. Thus, femoral injection may help to improve the detection of PFO and may explain the differences between TEE and TCD findings in previous studies.

[Diffusion-weighted magnetic resonance imaging in the diagnosis of cerebral infarct]. / Diffusionsgewichtete Kernspintomographie zum Nachweis zerebraler Infarkte.

Forty-one patients demonstrating clinical symptoms for cerebral infarction were investigated by magnetic resonance imaging with diffusion-weighted echo-planar imaging (DWI) and T2-weighted imaging (T2WI). In 8 patients only DWI showed the cerebral lesions clearly. One patient with positive DWI and T2WI suffered from HSV encephalitis. DWI is superior to T2WI in assessment of small cortical infarcts and cerebral infarction in patients with preexisting vascular lesions. DWI is not specific, so other causes like cerebral hematoma and encephalitis have to be considered.

Single dose, dose-escalating trial with fozivudine tidoxil (BM 21.1290).

BACKGROUND AND OBJECTIVES: In vitro and in vivo experimental data for fozivudine tidoxil [BM21.1290 (FZD) an ether-lipid conjugate of zidovudine] have shown better efficacy, no myelotoxicity and better tolerability compared with zidovudine. Therefore, the objectives of our study were to evaluate the safety of FZD in patients with human immunodeficiency virus (HIV) infection and to establish basic pharmacokinetic data. PATIENTS AND METHODS: In a Phase I dose-escalating trial, seven different single dose applications were studied in 39 patients: 50, 100, 300, 600, 900, 1200 and 1800 mg in capsule and tablet formulations. Inclusion criteria were HIV infection, CD4 count > 100 cells/mm3 and informed consent. Exclusion criteria were active opportunistic manifestations, concomitant zidovudine therapy and neutropenia (< 750 neutrophils/mm3). Safety parameters, 24 h plasma levels and urinary excretion were determined. RESULTS: The tolerance of FZD was excellent up to single doses of 1800 mg. In only one case, a single episode of loose stool was reproducible in a second treatment period and was therefore considered to be a probable drug-related event. In an amendment to the trial, a tablet formulation of FZD did not induce diarrhoea in this patient. FZD was available in measurable concentrations after 2 to 4 h. Maximum concentrations were reached after 4 to 8 h. After normalization for a dose of 100 mg/patient, the mean AUC was 8.6 mg x h/l and the mean Cmax was 1.13 mg/l; t1/2 was 3.78 h. Interestingly, plasma concentrations of zidovudine and zidovudine glucuronide were much lower than with equimolar zidovudine doses. CONCLUSIONS: The zidovudine conjugate FZD is safe and well tolerated at the seven doses tested. Phase II trials are warranted.

Time course of the acetazolamide effect in patients with extracranial carotid artery disease.

The acetazolamide test of cerebrovascular reserve is performed as a two-point transcranial Doppler (TCD) measurement of the flow velocity in the middle cerebral artery (MCA) before and 15 to 20 minutes after injection of the carbonic anhydrase inhibitor. The time course was evaluated by bilateral TCD monitoring over 45 minutes in 51 patients with extracranial carotid artery disease. Twenty-nine patients in Group 1 showed a unilateral and 22 patients in Group 2, a bilateral stenosis of the internal carotid artery (ICA). Thirty-one normal hemispheres in 18 normal subjects provided baseline control values. The most useful parameter for the description of the time course was the integral of the mean flow velocity. In both groups integral of the mean flow velocity was significantly reduced compared to that in normal persons (Group 1: 587.2 +/- 538.3 cm, p < 0.01; Group 2: 728.9 +/- 397.1 cm, p < 0.01; normal persons: 967.8 +/- 350.0 cm). The maximal increase of mean flow velocity in a two-point measurement also was significantly lower in the patient groups, but did not reach the same level of significance in Group 2 (Group 1: 19.6 +/- 12.3 cm/sec, p < 0.01; Group 2: 24.2 +/- 10.4 cm/sec, p < 0.05). Thirty-four of 73 hemispheres had reduced integral of the mean flow velocity, but only 29 had a reduced maximal increase. These data indicate that continuous monitoring and evaluation of the time course of the acetazolamide effect provide additional information on cerebrovascular reserve and help to detect an increased number of patients with impaired cerebrovascular reserve.

Comparative clinical efficacy and tolerability of oxerutins and horse chestnut extract in patients with chronic venous insufficiency.

Oxerutins (O-(beta-hydroxyethyl)rutosides, HR, Venoruton) and horse chestnut extract (HCE) are active principles of first priority for the pharmacological treatment of chronic venous insufficiency (CVI). The efficacies of both compounds were shown in numerous, double-blind, randomized, placebo controlled clinical trials. Besides the direct comparison of the two compounds the aim of the study was to investigate the initial dose/maintenance dose concept for HR. 137 female, postmenopausal patients with CVI II finished the study according to protocol. Following one week placebo run-in the patients were treated either with 1000 mg/d HR, 600 mg/d HCE or 1000 mg/d for 4 weeks and than with 500 mg/d HR within the initial dose/maintainance dose concept for 12 weeks and observed for further 6 weeks. A main confirmative criterion was the volume reduction of the leg. Subjective criteria were descriptively evaluated. HR (1000 mg/d) was proven to be equivalent or better, reducing the leg volume (AUB0-18) by -5273 +/- 11418 ml.d compared to -3187 +/- 10842 ml.d under HR (1000 mg/d and 500 mg/d), and -3004 +/- 7429 ml.d under HCE-treatment. Both compounds exhibit a substantial carry-over effect. The maintenance posology of HR is able to stabilize the therapeutic obtained under initial dose conditions.

Time course of acetazolamide effect in normal persons.

The intravenous injection of the carbonic anhydrase inhibitor acetazolamide causes a sustained increase of blood flow velocity in the middle cerebral artery. This effect is used in the acetazolamide test of the so-called cerebrovascular reserve capacity. The acetazolamide test is performed routinely as a two-point measurement of the blood flow velocity by transcranial Doppler before and 15 to 20 minutes after drug injection. Based on the assumption that evaluation of the time course will more sensitively detect an impaired cerebrovascular reserve capacity, suitable parameters for description of the time course were developed and normal values were established from 18 healthy persons (31 hemispheres). The mean value for the maximal increase of the mean flow velocity (MFV) was 29.7 +/- 8.3 cm/sec (as percentage of increase, 62.0 +/- 17.3%) and the time of the maximal increase was 15.35 +/- 8.46 seconds. Also calculated were the velocity of the MFV rise to the maximal value (3.0 +/- 3.2 cm/sec/min), the mean of the changes of the continuously measured MFV to the baseline value (21.0 +/- 7.4 cm/sec), and the integral of MFV represented by the plane under the MFV curve (967.8 +/- 350.0 cm). The best parameter for the description of the time dependency of the acetazolamide effect is the integral of MFV.

Pharmacokinetics and relative bioavailability after single dose administration of 25 mg ketoprofen solution as compared to tablets.

The relative bioavailability of ketoprofen from a liquid formulation as compared to a tablet formulation as reference after single oral dose administration was investigated in 16 healthy male subjects. The subjects received in a randomized, crossover design during one study period of 5 days 2.5 mg of ketoprofen as tablet or liquid formulation administered as single dose with a washout interval of 48 h. The plasma concentrations of S(+)- and R(-)-ketoprofen were determined before and up to 24 h post-administration. S(+)- and R(-)-ketoprofen in the collected plasma samples was determined using an internally standardized validated HPLC method. Regarding the geometric mean concentration-time courses there were no relevant differences between the two ketoprofen enantiomers for both formulations. Remarkable differences in the shape of concentration-time courses between the two formulations were found with higher Cmax (by about 70%) and earlier tmax (by 15 min) values for the ketoprofen solution. The treatments were widely equivalent with regard to AUC. The quotients of geometric means as well as 90% confidence intervals for AUC of R(-)-ketoprofen were 95.72% (92.55-99.00%) and for S(+)-ketoprofen 94.23% (89.91-98.76%). The administration of the ketoprofen solution resulted earlier in higher concentrations (by about 70%) for both enantiomers, whereas the extent of absorption expressed by AUC was nearly the same (about 95%) as compared to the equimolar tablet formulation. The differences between the two formulations for Cmax,norm and tmax were statistically significant.

[The value of various transcranial color doppler tests for determining cerebrovascular reserve capacity]. / Wertigkeit verschiedener TCD-Tests zur Ermittlung der zerebrovaskulären Reservekapazität.

One of the techniques for the assessment of the cerebrovascular reserve capacity is the so-called "breath-holding" test. In order to minimise haemodynamic changes following deep inspiration the patients should hold their breath at the end of a normal inspiration. We studied three different ways (breath holding following normal inspiration [NI], deep inspiration [DI], hyperventilation [HV]), of performing this test in 20 healthy volunteers. The acetazolamide test was taken as a reference. The mean flow velocity (FVmean) in the middle cerebral artery was recorded continuously using a TCD monitoring system. Blood pressure, cardiac output and heart rate were measured simultaneously. Breath holding after deep inspiration resulted in longer apnoea (DI: 68.1 +/- 24.1 s; NI: 44.8 +/- 18.4 s; p < 0.01), produced the highest increase of FVmean (DI: +72.2 +/- 29.8%; NI: +69.2 +/- 29.0%) and was the least inconvenient to the patients. Following HV apnoea was longest (93.0 +/- 33.5 s; p < 0.01), but resulted in the lowest increase of FVmean were not significant. A significantly lower increase of FVmean (44.2 +/- 13.4%, p < 0.01 resp.) could be observed after intravenous injection of 1 g acetazolamide. There were no significant haemodynamic changes in any case. Thus, this bedside test does not appear to be influenced by variations in breath holding.

Renal elimination of magnesium as a parameter of bioavailability of oral magnesium therapy.

Magnesium is an important cation in human physiology, especially in the regulation of membrane proteins, as a cofactor for various enzyme systems and in neuromuscular transmission. Magnesium deficiency leads to severe impairment in muscle function, particularly in cardiovascular diseases. Classical bioavailability studies with magnesium cannot be carried out for several reasons. As the magnesium concentration in plasma is extraordinarily well regulated, renal elimination proves to be the best method to determine the absorption of orally administered magnesium. Magnesium pools must first be filled, and the saturation phase of renal elimination then equals the degree of absorption. This parameter of bioavailability shows the percentage of eliminated magnesium in comparison to the administered dose. Eighteen healthy male volunteers were included in this study to compare 5 mg magnesium-DL-hydrogen aspartate with magnesium-L-hydrogen aspartate. After a saturation phase, the test substances were administered in random order. Blood samples for determination of magnesium concentrations were taken, but no typical pharmacokinetic concentration curves were obtained. The areas under the concentration-time curves were equal for both formulations (x = 40.22 [mval*h/l]). The bioavailability of both substances was determined from the renal elimination. No significant difference was found between both treatments. Bioavailability of 5 mg magnesium-DL-hydrogen aspartate was 44.5% and for magnesium-L-hydrogen aspartate 41.7%. It is evident that this method of magnesium determination is practical, comfortable for volunteers and gives reliable results in comparing the absorption of magnesium formulations.

Gastric potential difference measurement as a quantification of gastrointestinal tolerability comparing a buffered acetylsalicylic acid formulation versus plain acetylsalicylic acid.

Two different acetylsalicylic acid (ASA, CAS 50-78-2) formulations (Aspirin) were compared regarding their gastric mucosal tolerability. After administration of plain ASA, buffered ASA and ASA placebo the decrease of gastric potential difference (GPD) was measured. Evaluation of the GPD parameters showed a better tolerability of buffered ASA than of plain ASA. It was therefore concluded that buffered ASA effects less gastric mucosal irritation than plain ASA.

[A personal computer-based system for online monitoring of neurologic intensive care patients]. / Ein PC-gestütztes System zum Online-Monitoring von neurologischen Intensivpatienten.

In the management of neurological intensive care patients with an intracranial space-consuming process the measurement and recording of intracranial pressure together with arterial blood pressure is of special interest. These parameters can be used to monitor the treatment of brain edema and hypertension. Intracranial pressure measurement is also important in the diagnosis of the various subtypes of hydrocephalus. Not only the absolute figures, but also the recognition of specific pressure-patterns is of particular clinical and scientific interest. This new, easily installed and inexpensive system comprises a PC and a conventional monitor, which are connected by an AD-conversion card. Our software, specially developed for this system demonstrates, stores and prints the online-course and the trend of the measurements. In addition it is also possible to view the online-course of conspicuous parts of the trend curve retrospectively and to use these values for statistical analyses. Object-orientated software development techniques were used for flexible graphic output on the screen, printer or to a file. Though developed for this specific purpose, this system is also suitable for recording continuous, longer-term measurements in general.