Background: Association studies have suggested that lower circulating 25-hydroxyvitamin D 25(OH)D in African Americans may partially underlie higher rates of cardiovascular disease and cancer in this ...population. Nonetheless, the relation between vitamin D supplementation and 25(OH)D concentrations in African Americans remains undefined.Objective: Our primary objective was to determine the dose-response relation between vitamin D and plasma 25(OH)D.Design: A total of 328 African Americans in Boston, MA, were enrolled over 3 winters from 2007 to 2010 and randomly assigned to receive a placebo or 1000, 2000, or 4000 IU vitamin D3/d for 3 mo. Subjects completed sociodemographic and dietary questionnaires, and plasma samples were drawn at baseline and 3 and 6 mo.Results: Median plasma 25(OH)D concentrations at baseline were 15.1, 16.2, 13.9, and 15.7 ng/mL for subjects randomly assigned to receive the placebo or 1000, 2000, or 4000 IU/d, respectively (P = 0.63). The median plasma 25(OH)D concentration at 3 mo differed significantly between supplementation arms at 13.7, 29.7, 34.8, and 45.9 ng/mL, respectively (P < 0.001). An estimated 1640 IU vitamin D3/d was needed to raise the plasma 25(OH)D concentration to ≥20 ng/mL in ≥97.5% of participants, whereas a dose of 4000 IU/d was needed to achieve concentrations ≥33 ng/mL in ≥80% of subjects. No significant hypercalcemia was seen in a subset of participants.Conclusions: Within African Americans, an estimated 1640 IU vitamin D3/d was required to achieve concentrations of plasma 25(OH)D recommended by the Institute of Medicine, whereas 4000 IU/d was needed to reach concentrations predicted to reduce cancer and cardiovascular disease risk in prospective observational studies. These results may be helpful for informing future trials of disease prevention. This trial was registered at clinicaltrials.gov as NCT00585637.
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We present protease specificity profiling based on quantitative proteomics in combination with proteome-derived peptide libraries. Peptide libraries are generated by endoproteolytic digestion of ...proteomes without chemical modification of primary amines before exposure to a protease under investigation. After incubation with a test protease, treated and control libraries are differentially isotope-labeled using cost-effective reductive dimethylation. Upon analysis by liquid chromatography–tandem mass spectrometry, cleavage products of the test protease appear as semi-specific peptides that are enriched for the corresponding isotope label. We validate our workflow with two proteases with well-characterized specificity profiles: trypsin and caspase-3. We provide the first specificity profile of a protease encoded by a human endogenous retrovirus and for chlamydial protease-like activity factor (CPAF). For CPAF, we also highlight the structural basis of negative subsite cooperativity between subsites S1 and S2′. For A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) -4, -5, and -15, we show a canonical preference profile, including glutamate in P1 and glycine in P3′. In total, we report nearly 4000 cleavage sites for seven proteases. Our protocol is fast, avoids enrichment or synthesis steps, and enables probing for lysine selectivity as well as subsite cooperativity. Due to its simplicity, we anticipate usability by most proteomic laboratories.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Current cancer chemotherapies are limited by the lack of tumor-specific targets, which would allow for selective eradication of malignant cells without affecting healthy tissues. In contrast to ...normal cells, most tumor cells contain multiple centrosomes, which tend to cause the formation of multipolar mitotic spindles, chromosome segregation defects, and cell death. Nevertheless, many cancer cells divide successfully because they can cluster multiple centrosomes into two spindle poles. Inhibition of this centrosomal clustering, with consequent induction of multipolar spindles and subsequent cell death, would specifically target cancer cells and overcome one limitation of current cancer treatments. We have performed a genome-wide RNA interference screen to identify proteins involved in the prevention of spindle multipolarity in human cancer cells with supernumerary centrosomes. The chromosomal passenger complex, Ndc80 microtubule-kinetochore attachment complex, sister chromatid cohesion, and microtubule formation via the augmin complex were identified as necessary for centrosomal clustering. We show that spindle tension is required to cluster multiple centrosomes into a bipolar spindle array in tumor cells with extra centrosomes. These findings may explain the specificity of drugs that interfere with spindle tension for cancer cells and provide entry points for the development of therapeutics.
The amino-acids tryptophan, phenylalanine and tyrosine seem to play an important role in the pathophysiology of depressive disorders. We measured daily brain extracellular levels of these amino-acids ...using cerebral microdialysis (CMD) and high performance liquid chromatography in 26 consecutive subarachnoid hemorrhage (SAH) patients and associated them with the presence of depressive disorders. Patients were grouped as follows: medical history of depression (prior to SAH), antidepressant intake 12 months after SAH (but not before), or neither. CMD-tryptophan, CMD-phenylalanine and CMD-tyrosine levels were significantly lower in patients with preexisting depressive disorders compared to those without depression (p < 0.01). Disease severity and SAH-related complications were not associated with amino-acid concentrations. We found a positive correlation between nutritionally administered and brain interstitial levels of tryptophan and phenylalanine in non-depressed patients (R = 0.26 and R = 0.24, p < 0.05), which was not present in patients with preexisting depression (p > 0.1). In conclusion, brain interstitial levels of tryptophan, phenylalanine and tyrosine measured in the context of the clinical management of SAH were significantly decreased in patients with a medical history of depression. This study supports the hypothesis that the availability of these neurotransmitter precursor amino-acids in the human brain may play an important role in the pathophysiology of depressive disorders.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The Amazon rain forest plays a major role in global hydrological cycling, and biogenic aerosols are likely to influence the formation of clouds and precipitation. Information about the sources and ...altitude profiles of primary biological aerosol particles, however, is sparse. We used fluorescence in situ hybridization (FISH), a molecular biological staining technique largely unexplored in aerosol research, to investigate the sources and spatiotemporal distribution of Amazonian bioaerosols on the domain level. We found wet season bioaerosol number concentrations in the range of 1–5 × 105 m−3 accounting for > 70 % of the coarse mode aerosol. Eukaryotic and bacterial particles predominated, with fractions of ∼ 56 % and ∼ 26 % of the intact airborne cells. Archaea occurred at very low concentrations. Vertical profiles exhibit a steep decrease in bioaerosol numbers from the understory to 325 m height on the Amazon Tall Tower Observatory (ATTO), with a stronger decrease in Eukarya compared to Bacteria. Considering earlier investigations, our results can be regarded as representative for near-pristine Amazonian wet season conditions. The observed concentrations and profiles provide new insights into the sources and dispersion of different types of Amazonian bioaerosols as a solid basis for model studies on biosphere–atmosphere interactions such as bioprecipitation cycling.
Objective
Percutaneous biliary interventions (PBIs) can be associated with a high patient radiation dose, which can be reduced when national diagnostic reference levels (DRLs) are kept in mind. The ...aim of this multicentre study was to investigate patient radiation exposure in different percutaneous biliary interventions, in order to recommend national DRLs.
Methods
A questionnaire asking for the dose area product (DAP) and the fluoroscopy time (FT) in different PBIs with ultrasound- or fluoroscopy-guided bile duct punctures was sent to 200 advanced care hospitals. Recommended national DRLs are set at the 75th percentile of all DAPs.
Results
Twenty-three facilities (9 interventional radiology depts. and 14 gastroenterology depts.) returned the questionnaire (12%). Five hundred sixty-five PBIs with 19 different interventions were included in the analysis. DAPs (range 4–21,510 cGy·cm
2
) and FTs (range 0.07–180.33 min) varied substantially depending on the centre and type of PBI. The DAPs of initial PBIs were significantly (
p
< 0.0001) higher (median 2162 cGy·cm
2
) than those of follow-up PBIs (median 464 cGy·cm
2
). There was no significant difference between initial PBIs with ultrasound-guided bile duct puncture (2162 cGy·cm
2
) and initial PBIs with fluoroscopy-guided bile duct puncture (2132 cGy·cm
2
) (
p
= 0.85). FT varied substantially (0.07–180.33 min).
Conclusions
DAPs and FTs in percutaneous biliary interventions showed substantial variations depending on the centre and the type of PBI. PBI with US-guided bile duct puncture did not reduce DAP, when compared to PBI with fluoroscopy-guided bile duct puncture. National DRLs of 4300 cGy·cm
2
for initial PBIs and 1400 cGy·cm
2
for follow-up PBIs are recommended.
Key Points
•
DAPs and FTs in percutaneous biliary interventions showed substantial variations depending on the centre and the type of PBI.
•
PBI with US-guided bile duct puncture did not reduce DAP when compared to PBI with fluoroscopy-guided bile duct puncture.
• DRLs of 4300 cGy
·
cm
2
for initial PBIs (establishing a transhepatic tract) and 1400 cGy
·
cm
2
for follow-up PBIs (transhepatic tract already established) are recommended.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Most organic pollutants (POP) are persistent in the environment, accumulate in fatty tissues, and so a transfer through the food chain is probably, thereby causing various health effects. We ...quantified PCDD/F, PBDD/F, PCB, PBDE, perfluorinated substances, and ADONA in breast milk samples collected in two German federal states and breast milk and blood samples from subjects additionally exposed to PFOA.
The median (95th percentile) concentrations were 2.43 (6.58) pgWHO2005TEQ/g l.w. for PCDD/F, 2.45 (4.82) pgWHO2005TEQ/g l.w. for dioxin-like PCB (dl-PCB), and 0.62 (2.69) pgWHO2005TEQ/g l.w. for PBDD/F. The relative contributions of the median values of PCDD/F, dl-PCB, and PBDD/F to the total-TEQ were approximately 41%, 42%, and 11%, respectively. Nondioxin-like PCB (ndl-PCB) concentrations were clearly dominated by the higher chlorinated PCB congeners, with medians of 23.2 ng/g l.w. for PCB 153, 13.9 ng/g l.w. for PCB 138, and 13.0 ng/g l.w. for PCB 180. The sum of the 3 congeners (PCB 138, 153, and 180) were multiplied with 1.64 (total PCB) and showed a median of 82.16 ng/g l.w. and a 95th percentile of 173.3 ng/g l.w.
Only PFOA and PFOS could be quantified in 29% and 17% of in total 180 samples with 95th percentiles of 53 ng/l and 33 ng/l, respectively. Milk samples (n = 13) from subjects living on PFOA contaminated sites showed higher levels between 33 and 854 ng/l PFOA (mean: 199 ng/l), whilst PFOS could be quantified only in three samples.
The sum of 17 PBDE congeners showed medians (95th percentile) of 1737 pg/g l.w. (22,806 pg/g l.w.), with the highest medians of 422 pg/g l.w. for BDE 209 and 378 pg/g l.w. for BDE 153.
Overall, our study confirms the declining contamination level in breast milk during the last decade, but points out the need to further reduce the environmental contamination with persistent substances and subsequently the exposure in childhood.
Display omitted
•We analyzed persistent substances in German breast milk samples.•Targets are PCDDs/Fs, PBDDs/Fs, PCBs, PBDE, and PFAS.•Concentration of the target compounds further declined.•Exposure of many substances partly exceed tolerable intake values.•A consistent reduction of environmental contamination is still needed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background:
Tumor therapeutics are aimed to affect tumor cells selectively while sparing healthy ones. For this purpose, a huge variety of different drugs are in use. Recently, also blockers of ...voltage-gated sodium channels (VGSCs) have been recognized to possess potentially beneficial effects in tumor therapy. As these channels are a frequent target of numerous drugs, we hypothesized that currently used tumor therapeutics might have the potential to block VGSCs in addition to their classical anti-cancer activity. In the present work, we have analyzed the imipridone TIC10, which belongs to a novel class of anti-cancer compounds, for its potency to interact with VGSCs.
Methods:
Electrophysiological experiments were performed by means of the patch-clamp technique using heterologously expressed human heart muscle sodium channels (hNav1.5), which are among the most common subtypes of VGSCs occurring in tumor cells.
Results:
TIC10 angular inhibited the hNa
v
1.5 channel in a state- but not use-dependent manner. The affinity for the resting state was weak with an extrapolated K
r
of about 600 μM. TIC10 most probably did not interact with fast inactivation. In protocols for slow inactivation, a half-maximal inhibition occurred around 2 µM. This observation was confirmed by kinetic studies indicating that the interaction occurred with a slow time constant. Furthermore, TIC10 also interacted with the open channel with an affinity of approximately 4 µM. The binding site for local anesthetics or a closely related site is suggested as a possible target as the affinity for the well-characterized F1760K mutant was reduced more than 20-fold compared to wild type. Among the analyzed derivatives, ONC212 was similarly effective as TIC10 angular, while TIC10 linear more selectively interacted with the different states.
Conclusion:
The inhibition of VGSCs at low micromolar concentrations might add to the anti-tumor properties of TIC10.
In children with hepatocellular carcinoma (pHCC) the 5-year overall survival rate is poor. Effects of cytostatic therapies such as cisplatin and doxorubicin are limited due to chemoresistance and ...tumor relapse. In adult HCC, several antitumor properties are described for the use of curcumin. Curcumin is one of the best-investigated phytochemicals in complementary oncology without relevant side effects. Its use is limited by low bioavailability. Little is known about the influence of curcumin on pediatric epithelial hepatic malignancies. We investigated the effects of curcumin in combination with cisplatin on two pediatric epithelial liver tumor cell lines. As mechanisms of action inhibition of NFkappaB, beta-catenin, and decrease of cyclin D were identified. Using a mouse xenograft model we could show a significant decrease of alpha-fetoprotein after combination therapy of oral micellar curcumin and cisplatin. Significant concentrations of curcuminoids were found in blood samples, organ lysates, and tumor tissue after oral micellar curcumin administration. Micellar curcumin in combination with cisplatin can be a promising strategy for treatment of pediatric HCC.
OBJECTIVE:Antibiotic therapy is a major risk factor for the development of diarrhea and colitis with varying severity. Often the origin of antibiotic-associated gastrointestinal deterioration remains ...elusive and no specific infectious agents could be discerned.
PATIENTS:We represent three cases of intractable high-volume diarrhea associated with combined antibiotic and steroid therapy in critically ill patients not fitting into established disease entities. Cases presented with severe apoptotic enterocolitis resembling acute intestinal graft-versus-host-disease. Microbiologic workup precluded known enteropathogens, but microbiota analysis revealed a severely depleted gut microbiota with concomitant opportunistic pathogen overgrowth.
INTERVENTIONS:Fecal microbiota transplantation, performed in one patient, was associated with correction of dysbiosis, rapid clinical improvement, and healing of enterocolitis.
CONCLUSIONS:Our series represents a severe form of antibiotic-associated colitis in critically ill patients signified by microbiota depletion, and reestablishment of a physiologic gastrointestinal microbiota might be beneficial for this condition.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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