N-acetylcysteine reduces oxidative stress in sickle cell patients

Oxidative stress is of importance in the pathophysiology of sickle cell disease (SCD). In this open label randomized pilot study the effects of oral N-acetylcysteine (NAC) on phosphatidylserine (PS) expression as marker of cellular oxidative damage (primary end point), and markers of hemolysis, coagulation and endothelial activation and NAC tolerability (secondary end points) were studied. Eleven consecutive patients (ten homozygous [HbSS] sickle cell patients, one HbSβ0-thalassemia patient) were randomly assigned to treatment with either 1,200 or 2,400 mg NAC daily during 6 weeks. The data indicate an increment in whole blood glutathione levels and a decrease in erythrocyte outer membrane phosphatidylserine exposure, plasma levels of advanced glycation end-products (AGEs) and cell-free hemoglobin after 6 weeks of NAC treatment in both dose groups. One patient did not tolerate the 2,400 mg dose and continued with the 1,200 mg dose. During the study period, none of the patients experienced painful crises or other significant SCD or NAC related complications. These data indicate that N-acetylcysteine treatment of sickle cell patients may reduce SCD related oxidative stress

Functional Analysis of the Cytoskeleton Protein MreB from Chlamydophila pneumoniae

In rod-shaped bacteria, the bacterial actin ortholog MreB is considered to organize the incorporation of cell wall precursors into the side-wall, whereas the tubulin homologue FtsZ is known to tether incorporation of cell wall building blocks at the developing septum. For intracellular bacteria, there is no need to compensate osmotic pressure by means of a cell wall, and peptidoglycan has not been reliably detected in Chlamydiaceae. Surprisingly, a nearly complete pathway for the biosynthesis of the cell wall building block lipid II has been found in the genomes of Chlamydiaceae. In a previous study, we discussed the hypothesis that conservation of lipid II biosynthesis in cell wall-lacking bacteria may reflect the intimate molecular linkage of cell wall biosynthesis and cell division and thus an essential role of the precursor in cell division. Here, we investigate why spherical-shaped chlamydiae harbor MreB which is almost exclusively found in elongated bacteria (i.e. rods, vibrios, spirilla) whereas they lack the otherwise essential division protein FtsZ. We demonstrate that chlamydial MreB polymerizes in vitro and that polymerization is not inhibited by the blocking agent A22. As observed for MreB from Bacillus subtilis, chlamydial MreB does not require ATP for polymerization but is capable of ATP hydrolysis in phosphate release assays. Co-pelleting and bacterial two-hybrid experiments indicate that MreB from Chlamydophila (Chlamydia) pneumoniae interacts with MurF, MraY and MurG, three key components in lipid II biosynthesis. In addition, MreB polymerization is improved in the presence of MurF. Our findings suggest that MreB is involved in tethering biosynthesis of lipid II and as such may be necessary for maintaining a functional divisome machinery in Chlamydiaceae

Altimetry for the future: Building on 25 years of progress

In 2018 we celebrated 25 years of development of radar altimetry, and the progress achieved by this methodology in the fields of global and coastal oceanography, hydrology, geodesy and cryospheric sciences. Many symbolic major events have celebrated these developments, e.g., in Venice, Italy, the 15th (2006) and 20th (2012) years of progress and more recently, in 2018, in Ponta Delgada, Portugal, 25 Years of Progress in Radar Altimetry. On this latter occasion it was decided to collect contributions of scientists, engineers and managers involved in the worldwide altimetry community to depict the state of altimetry and propose recommendations for the altimetry of the future. This paper summarizes contributions and recommendations that were collected and provides guidance for future mission design, research activities, and sustainable operational radar altimetry data exploitation. Recommendations provided are fundamental for optimizing further scientific and operational advances of oceanographic observations by altimetry, including requirements for spatial and temporal resolution of altimetric measurements, their accuracy and continuity. There are also new challenges and new openings mentioned in the paper that are particularly crucial for observations at higher latitudes, for coastal oceanography, for cryospheric studies and for hydrology. The paper starts with a general introduction followed by a section on Earth System Science including Ocean Dynamics, Sea Level, the Coastal Ocean, Hydrology, the Cryosphere and Polar Oceans and the ‘‘Green” Ocean, extending the frontier from biogeochemistry to marine ecology. Applications are described in a subsequent section, which covers Operational Oceanography, Weather, Hurricane Wave and Wind Forecasting, Climate projection. Instruments’ development and satellite missions’ evolutions are described in a fourth section. A fifth section covers the key observations that altimeters provide and their potential complements, from other Earth observation measurements to in situ data. Section 6 identifies the data and methods and provides some accuracy and resolution requirements for the wet tropospheric correction, the orbit and other geodetic requirements, the Mean Sea Surface, Geoid and Mean Dynamic Topography, Calibration and Validation, data accuracy, data access and handling (including the DUACS system). Section 7 brings a transversal view on scales, integration, artificial intelligence, and capacity building (education and training). Section 8 reviews the programmatic issues followed by a conclusion

Altimetry for the future: building on 25 years of progress

In 2018 we celebrated 25 years of development of radar altimetry, and the progress achieved by this methodology in the fields of global and coastal oceanography, hydrology, geodesy and cryospheric sciences. Many symbolic major events have celebrated these developments, e.g., in Venice, Italy, the 15th (2006) and 20th (2012) years of progress and more recently, in 2018, in Ponta Delgada, Portugal, 25 Years of Progress in Radar Altimetry. On this latter occasion it was decided to collect contributions of scientists, engineers and managers involved in the worldwide altimetry community to depict the state of altimetry and propose recommendations for the altimetry of the future. This paper summarizes contributions and recommendations that were collected and provides guidance for future mission design, research activities, and sustainable operational radar altimetry data exploitation. Recommendations provided are fundamental for optimizing further scientific and operational advances of oceanographic observations by altimetry, including requirements for spatial and temporal resolution of altimetric measurements, their accuracy and continuity. There are also new challenges and new openings mentioned in the paper that are particularly crucial for observations at higher latitudes, for coastal oceanography, for cryospheric studies and for hydrology. The paper starts with a general introduction followed by a section on Earth System Science including Ocean Dynamics, Sea Level, the Coastal Ocean, Hydrology, the Cryosphere and Polar Oceans and the “Green” Ocean, extending the frontier from biogeochemistry to marine ecology. Applications are described in a subsequent section, which covers Operational Oceanography, Weather, Hurricane Wave and Wind Forecasting, Climate projection. Instruments’ development and satellite missions’ evolutions are described in a fourth section. A fifth section covers the key observations that altimeters provide and their potential complements, from other Earth observation measurements to in situ data. Section 6 identifies the data and methods and provides some accuracy and resolution requirements for the wet tropospheric correction, the orbit and other geodetic requirements, the Mean Sea Surface, Geoid and Mean Dynamic Topography, Calibration and Validation, data accuracy, data access and handling (including the DUACS system). Section 7 brings a transversal view on scales, integration, artificial intelligence, and capacity building (education and training). Section 8 reviews the programmatic issues followed by a conclusion

Bayesian pharmacokinetics of lithium after an acute self-intoxication and subsequent haemodialysis: a case report

We report a case of a 39-year-old male with bipolar affective disorder who was admitted to hospital with an intentional acute lithium intoxication resulting in renal insufficiency. The patient had previously been treated with lithium, risperidone, fluoxetine and lorazepam, and successfully titrated to lithium levels of 0.7 mmol/l. After overdosing, the lithium level was 5.89 mmol/l and haemodialysis was initiated. A full pharmacokinetic time profile of lithium was obtained. After successful haemodialysis treatment, lithium levels recovered below toxic levels of 1.5 mmol/l in 53 hr. Without intervention non-toxic levels were not expected to have been reached within 6 days, based on computer simulation of predialysis levels. The patient was discharged 6 days after admission without residual symptoms. It was concluded that the lithium intoxication resulted from a combination of lithium overdose and subsequent renal insufficiency due to the overdose. A possible fluoxetine-risperidone interaction was not considered clinically apparen

Symptomatic venous thromboembolism in cancer patients treated with chemotherapy - An underestimated phenomenon

Background: The exact incidence of venous thromboembolism (VTE) in cancer patients is unknown, partly because of confounding factors. Prophylactic treatment is warranted in surgical patients with cancer because of a high incidence of VTE. We performed a retrospective study to evaluate if the same applies for cancer patients treated with chemotherapy. Methods: The medical records of 206 consecutive patients with malignancy, treated with chemotherapy, were identified. The kind of malignancy and chemotherapeutic treatment were recorded, as was the date of treatment. The records were reviewed for other risk factors for VTE, and were searched for proved deep venous thrombosis or pulmonary embolism. Results: Of those 206 patients, 15 (7.3%) had proved VTE during or within 3 months after chemotherapeutic treatment. The annual incidence was 10.9%. The incidence of VTE was specifically high in the 39 patients treated with a combination of fluorouracil and leucovorin calcium because of colorectal cancer (6 [15%] of the patients were affected). The occurrence of VTE in the latter group of patients was not influenced by factors such as surgery, central venous catheters, or tumor load. Conclusions: The annual incidence of VTE in patients treated with chemotherapy was high, specifically in patients with colorectal cancer treated with fluorouracil-leucovorin. If these observations are confirmed, trials to evaluate the use of prophylactic anticoagulant treatment should be conducte

Neutropenia and docetaxel exposure in metastatic castration-resistant prostate cancer patients : A meta-analysis and evaluation of a clinical cohort

The incidence of neutropenia in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel has been reported to be lower compared to patients with other solid tumors treated with a similar dose. It is suggested that this is due to increased clearance of docetaxel in mCRPC patients, resulting in decreased exposure. The aims of this study were to (1) determine if exposure in mCRPC patients is lower vs patients with other solid tumors by conducting a meta-analysis, (2) evaluate the incidence of neutropenia in patients with mCRPC vs other solid tumors in a clinical cohort, and (3) discuss potential clinical consequences. A meta-analysis was conducted of studies which reported areas under the plasma concentration-time curves (AUCs) of docetaxel and variability. In addition, grade 3/4 neutropenia was evaluated using logistic regression in a cohort of patients treated with docetaxel. The meta-analysis included 36 cohorts from 26 trials (n = 1150 patients), and showed that patients with mCRPC had a significantly lower mean AUC vs patients with other solid tumors (fold change [95% confidence interval (CI)]: 1.8 [1.5-2.2]), with corresponding AUCs of 1.82 and 3.30 mg∙h/L, respectively. Logistic regression, including 812 patient, demonstrated that patients with mCRPC had a 2.2-fold lower odds of developing grade 3/4 neutropenia compared to patients with other solid tumors (odds ratio [95%CI]: 0.46 [0.31-0.90]). These findings indicate that mCRPC patients have a lower risk of experiencing severe neutropenia, possibly attributable to lower systemic exposure to docetaxel

Neutropenia and docetaxel exposure in metastatic castration-resistant prostate cancer patients : A meta-analysis and evaluation of a clinical cohort

The incidence of neutropenia in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel has been reported to be lower compared to patients with other solid tumors treated with a similar dose. It is suggested that this is due to increased clearance of docetaxel in mCRPC patients, resulting in decreased exposure. The aims of this study were to (1) determine if exposure in mCRPC patients is lower vs patients with other solid tumors by conducting a meta-analysis, (2) evaluate the incidence of neutropenia in patients with mCRPC vs other solid tumors in a clinical cohort, and (3) discuss potential clinical consequences. A meta-analysis was conducted of studies which reported areas under the plasma concentration-time curves (AUCs) of docetaxel and variability. In addition, grade 3/4 neutropenia was evaluated using logistic regression in a cohort of patients treated with docetaxel. The meta-analysis included 36 cohorts from 26 trials (n = 1150 patients), and showed that patients with mCRPC had a significantly lower mean AUC vs patients with other solid tumors (fold change [95% confidence interval (CI)]: 1.8 [1.5-2.2]), with corresponding AUCs of 1.82 and 3.30 mg∙h/L, respectively. Logistic regression, including 812 patient, demonstrated that patients with mCRPC had a 2.2-fold lower odds of developing grade 3/4 neutropenia compared to patients with other solid tumors (odds ratio [95%CI]: 0.46 [0.31-0.90]). These findings indicate that mCRPC patients have a lower risk of experiencing severe neutropenia, possibly attributable to lower systemic exposure to docetaxel

Neutropenia and docetaxel exposure in metastatic castration-resistant prostate cancer patients : A meta-analysis and evaluation of a clinical cohort

The incidence of neutropenia in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel has been reported to be lower compared to patients with other solid tumors treated with a similar dose. It is suggested that this is due to increased clearance of docetaxel in mCRPC patients, resulting in decreased exposure. The aims of this study were to (1) determine if exposure in mCRPC patients is lower vs patients with other solid tumors by conducting a meta-analysis, (2) evaluate the incidence of neutropenia in patients with mCRPC vs other solid tumors in a clinical cohort, and (3) discuss potential clinical consequences. A meta-analysis was conducted of studies which reported areas under the plasma concentration-time curves (AUCs) of docetaxel and variability. In addition, grade 3/4 neutropenia was evaluated using logistic regression in a cohort of patients treated with docetaxel. The meta-analysis included 36 cohorts from 26 trials (n = 1150 patients), and showed that patients with mCRPC had a significantly lower mean AUC vs patients with other solid tumors (fold change [95% confidence interval (CI)]: 1.8 [1.5-2.2]), with corresponding AUCs of 1.82 and 3.30 mg∙h/L, respectively. Logistic regression, including 812 patient, demonstrated that patients with mCRPC had a 2.2-fold lower odds of developing grade 3/4 neutropenia compared to patients with other solid tumors (odds ratio [95%CI]: 0.46 [0.31-0.90]). These findings indicate that mCRPC patients have a lower risk of experiencing severe neutropenia, possibly attributable to lower systemic exposure to docetaxel