Summary Background Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in ...patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years. Methods Patients with clinically resectable, locally advanced cancer of the oesophagus or oesophagogastric junction (clinical stage T1N1M0 or T2–3N0–1M0, according to the TNM cancer staging system, sixth edition) were randomly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin AUC 2 mg/mL per min and intravenous paclitaxel 50 mg/m2 of body-surface area for 23 days) with concurrent radiotherapy (41·4 Gy, given in 23 fractions of 1·8 Gy on 5 days per week) followed by surgery, or surgery alone. The primary endpoint was overall survival, analysed by intention-to-treat. No adverse event data were collected beyond those noted in the initial report of the trial. This trial is registered with the Netherlands Trial Register, number NTR487, and has been completed. Findings Between March 30, 2004, and Dec 2, 2008, 368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled into this study and randomly assigned to the two treatment groups: 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone. Two patients in the neoadjuvant chemoradiotherapy group withdrew consent, so a total of 366 patients were analysed (178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group). Of 171 patients who received any neoadjuvant chemoradiotherapy in this group, 162 (95%) were able to complete the entire neoadjuvant chemoradiotherapy regimen. After a median follow-up for surviving patients of 84·1 months (range 61·1–116·8, IQR 70·7–96·6), median overall survival was 48·6 months (95% CI 32·1–65·1) in the neoadjuvant chemoradiotherapy plus surgery group and 24·0 months (14·2–33·7) in the surgery alone group (HR 0·68 95% CI 0·53–0·88; log-rank p=0·003). Median overall survival for patients with squamous cell carcinomas was 81·6 months (95% CI 47·2–116·0) in the neoadjuvant chemoradiotherapy plus surgery group and 21·1 months (15·4–26·7) in the surgery alone group (HR 0·48 95% CI 0·28–0·83; log-rank p=0·008); for patients with adenocarcinomas, it was 43·2 months (24·9–61·4) in the neoadjuvant chemoradiotherapy plus surgery group and 27·1 months (13·0–41·2) in the surgery alone group (HR 0·73 95% CI 0·55–0·98; log-rank p=0·038). Interpretation Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery in patients with resectable oesophageal or oesophagogastric junctional cancer. This improvement is clinically relevant for both squamous cell carcinoma and adenocarcinoma subtypes. Therefore, neoadjuvant chemoradiotherapy according to the CROSS trial followed by surgical resection should be regarded as a standard of care for patients with resectable locally advanced oesophageal or oesophagogastric junctional cancer. Funding Dutch Cancer Foundation (KWF Kankerbestrijding).
Groundwater constitutes a major source of fresh water globally. However, it faces serious quality challenges from both conventional pollutants and contaminants of emerging concern (CECs) such as ...pharmaceutically active compounds (PhACs), personal care products (PCPs) and pesticides. There exists a significant knowledge gap regarding the occurrence of CECs in groundwater, especially in Africa. This study presents unique data on the concentration of fourteen PhACs, five PCPs and nine pesticides in groundwater wells in Nzoia River basin, Kenya. Generally, PCPs were the most dominant class with concentrations up to 10 μg/L (methylparaben). Anti(retro)virals, being important in the treatment of HIV/AIDS, were more prevalent among the PhACs as compared to the developed world, with concentrations up to 700 ng/L (nevirapine). In contrast, pesticides were measured at lower concentrations, the maximum being 42 ng/L (metolachlor). A basic risk assessment shows that – among the detected CECs – carbamazepine may pose medium human health risk and requires further investigation among infants and children. Point-of-use (POU) technologies are being increasingly promoted especially in the developing nations to provide drinking water solutions at the household level, but very little data is available on their performance towards CECs removal. Therefore, besides measuring CECs in groundwater, we investigated ceramic filters and solar disinfection (SODIS) as possible POU treatment options. Both techniques show potential to treat CECs in groundwater, with removal efficiencies higher than 90% obtained for 41 and 22 compounds in ceramic filters and SODIS, respectively. Moreover, for the more recalcitrant compounds (e.g. sulfadoxin), the performance is improved by up to three orders of magnitude when using TiO2 as a photocatalyst in SODIS.
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•Drinking water shallow wells polluted with contaminants of emerging concern (CECs).•28 CECs measured in Kenyan groundwater, with paraben concentrations up 10 μg/L.•Paracetamol, antibiotics and anti(retro)virals much more abundant than pesticides.•Indications for human risk (HQ > 0.1) because of exposure to pharmaceutical residues.•Promising CECs removal by easy to use and low cost point-of-use (POU) techniques.
Background: Integration of information from multiple sensory sources is an important prerequisite for successful social behavior, especially during face‐to‐face conversation. It has been suggested ...that communicative impairments among individuals with pervasive developmental disorders (PDD) might be caused by an inability to integrate synchronously presented visual and auditory cues.
Method: We investigated audiovisual integration of speech stimuli among a group of high‐functioning adult PDD individuals and age‐ and IQ‐matched controls using electroencephalography, measuring both early pre‐phonological, as well as late phonologically driven integration.
Results: Pre‐phonological AV interactions are intact, while AV interactions corresponding to more complex phonological processes are impaired in individuals with PDD.
Conclusions: The present findings argue for a pattern of impairments on tasks related to complex audiovisual integration combined with relative sparing of low‐level integrational abilities. This combination may very well contribute to the communicative disabilities which are typical for the disorder.
Background
Apolipoprotein‐I (ApoA‐I), the major component of high‐density lipoprotein (HDL) particles, mediates cholesterol efflux by which it facilitates the removal of excess cholesterol from ...peripheral tissues. Therefore, elevating ApoA‐I production leading to the production of new pre‐β‐HDL particles is thought to be beneficial in the prevention of cardiovascular diseases. Recently, we observed that amoxicillin treatment led to decreased HDL concentrations in healthy human volunteers. We questioned whether this antibiotic effect was directly or indirectly, via changed short‐chain fatty acids (SCFA) concentrations through an altered gut microflora. Therefore, we here evaluated the effects of amoxicillin and various SCFA on hepatic ApoA‐I expression, secretion, and the putative underlying pathways.
Methods and Results
Human hepatocytes (HepG2) were exposed to increasing dose of amoxicillin or SCFA for 48 hours. ApoA‐I messenger RNA (mRNA) transcription and secreted protein were analyzed using quantitative polymerase chain reaction and enzyme‐linked immunosorbent assay, respectively. To study underlying mechanisms, changes in mRNA expression of KEAP1, CPT1, and PPARα, as well as a PPARα transactivation assay, were analyzed. Amoxicillin dose‐dependently decreased ApoA‐I mRNA transcription as well as ApoA‐I protein secretion. SCFA treatment resulted in a dose‐dependent stimulation of ApoA‐I mRNA transcription, however, the ApoA‐I protein secretion was decreased. Furthermore, SCFA treatment increased PPARα transactivation, PPARα and CPT1 mRNA transcription, whereas KEAP1 mRNA transcription was decreased.
Conclusion
Direct treatment of HepG2 cells with amoxicillin has either direct effects on lowering ApoA‐I transcription and secretion or indirect effects via modified SCFA concentrations because SCFA were found to stimulate hepatic ApoA‐I expression. Furthermore, BET inhibition and PPARα activation were identified as possible mechanisms behind the observed effects on ApoA‐I transcription.
The effects of short‐chain fatty acids on the transcription and secretion of apolipoprotein A‐I in human hepatocytes in vitro.
Although there is increased global environmental concern about emerging organic micropollutants (EOMPs) such as pharmaceuticals, personal care products (PPCPs) and polar pesticides, limited ...information is available on their occurrence in Africa. This study presents unique data on concentrations and loads of 31 PPCPs and 10 pesticides in four wastewater stabilization ponds (WSPs) and receiving rivers (flowing through urban centres) in Kenya. The WSPs indicate a high potential to remove pharmaceutically active compounds (PhACs) with removals by up to >4 orders of magnitude (>99.99% removal), mainly occurring at the facultative stage. However, there are large differences in removal among the different classes, and a shift in the relative PhACs occurrence is observed during wastewater treatment. Whereas the influent is dominated by high-consumption PhACs like anti-inflammatory drugs (e.g. paracetamol and ibuprofen, up to 1000 μg L−1), the most recalcitrant PhACs including mainly antibiotics (e.g. sulfadoxin and sulfamethoxazole) and antiretrovirals (e.g. lamivudine and nevirapine) are largely abundant (up to 100 μg L−1) in treated effluent.
Overall, concentrations of EOMPs in the Nzoia Basin rivers are the highest in dry season (except pesticides) and in small tributaries. They are of the same order of magnitude as those measured in the western world, but clearly lower than what we recently measured in the Ngong River, Nairobi region. Based on the specific consumption patterns and recalcitrant behavior, high concentrations (>1000 ng L−1) are observed in the rivers for PPCPs like lamivudine, zidovudine, sulfamethoxazole and methylparaben. Concentration levels of pesticides are in general one order of magnitude lower (<250 ng L−1). Our data suggest a continuous input of EOMPs to the rivers from both point (WSPs) and diffuse (urban centres) sources. To better understand and manage the impact of both sources, EOMP removal mechanisms in WSPs and their attenuation in rivers merit further research.
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•More than 90% removal for most PhACs in wastewater stabilization ponds.•Antiretrovirals and antibiotics most prevalent (up to 100 μg L−1) in effluent water.•First data on PCPs in Kenyan rivers, showing paraben concentrations up to 1 μg L−1.•Pesticides in river water, although much lower concentrations than PhACs.•Smaller tributaries more vulnerable to PPCPs & pesticides than the main River Nzoia.
Abstract Objective To make scientifically sound and practical recommendations for daily sleep duration across the life span. Methods The National Sleep Foundation convened a multidisciplinary expert ...panel (“Panel”) with broad representation from leading stakeholder organizations. The Panel evaluated the latest scientific evidence and participated in a formal consensus and voting process. Then, the RAND/UCLA Appropriateness Method was used to formulate sleep duration recommendations. Results The Panel made sleep duration recommendations for 9 age groups. Sleep duration ranges, expressed as hours of sleep per day, were designated as recommended, may be appropriate , or not recommended . Recommended sleep durations are as follows: 14-17 hours for newborns, 12-15 hours for infants, 11-14 hours for toddlers, 10-13 hours for preschoolers, 9-11 hours for school-aged children, and 8-10 hours for teenagers. Seven to 9 hours is recommended for young adults and adults, and 7-8 hours of sleep is recommended for older adults. The self-designated basis for duration selection and critical discussions are also provided. Conclusions Consensus for sleep duration recommendations was reached for specific age groupings. Consensus using a multidisciplinary expert Panel lends robust credibility to the results. Finally, limitations and caveats of these recommendations are discussed.
Abstract Objective The objective was to conduct a scientifically rigorous update to the National Sleep Foundation’s sleep duration recommendations. Methods The National Sleep Foundation convened an ...18-member multidisciplinary expert panel, representing 12 stakeholder organizations, to evaluate scientific literature concerning sleep duration recommendations. We determined expert recommendations for sufficient sleep durations across the lifespan using the RAND/UCLA Appropriateness Method. Results The panel agreed that, for healthy individuals with normal sleep, the appropriate sleep duration for newborns is between 14 and 17 hours, infants between 12 and 15 hours, toddlers between 11 and 14 hours, preschoolers between 10 and 13 hours, and school-aged children between 9 and 11 hours. For teenagers, 8 to 10 hours was considered appropriate, 7 to 9 hours for young adults and adults, and 7 to 8 hours of sleep for older adults. Conclusions Sufficient sleep duration requirements vary across the lifespan and from person to person. The recommendations reported here represent guidelines for healthy individuals and those not suffering from a sleep disorder. Sleep durations outside the recommended range may be appropriate, but deviating far from the normal range is rare. Individuals who habitually sleep outside the normal range may be exhibiting signs or symptoms of serious health problems or, if done volitionally, may be compromising their health and well-being.
We aimed to determine the prevalence of pulmonary TB amongst the adult population (≥15 years) in 2016 in Kenya.
A nationwide cross-sectional survey where participants first underwent TB symptom ...screening and chest x-ray. Subsequently, participants who reported cough >2weeks and/or had a chest x-ray suggestive of TB, submitted sputum specimen for laboratory examination by smear microscopy, culture and Xpert MTB/RIF.
The survey identified 305 prevalent TB cases translating to a prevalence of 558 95%CI 455-662 per 100,000 adult population. The highest disease burden was reported among people aged 25-34 years (716 95% CI 526-906), males (809 (95% CI 656-962) and those who live in urban areas (760 95% CI 539-981). Compared to the reported TB notification rate for Kenya in 2016, the prevalence to notification ratio was 2.5:1. The gap between the survey prevalence and notification rates was highest among males, age groups 25-34, and the older age group of 65 years and above. Only 48% of the of the survey prevalent cases reported cough >2weeks. In addition, only 59% of the identified cases had the four cardinal symptoms for TB (cough ≥2 weeks, fever, night sweat and weight loss. However, 88.2% had an abnormal chest x-ray suggestive of TB. The use of Xpert MTB/RIF identified 77.7% of the cases compared to smear microscopy's 46%. Twenty-one percent of the survey participants with respiratory symptoms reported to have sought prior health care at private clinics and chemists. Among the survey prevalent cases who reported TB related symptoms, 64.9% had not sought any health care prior to the survey.
This survey established that TB prevalence in Kenya is higher than had been estimated, and about half of the those who fall ill with the disease each year are missed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Phylogeny of Echinoderm Hemoglobins Christensen, Ana B; Herman, Joseph L; Elphick, Maurice R ...
PloS one,
08/2015, Letnik:
10, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Recent genomic information has revealed that neuroglobin and cytoglobin are the two principal lineages of vertebrate hemoglobins, with the latter encompassing the familiar myoglobin and ...α-globin/β-globin tetramer hemoglobin, and several minor groups. In contrast, very little is known about hemoglobins in echinoderms, a phylum of exclusively marine organisms closely related to vertebrates, beyond the presence of coelomic hemoglobins in sea cucumbers and brittle stars. We identified about 50 hemoglobins in sea urchin, starfish and sea cucumber genomes and transcriptomes, and used Bayesian inference to carry out a molecular phylogenetic analysis of their relationship to vertebrate sequences, specifically, to assess the hypothesis that the neuroglobin and cytoglobin lineages are also present in echinoderms.
The genome of the sea urchin Strongylocentrotus purpuratus encodes several hemoglobins, including a unique chimeric 14-domain globin, 2 androglobin isoforms and a unique single androglobin domain protein. Other strongylocentrotid genomes appear to have similar repertoires of globin genes. We carried out molecular phylogenetic analyses of 52 hemoglobins identified in sea urchin, brittle star and sea cucumber genomes and transcriptomes, using different multiple sequence alignment methods coupled with Bayesian and maximum likelihood approaches. The results demonstrate that there are two major globin lineages in echinoderms, which are related to the vertebrate neuroglobin and cytoglobin lineages. Furthermore, the brittle star and sea cucumber coelomic hemoglobins appear to have evolved independently from the cytoglobin lineage, similar to the evolution of erythroid oxygen binding globins in cyclostomes and vertebrates.
The presence of echinoderm globins related to the vertebrate neuroglobin and cytoglobin lineages suggests that the split between neuroglobins and cytoglobins occurred in the deuterostome ancestor shared by echinoderms and vertebrates.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The phagocytes of the innate immune system, macrophages and neutrophils, contribute to antibacterial defense, but their functional specialization and cooperation is unclear. Here, we report that ...three distinct phagocyte subsets play highly coordinated roles in bacterial urinary tract infection. Ly6C− macrophages acted as tissue-resident sentinels that attracted circulating neutrophils and Ly6C+ macrophages. Such Ly6C+ macrophages played a previously undescribed helper role: once recruited to the site of infection, they produced the cytokine TNF, which caused Ly6C− macrophages to secrete CXCL2. This chemokine activated matrix metalloproteinase-9 in neutrophils, allowing their entry into the uroepithelium to combat the bacteria. In summary, the sentinel macrophages elicit the powerful antibacterial functions of neutrophils only after confirmation by the helper macrophages, reminiscent of the licensing role of helper T cells in antiviral adaptive immunity. These findings identify helper macrophages and TNF as critical regulators in innate immunity against bacterial infections in epithelia.
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•Neutrophils, Ly6C− and Ly6C+ macrophages perform distinct antibacterial functions•Ly6C+ macrophages act as innate immune helper cells in antibacterial defense•TNF is the innate helper factor; it permits neutrophil migration into epithelium•Distinct CXCR2 ligands mediate endothelial and epithelial neutrophil migration
In urinary tract infection, neutrophils are recruited from the blood to the infected organ by tissue-resident sentinel macrophages but are only directed to the frontline, the uroepithelium, after receiving a confirmation signal from recruited helper macrophages
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