Excretion of paracetamol in human breast milk Bitzén, P O; Gustafsson, B; Jostell, K G ...
European journal of clinical pharmacology,
01/1981, Letnik:
20, Številka:
2
Journal Article
Recenzirano
Breast milk and plasma levels of paracetamol were monitored in 3 lactating women after ingestion of a single 500 mg dose of paracetamol. The paracetamol concentrations were consistently lower in ...milk, with a mean milk/plasma AUC ratio of 0.76. This value was in close agreement with the milk/plasma partition ratio of 0.81 found in vitro, and could be related to quantitative binding differences between the two fluids. The half-lives of paracetamol in plasma and breast milk were almost identical, with an overall mean of 2.7 h. As less than 0.1% of the maternal dose would be present in 100 ml milk, breast feeding need not be discontinued due to paracetamol treatment in conventional dosage.
The dynamics of the lower cell of the meridional overturning circulation (MOC) in the Southern Ocean are compared in two versions of a global climate model: one with high-resolution (0.1°) ocean and ...sea ice and the other a lower-resolution (1.0°) counterpart. In the high-resolution version, the lower cell circulation is stronger and extends farther northward into the abyssal ocean. Using the water-mass-transformation framework, it is shown that the differences in the lower cell circulation between resolutions are explained by greater rates of surface water-mass transformation within the higher-resolution Antarctic sea ice pack and by differences in diapycnal-mixing-induced transformation in the abyssal ocean.
While both surface and interior transformation processes work in tandemto sustain the lower cell in the control climate, the circulation is far more sensitive to changes in surface transformation in response to atmospheric warming from raising carbon dioxide levels. The substantial reduction in overturning is primarily attributed to reduced surface heat loss. At high resolution, the circulation slows more dramatically, with an anomaly that reaches deeper into the abyssal ocean and alters the distribution of Southern Ocean warming. The resolution dependence of associated heat uptake is particularly pronounced in the abyssal ocean (below 4000m), where the higher-resolution version of the model warms 4.5 times more than its lower-resolution counterpart.
Of 23 patients with non-insulin-dependent diabetes mellitus (NIDDM), whose fasting blood glucose had not reached less than or equal to 6.0 mmol.l-1 after 10 weeks of dietary regulation, 15, who had ...had a weight reduction of -2.8 kg by dietary control, did achieve a fasting blood glucose less than or equal to 6.0 mmol.l-1 after addition of less than or equal to 20 mg glipizide daily. They had a sustained (greater than or equal to 2 years) increase in meal-induced insulin secretion (32% increase in postprandial C-peptide AUC), and a sustained reduction in postprandial hyperglycaemia (34% reduction in AUC). Ten of the patients took a mean daily dose less than 5 mg (4.8 mg) and had a sustained increase in insulin secretion rate (increased C-peptide slope). The 15 patients had no elevation of basal insulin secretion and no impairment of weight reduction. The remaining 8 subjects, who showed little or no weight reduction on dietary control, had little or no reduction in fasting blood glucose despite long-term treatment with 20 mg glipizide daily, a less sustained increase in meal-induced insulin secretion, a smaller reduction of postprandial hyperglycaemia, and an increase in body weight. On diagnosis the 8 subjects did not differ from the other 15 subjects in age, body weight, blood glucose, HbA1c, C-peptide or insulin, nor in their glucose and insulin responses to a test dose of glipizide; the main reason for the apparent drug failure appeared to be deficient compliance with dietary regulation rather than a primary inability to respond to sulphonylurea treatment.
Simulations performed with general circulation models and a model of intermediate complexity show that the variability of the September sea ice extent in the Arctic of the 21st century increases ...first when the mean extent decreases from present‐day values. A maximum of the variance is found when the mean September ice extent is around 3 million km2. For lower extents, the variance declines with the mean extent. The behavior is clearly different in Antarctica where the variance always decreases as the mean ice extent decreases, following roughly a square‐root law compatible with very simple geometric arguments. Several mechanisms are responsible for the non‐linear behavior of the Arctic. However, the strong interhemispheric contrast suggests that the difference in geometrical setting, with an open ocean in the south and a semi‐closed basin in the north, plays a significant role.
An early defect in subjects with non-insulin-dependent diabetes mellitus (NIDDM) and the preceding phase of impaired glucose tolerance (IGT) is a reduction in early insulin release and hence a ...prolonged elevation of postprandial blood glucose. We therefore assessed whether a rapidly acting sulphonylurea (glipizide 5 mg 0.5 h before a test meal) could correct these disturbances in 38 IGT/NIDDM subjects, whose early insulin release and postprandial blood glucose elevations remained unimproved after 10 weeks of dietary regulation. We also assessed whether the efficacy of glipizide was dependent upon the ambient blood glucose concentration, and if early systemic availability of the drug was important for the blood glucose lowering effect. A single dose of glipizide normalized early insulin release and hence reduced the postprandial blood glucose increase that was not lowered by dietary regulation. The efficacy of glipizide was dependent upon the early systemic availability of the drug, but early systemic availability and efficacy were independent of the extent of blood glucose elevation, at least within a range of 6-12 mmol.l-1 of fasting blood glucose.
Purpose
This work faces three challenges of sodium (
23
Na) torso MRI on the way to quantitative
23
Na MRI: Development of a
23
Na radiofrequency transmit and receive coil covering a large part of ...the human body in width and length for
23
Na MRI at 7 T; reduction of blurring due to respiration in free‐breathing
23
Na MRI using a self‐gating approach; and reduction of image noise using a compressed‐sensing reconstruction.
Methods
An oval‐shaped birdcage resonator with a large field of view of (400 mm)
3
and a homogeneous transmit and receive field distribution was designed, simulated, and implemented on a 7T MR system. In free‐breathing 3‐dimensional radial
23
Na MRI (acquisition time ≈ 30 minutes), retrospective respiratory self‐gating was applied, which sorts the acquired projections into two respiratory states based on the intrinsic respiration‐dependent signal changes. Furthermore, a 3‐dimensional dictionary‐learning compressed‐sensing reconstruction was applied.
Results
The developed body coil provided homogeneous radiofrequency excitation (flip angle error of 4.9% in central region of interest of 23 × 13 × 10 cm
3
) and homogeneous signal reception. The self‐gating approach allowed for separation of the full data set into two subsets associated with different respiratory states (inhaled and exhaled), and thereby reduced blurring due to respiration in the separated images. Image noise was markedly reduced by the compressed‐sensing algorithm.
Conclusion
The presented body coil enables full body width
23
Na MRI with long z‐axis coverage at 7 T for the first time. Additionally, the retrospective respiratory self‐gating performance is demonstrated for free‐breathing lung and abdominal
23
Na MRI in 3 subjects.
Purpose
This work faces three challenges of sodium (23Na) torso MRI on the way to quantitative 23Na MRI: Development of a 23Na radiofrequency transmit and receive coil covering a large part of the ...human body in width and length for 23Na MRI at 7 T; reduction of blurring due to respiration in free‐breathing 23Na MRI using a self‐gating approach; and reduction of image noise using a compressed‐sensing reconstruction.
Methods
An oval‐shaped birdcage resonator with a large field of view of (400 mm)3 and a homogeneous transmit and receive field distribution was designed, simulated, and implemented on a 7T MR system. In free‐breathing 3‐dimensional radial 23Na MRI (acquisition time ≈ 30 minutes), retrospective respiratory self‐gating was applied, which sorts the acquired projections into two respiratory states based on the intrinsic respiration‐dependent signal changes. Furthermore, a 3‐dimensional dictionary‐learning compressed‐sensing reconstruction was applied.
Results
The developed body coil provided homogeneous radiofrequency excitation (flip angle error of 4.9% in central region of interest of 23 × 13 × 10 cm3) and homogeneous signal reception. The self‐gating approach allowed for separation of the full data set into two subsets associated with different respiratory states (inhaled and exhaled), and thereby reduced blurring due to respiration in the separated images. Image noise was markedly reduced by the compressed‐sensing algorithm.
Conclusion
The presented body coil enables full body width 23Na MRI with long z‐axis coverage at 7 T for the first time. Additionally, the retrospective respiratory self‐gating performance is demonstrated for free‐breathing lung and abdominal 23Na MRI in 3 subjects.
•Response associates with higher T cell to AML ratio, whereas resistance is marked by insufficient clearing of diseased progenitor cells.•Distinct T-cell phenotypes of bone marrow and extramedullary ...AML are linked to differential efficacy of ipilimumab treatment.
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The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent after ipilimumab exposure, which altered CD4+ T-cell gene expression, in line with ongoing T-cell differentiation and increased frequency of marrow-infiltrating regulatory T cells. For post-HSCT samples, relapse could be attributed to insufficient clearing of malignant clones in progenitor cell populations. In contrast to AML/MDS bone marrow, the transcriptomes of leukemia cutis samples from patients with durable remission after ipilimumab monotherapy showed evidence of increased infiltration with antigen-experienced resident memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, activity of combined decitabine and ipilimumab is impacted by cellular expression states within the microenvironmental niche of leukemic cells. The inadequate elimination of leukemic progenitors mandates urgent development of novel approaches for targeting these cell populations to generate long-lasting responses. This trial was registered at www.clinicaltrials.gov as #NCT02890329.
Two articles in this week’s issue focus on the use of ipilimumab and decitabine for patients with myelodysplasia (MDS) and acute myeloid leukemia (AML) before and after hematopoietic stem cell transplantation (HSCT) for high-risk disease. In the first article, Garcia et al report on the results of a phase 1 trial of the combination in 54 patients, demonstrating overall response rate of 52% in patients who are HSCT-naïve and 20% in patients post-HSCT; responses are usually short-lived. In the second article, Penter and colleagues characterize gene expression responses to therapy and conclude that decitabine acts directly to clear leukemic cells while ipilimumab acts on infiltrating lymphocytes in marrow and extramedullary sites. Responses are determined by leukemic cell burden and by the frequency and phenotype of infiltrating lymphocytes. Increasing bone marrow regulatory T cells is identified as a potential contributor to checkpoint inhibitor escape.
Chilli peppers have been shown to enhance diet-induced thermogenesis (DIT) and reduce energy intake (EI) in some studies, but there are few data on other pungent spices. The primary aim of the ...present study was to test the acute effects of black pepper (pepper), ginger, horseradish and mustard in a meal on 4 h postprandial DIT. The secondary aim was to examine the effects on subjective appetite measures, ad libitum EI and energy balance. In a five-way placebo-controlled, single-blind, cross-over trial, twenty-two young (age 24·9 (SD 4·6) years), normal-weight (BMI 21·8 (SD 2·1) kg/m²) males were randomly assigned to receive a brunch meal with either pepper (1·3 g), ginger (20 g), horseradish (8·3 g), mustard (21 g) or no spices (placebo). The amounts of spices were chosen from pre-testing to make the meal spicy but palatable. No significant treatment effects were observed on DIT, but mustard produced DIT, which tended to be larger than that of placebo (14 %, 59 (SE 3) v. 52 (SE 2) kJ/h, respectively, P=0·08). No other spice induced thermogenic effects approaching statistical significance. Subjective measures of appetite (P>0·85), ad libitum EI (P=0·63) and energy balance (P=0·67) also did not differ between the treatments. Finally, horseradish decreased heart rate (P=0·048) and increased diastolic blood pressure (P= 0·049) compared with placebo. In conclusion, no reliable treatment effects on appetite, EI or energy balance were observed, although mustard tended to be thermogenic at this dose. Further studies should explore the possible strength and mechanisms of the potential thermogenic effect of mustard actives, and potential enhancement by, for example, combinations with other food components.
Objectives
To assess the image quality of T2-weighted (T2w) magnetic resonance imaging of the prostate and the visibility of prostate cancer at 7 Tesla (T).
Materials & methods
Seventeen prostate ...cancer patients underwent T2w imaging at 7T with only an external transmit/receive array coil. Three radiologists independently scored images for image quality, visibility of anatomical structures, and presence of artefacts. Krippendorff’s alpha and weighted kappa statistics were used to assess inter-observer agreement. Visibility of prostate cancer lesions was assessed by directly linking the T2w images to the confirmed location of prostate cancer on histopathology.
Results
T2w imaging at 7T was achievable with ‘satisfactory’ (3/5) to ‘good’ (4/5) quality. Visibility of anatomical structures was predominantly scored as ‘satisfactory’ (3/5) and ‘good’ (4/5). If artefacts were present, they were mostly motion artefacts and, to a lesser extent, aliasing artefacts and noise. Krippendorff’s analysis revealed an α = 0.44 between three readers for the overall image quality scores. Clinically significant cancer lesions in both peripheral zone and transition zone were visible at 7T.
Conclusion
T2w imaging with satisfactory to good quality can be routinely acquired, and cancer lesions were visible in patients with prostate cancer at 7T using only an external transmit/receive body array coil.
Key Points
•
Satisfactory to good T2-weighted image quality of the prostate is achievable at 7T.
•
Periprostatic lipids appear hypo-intense compared to healthy peripheral zone tissue at 7T.
•
Prostate cancer is visible on T2-weighted MRI at 7T.
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