A multicentennial mode of North Atlantic climate variability throughout the Last Glacial Maximum.

Paleoclimate proxy records from the North Atlantic region reveal substantially greater multicentennial temperature variability during the Last Glacial Maximum (LGM) compared to the current interglacial. As there was no obvious change in external forcing, causes for the increased variability remain unknown. Exploiting LGM simulations with a comprehensive coupled climate model along with high-resolution proxy records, we introduce an oscillatory mode of multicentennial variability, which is associated with moderate variations in the Atlantic meridional overturning circulation and depends on the large-scale salinity distribution. This self-sustained mode is amplified by sea-ice feedbacks and induces maximum surface temperature variability in the subpolar North Atlantic region. Characterized by a distinct climatic imprint and different dynamics, the multicentennial oscillation has to be distinguished from Dansgaard-Oeschger variability and emerges only under full LGM climate forcing. The potential of multicentennial modes of variability to emerge or disappear in response to changing climate forcing may have implications for future climate change.

[Fecal microbiota transplantation: indications, risks and opportunities]. / Fäkaler Mikrobiomtransfer ­ Indikationen, Risiken und Chancen.

Fecal microbiome transfer (FMT) involving the transfer of the microbiome of healthy stool donors to patients with various diseases has been performed in Germany in clinical studies and individual treatment attempts. There is no doubt that FMT is an effective therapeutic principle for recurrent Clostridium difficile infection and ulcerative colitis. From a medico-legal point of view, it should be stressed that, in Germany, the microbiome to be transferred is regarded as a drug, the manufacture of which is subject to the Medicines Act and the risk information from the Federal Institute for Drugs and Medical Devices. The background of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and the potential risk of transmitting pathogens must also be considered. There is an obligation to notify the competent state authorities to perform FMTs in the context of individual treatment attempts. In the context of the limited availability and the fundamental problem of infection, future studies aim to identify the therapeutically active components in the microbiome. Recombinant production is the aim. Initial results represent preliminary steps, as these concepts are not yet established in clinical practice.

Transfer of FRozen Encapsulated multi-donor Stool filtrate for active ulcerative Colitis (FRESCO): study protocol for a prospective, multicenter, double-blind, randomized, controlled trial.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with significant morbidity and mortality. Although the precise cause remains unknown, disturbances in the intestinal microbial community have been linked to its pathogenesis. Randomized controlled trials in UC and relapsing Clostridioides difficile infection (CDI) have established fecal microbiota (FM) transfer (FMT) as an effective therapy. In this context, preliminary results indicated that the transfer of sterile fecal microbiota filtrates (<0.2 µm; FMF, FMFT) of donor stool also drives gastrointestinal microbiota changes and eliminates symptoms in CDI patients. However, along with the success of FMT, regulatory agencies issued safety alerts following reports of serious adverse events due to transmission of enteric pathogens through FMT. To reduce this risk, we established an extensive test protocol for our donors and quarantine regulations for the produced capsules, but alternative concepts are desirable. METHODS: Our project is a randomized, controlled, longitudinal, prospective, three-arm, multicenter, double-blind study to determine the safety and efficacy of repeated long-term, multi-donor FM or FMF transfers compared to placebo using oral, frozen capsules in 174 randomized patients with mild to moderate active UC. The primary outcome will be clinical remission at week 12. DISCUSSION: This proposal aims to examine (a) the efficacy of encapsulated transfer of FM and FMF as a therapy for mild to moderate UC, (b) the short- and long-term safety of FMT and FMFT in patients with UC, and (c) the microbial and immunologic changes that occur after FMT and FMFT to help understand how and why it affects inflammatory bowel disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT03843385 . DRKS (Deutsches Register für Klinische Studien) DRKS00020471.

North Atlantic forcing of tropical Indian Ocean climate.

The response of the tropical climate in the Indian Ocean realm to abrupt climate change events in the North Atlantic Ocean is contentious. Repositioning of the intertropical convergence zone is thought to have been responsible for changes in tropical hydroclimate during North Atlantic cold spells, but the dearth of high-resolution records outside the monsoon realm in the Indian Ocean precludes a full understanding of this remote relationship and its underlying mechanisms. Here we show that slowdowns of the Atlantic meridional overturning circulation during Heinrich stadials and the Younger Dryas stadial affected the tropical Indian Ocean hydroclimate through changes to the Hadley circulation including a southward shift in the rising branch (the intertropical convergence zone) and an overall weakening over the southern Indian Ocean. Our results are based on new, high-resolution sea surface temperature and seawater oxygen isotope records of well-dated sedimentary archives from the tropical eastern Indian Ocean for the past 45,000 years, combined with climate model simulations of Atlantic circulation slowdown under Marine Isotope Stages 2 and 3 boundary conditions. Similar conditions in the east and west of the basin rule out a zonal dipole structure as the dominant forcing of the tropical Indian Ocean hydroclimate of millennial-scale events. Results from our simulations and proxy data suggest dry conditions in the northern Indian Ocean realm and wet and warm conditions in the southern realm during North Atlantic cold spells.

Pronounced interannual variability in tropical South Pacific temperatures during Heinrich Stadial 1.

The early last glacial termination was characterized by intense North Atlantic cooling and weak overturning circulation. This interval between ~18,000 and 14,600 years ago, known as Heinrich Stadial 1, was accompanied by a disruption of global climate and has been suggested as a key factor for the termination. However, the response of interannual climate variability in the tropical Pacific (El Niño-Southern Oscillation) to Heinrich Stadial 1 is poorly understood. Here we use Sr/Ca in a fossil Tahiti coral to reconstruct tropical South Pacific sea surface temperature around 15,000 years ago at monthly resolution. Unlike today, interannual South Pacific sea surface temperature variability at typical El Niño-Southern Oscillation periods was pronounced at Tahiti. Our results indicate that the El Niño-Southern Oscillation was active during Heinrich Stadial 1, consistent with climate model simulations of enhanced El Niño-Southern Oscillation variability at that time. Furthermore, a greater El Niño-Southern Oscillation influence in the South Pacific during Heinrich Stadial 1 is suggested, resulting from a southward expansion or shift of El Niño-Southern Oscillation sea surface temperature anomalies.

Magnetic Active Agent Release System (MAARS): evaluation of a new way for a reproducible, externally controlled drug release into the small intestine.

Human absorption studies are used to test new drug candidates for their bioavailability in different regions of the gastrointestinal tract. In order to replace invasive techniques (e.g. oral or rectal intubation) a variety of externally controlled capsule-based drug release systems has been developed. Most of these use ionizing radiation, internal batteries, heating elements or even chemicals for the localization and disintegration process of the capsule. This embodies potential harms for volunteers and patients. We report about a novel technique called "Magnetic Active Agent Release System" (MAARS), which uses purely magnetic effects for this purpose. In our trial thirteen healthy volunteers underwent a complete monitoring and release procedure of 250 mg acetylsalicylic acid (ASA) targeting the flexura duodenojejunalis and the mid-part of the jejunum. During all experiments MAARS initiated a sufficient drug release and was well tolerated. Beside this we also could show that the absorption of ASA is about two times faster in the more proximal region of the flexura duodenojejunalis with a tmax of 47±13 min compared to the more distal jejunum with tmax values of 100±10 min (p=0.031).

Population pharmacokinetics of the BEACOPP polychemotherapy regimen in Hodgkin's lymphoma and its effect on myelotoxicity.

BACKGROUND AND OBJECTIVE: The BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) chemotherapy regimen for the treatment of advanced Hodgkin's lymphoma has a superior outcome, but its toxicity (mainly haematotoxicity) is pronounced and highly variable. The present study was conducted to address the role of pharmacokinetics in individual toxicity. STUDY DESIGN: Three plasma samples and a 24-hour urine collection for day 1 of the first three cycles of chemotherapy were analysed in 30 patients, and the pharmacokinetic parameters of the respective drugs were estimated by population pharmacokinetic methods (nonlinear mixed-effects model [NONMEM] software). Demographic data, doses and durations of infusion were also recorded. The effect of these parameters on platelet counts was estimated by analysis of covariance using a general linear model. RESULTS: The pharmacokinetic parameters and respective covariates were similar to the published data. The body surface area, peak concentrations of etoposide, urinary recovery of dechloroethylcyclophosphamide (formed by cytochrome P450 [CYP] 3A4) relative to the cyclophosphamide dose and number of cycles had a significant effect on toxicity. These factors explained 37% of the interindividual variability in the change in platelet counts from day 1 to day 8 of each cycle. CONCLUSION: The results show that the individual pharmacokinetics of BEACOPP drugs are an important link between dosage and toxicity. Accordingly, individualisation of treatment based on pharmacokinetics may result in more uniform toxicity. Individualisation may also allow escalation of the mean dose, which is probably related to better efficacy. As a consequence of the present study, infusion rates should be standardised, and the potential of a dose reduction in the first cycle and of CYP3A4 phenotyping should be addressed in clinical studies.

Influence of parameters on root surface roughness following treatment with a magnetostrictive ultrasonic scaler: an in vitro study.

BACKGROUND: This in vitro study aimed to evaluate the influence of different parameters, i.e., lateral force, instrument power setting, and the shape of the working tip, on the roughness of root surfaces following treatment with a magnetostrictive ultrasonic scaling device. METHODS: The study sample comprised a total of 102 extracted human molars, premolars, canines, and incisors. The samples were randomly divided into 10 equal units of 10 each for treatment with the ultrasonic device at a lateral force of 0.5 N and 2.0 N, a low and high instrument power setting, and with a straight and angulated shaped working tip. Twenty samples were treated manually using curets at a lateral force of 0.5 N and 2.0 N. Two samples were left untreated as controls. The mean (Ra) and maximum (Rmax) surface roughness of each sample was recorded. The statistical analysis was performed using analysis of variance (three-way ANOVA) at a level of significance of 5% (P < 0.05). RESULTS: The mean surface roughness (+/-SD) using different parameters ranged from 0.6 +/- 0.1 microm to 1.8 +/- 0.3 microm. The maximum surface roughness (+/-SD) was between 4.8 +/- 1.3 microm and 17.2 +/- 4.3 microm. The mean surface roughness (+/-SD) for samples treated with curets at a lateral force of 0.5 N was 0.5 +/- 0.0 microm and 0.4 +/- 0.1 microm at 2.0 N. The maximum surface roughness (+/-SD) was 3.7 +/- 0.8 microm at 0.5 N and 3.9 +/- 1.4 microm at 2.0 N. CONCLUSIONS: The findings of the present study indicate that the shape of the working tip and the lateral force significantly influence the mean and maximum surface roughness of root surfaces treated with a magnetostrictive ultrasonic scaling device. At any specific parameter, the surface roughness was significantly higher for the ultrasonic scaling device as compared to the hand curet.

Can xipamide or tacrolimus inhibit the glucuronidation of mycophenolic acid in rat liver slices?

The objective of this study was to investigate the effect of tacrolimus (Tac) and xipamide (X) on mycophenolic acid (MPA) glucuronidation in precision-cut rat liver slices. To assess a possible effect of these two drugs, the influence of the anti-inflammatory drug niflumic acid (NA)--a well-known inhibitor for MPA glucuronidation in human liver microsomes--was used as a standard. MPA and its main metabolite mycophenolic acid glucuronide (MPAG) were determined by means of high-performance liquid chromatography. MPA glucuronidation rate showed a significant linear correlation (p = 0.012) with MPA concentrations from 15.61 up to 124.88 microM in the medium. That means, the enzyme(s) responsible for the glucuronidation of MPA worked far below Km-value. With all MPA concentrations tested, neither the addition of Tac (31.30 nM) nor of X (28.25 nM) influenced the glucuronidation of MPA. In comparison, NA at a concentration of 70.92 nM showed a marked inhibitory effect (by 72%). The present pilot-study indicates that precision-cut rat liver slices are a suitable in vitro model to characterize the glucuronidation of MPA to its primary metabolite MPAG and interferences with other substances.

Pharmacokinetics of oxaliplatin during chronomodulated infusion in metastatic gastrointestinal cancer patients: a pilot investigation with preliminary results.

Several clinical trials have demonstrated that the three-drug combination of oxaliplatin, 5-fluorouracil (5-FU) and leucovorin (LV) administered chronomodulated improved antitumour efficacy in the treatment of metastatic colorectal cancer and was better tolerated than constant-rate infusion. However, only a few pharmacokinetic data of 5-FU during chronomodulated infusion are available but up to now not for oxaliplatin. In this pilot study, the platinum levels of plasma ultrafiltrate (PUF) and total plasma were monitored during chronomodulated infusion of oxaliplatin, 5-FU and LV in 7 patients with metastatic gastrointestinal cancer. A cycle of the 4-day chemotherapeutic regimen consisted of 12-h infusions with sinusoidal drug delivery rate of: oxaliplatin (25 mg/m2/d, peak at 16:00 hours), 5-FU and LV (750 mg/m2/d and 150 mg/m2/d, respectively, peak at 4:00 hours), the same scheme was reinitiated on day 15. Blood samples were collected on day 1 and day 4 during different cycles. Concentration-time profiles of ultrafilterable and total platinum in plasma during chronomodulated infusion were characterised. As expected, we found residual platinum levels in total plasma but not in PUF prior next cycle. Comparing day 1 with day 4, Cmax of platinum in PUF was significantly increased (84 +/- 13 ng/ml vs. 131 +/- 22 ng/ml, P = 0.012) as well as AUC0-24h of platinum in PUF (0.97 +/- 0.29 microg x h/ml vs. 1.90 +/- 0.44 microg x h/ml, P = 0.018). The same effect was observed for total plasma platinum suggesting an accumulation within the cycle. The observed interindividual variability of Cmax, tmax, AUC0-24h, t1/2 was moderate. Because of the small sample size in this pilot investigation, the findings need to be confirmed in larger pharmacokinetic studies. In a next step individual pharmacokinetic parameters should be associated with patient specific parameters and treatment-induced toxicity.