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To examine the association of symptoms with vitamin D deficiency and symptom response to cholecalciferol treatment in a randomized, double-blind, placebo-controlled trial. Adult primary care patients in Duluth, Minnesota, were screened for vitamin D deficiency in February 2007. Participants completed questionnaires pertaining to a variety of symptoms, vitamin D intake, and selected medical conditions. Patients with mild to moderate vitamin D deficiency (25-hydroxyvitamin D [25(OH)D], 10-25 ng/mL) participated in a randomized controlled trial (RCT) of vitamin D replacement and its effect on symptoms. Participants were randomly assigned to receive 50 000 units of cholecalciferol (vitamin D3) weekly or placebo for 8 weeks. Patients with severe vitamin D deficiency (25[OH]D <10 ng/mL) were treated in an unblinded fashion, and symptoms were reevaluated post treatment. A total of 610 patients underwent initial screening, and 100 patients with mild to moderate vitamin D deficiency participated in the RCT. Thirty-eight severely deficient patients were treated in an unblinded fashion. On initial screening, 46.2% of participants were deficient in vitamin D. Self-reported vitamin D supplementation, milk intake, celiac disease, gastric bypass, and chronic pancreatitis were predictive of vitamin D status. Severely deficient participants reported increased musculoskeletal symptoms, depression (including seasonal), and higher (worse) scores on a fibromyalgia assessment questionnaire. In the RCT, the treated group showed significant improvement in fibromyalgia assessment scores (P = 0.03), whereas the placebo-treated participants did not. Severely deficient patients did not show symptom improvement over the 8-week trial period or when followed up 1 year later. Compared with participants in the placebo group, patients in the treatment group showed mild short-term improvement in the overall fibromyalgia impact score, but did not show significant improvement in most musculoskeletal symptoms or in activities of daily living.

Polygenic risk scores (PRS) for prostate cancer incidence have been proposed to optimize prostate cancer screening. Prediction of lethal prostate cancer is key to any stratified screening program to avoid excessive overdiagnosis. Herein, PRS for incident prostate cancer was evaluated in two population-based cohorts of unscreened middle-aged men linked to cancer and death registries: the Västerbotten Intervention Project (VIP) and the Malmö Diet and Cancer study (MDC). SNP genotypes were measured by genome-wide SNP genotyping by array followed by imputation or genotyping of selected SNPs using mass spectrometry. The ability of PRS to predict lethal prostate cancer was compared to PSA and a commercialized pre-specified model based on four kallikrein markers. The PRS was associated with incident prostate cancer, replicating previously reported relative risks, and was also associated with prostate cancer death. However, unlike PSA, the PRS did not show stronger association with lethal disease: the hazard ratio for prostate cancer incidence vs. prostate cancer metastasis and death was 1.69 vs. 1.65 in VIP and 1.25 vs. 1.25 in MDC. PSA was a much stronger predictor of prostate cancer metastasis or death with an area-under-the-curve of 0.78 versus 0.63 for the PRS. Importantly, addition of PRS to PSA did not contribute additional risk stratification for lethal prostate cancer. We have shown that a PRS that predicts prostate cancer incidence does not have utility above and beyond that of PSA measured at baseline when applied to the clinically relevant endpoint of prostate cancer death. These findings have implications for public health policies for delivery of prostate cancer screening. Focusing polygenic risk scores on clinically significant endpoints such as prostate cancer metastasis or death would likely improve clinical utility.

Background Burn injury is associated with a long-standing inflammatory reaction. The use of albumin solutions for plasma volume support is controversial because of concerns of increased capillary leakage, which could aggravate the commonly seen interstitial oedema. Methods In the present open controlled clinical trial, an intravenous infusion of 20% albumin at 3 mL/kg was given over 30 min to 15 burn patients and 15 healthy volunteers. Blood samples and urine were collected for 5 h. Plasma dilution, plasma albumin and colloid osmotic pressure were compared. Mass balance calculations were used to estimate plasma volume expansion and capillary leakage of fluid and albumin. Results The patients were studied between 4 and 14 (median, 7) days after the burn injury, which spread over 7–48% (median, 15%) of the total body surface area. The albumin solution expanded the plasma volume by almost 15%, equivalent to twice the infused volume, in both groups. The urinary excretion exceeded the infused volume by a factor of 2.5. Capillary leakage of albumin occurred at a rate of 3.4 ± 1.5 g/h in burn patients and 3.7 ± 1.6 g/h in the volunteers ( P  = 0.61), which corresponded to 2.4 ± 1.0% and 2.5 ± 1.2% per hour of the intravascular pool ( P  = 0.85). The median half-life of the plasma volume expansion was 5.9 (25th–75th percentiles 2.7–11.7) h in the burn patients and 6.9 (3.4–8.5) h in the volunteers ( P  = 0.56). Conclusions Albumin 20% was an effective volume expander in patients at 1 week post-burn. No relevant differences were found between burn patients and healthy volunteers. Trial registration EudraCT 2016-000996-26 on May 31, 2016.

Intratumoral heterogeneity is a characteristic of glioblastomas that contain an intermixture of cell populations displaying different glioblastoma subtype gene expression signatures. Proportions of these populations change during tumor evolution, but the occurrence and regulation of glioblastoma subtype transition is not well described. To identify regulators of glioblastoma subtypes we utilized a combination of in vitro experiments and in silico analyses, using experimentally generated as well as publicly available data. Through this combined approach SOX2 was identified to confer a proneural glioblastoma subtype gene expression signature. SFRP2 was subsequently identified as a SOX2- antagonist, able to induce a mesenchymal glioblastoma subtype signature. A subset of patient glioblastoma samples with high SFRP2 and low SOX2 expression was particularly enriched with mesenchymal subtype samples. Phenotypically, SFRP2 decreased tumor sphere formation, stemness as assessed by limiting dilution assay, and overall cell proliferation but increased cell motility, whereas SOX2 induced the opposite effects. Furthermore, an SFRP2/non-canonical-WNT/KLF4/PDGFR/phospho-AKT/SOX2 signaling axis was found to be involved in the mesenchymal transition. Analysis of human tumor tissue spatial gene expression patterns showed distinct expression of SFRP2 - and S OX2- correlated genes in vascular and cellular areas, respectively. Finally, conditioned media from SFRP2 overexpressing cells increased CD206 on macrophages. Together, these findings present SFRP2 as a SOX2-antagonist with the capacity to induce a mesenchymal subtype transition in glioma cells located in vascular tumor areas, highlighting its role in glioblastoma tumor evolution and intratumoral heterogeneity.

Migration allows animals to exploit spatially separated and seasonally available resources at a continental to global scale. However, responding to global climatic changes might prove challenging, especially for long-distance intercontinental migrants. During glacial periods, when conditions became too harsh for breeding in the north, avian migrants have been hypothesized to retract their distribution to reside within small refugial areas. Here, we present data showing that an Afro-Palearctic migrant continued seasonal migration, largely within Africa, during previous glacial–interglacial cycles with no obvious impact on population size. Using individual migratory track data to hindcast monthly bioclimatic habitat availability maps through the last 120,000 y, we show altered seasonal use of suitable areas through time. Independently derived effective population sizes indicate a growing population through the last 40,000 y. We conclude that the migratory lifestyle enabled adaptation to shifting climate conditions. This indicates that populations of resource-tracking, long-distance migratory species could expand successfully during warming periods in the past, which could also be the case under future climate scenarios.

The numerical modeling of Zn speciation amongst the environmental inorganic ligands Cl , OH , CO , SO , and PO requires reliable values for the relevant stability (formation) constants. This paper compiles and provides a critical review of these constants and related thermodynamic data. It recommends values of log ° valid at = 0 mol·kg and 25 °C (298.15 K), and reports the empirical reaction ion interaction coefficients, ∆ , required to calculate log values at higher ionic strengths using the Brønsted-Guggenheim-Scatchard specific ion interaction theory (SIT). Values for the corresponding reaction enthalpies, ∆ , are reported where available. There is scope for additional high-quality measurements for the Zn + H + CO system and for the Zn + OH and Zn + SO systems at > 0. In acidic and weakly alkaline fresh water systems (pH < 8), in the absence of organic ligands (e.g., humic substances), Zn speciation is dominated by Zn (aq). In this respect, Zn contrasts with Cu and Pb (the subjects of earlier reviews in this series) for which carbonato- and hydroxido- complex formation become important at pH > 7. The speciation of Zn is dominated by ZnCO (aq) only at pH > 8.4. In seawater systems, the speciation at pH = 8.2 is dominated by Zn (aq) with ZnCl , Zn(Cl) (aq), ZnCO (aq), and ZnSO (aq) as minor species. This behaviour contrasts with that for Cu and Pb for which at the pH of seawater in equilibrium with the atmosphere at 25 °C (log {[H ]/ °} ≈ 8.2) the MCO (aq) complex dominates over the MCl species. The lower stability of the different complexes of Zn compared with those of Cu , Pb , and Cd is also illustrated by the percentage of uncomplexed M in seawater, which is ca. 55, 3, 2, and 3.3 % of [M , respectively.

Purpose Carotid near-occlusion is a tight atherosclerotic stenosis of the internal carotid artery (ICA) resulting in decrease in diameter of the vessel lumen distal to the stenosis. Near-occlusions can be classified as with or without full collapse, and may have high peak systolic velocity (PSV) across the stenosis, mimicking conventional > 50% carotid artery stenosis. We aimed to determine how frequently near-occlusions have high PSV in the stenosis and determine how accurately carotid Doppler ultrasound can distinguish high-velocity near-occlusion from conventional stenosis. Methods Included patients had near-occlusion or conventional stenosis with carotid ultrasound and CT angiogram (CTA) performed within 30 days of each other. CTA examinations were analyzed by two blinded expert readers. Velocities in the internal and common carotid arteries were recorded. Mean velocity, pulsatility index, and ratios were calculated, giving 12 Doppler parameters for analysis. Results Of 136 patients, 82 had conventional stenosis and 54 had near-occlusion on CTA. Of near-occlusions, 40 (74%) had high PSV (≥ 125 cm/s) across the stenosis. Ten Doppler parameters significantly differed between conventional stenosis and high-velocity near-occlusion groups. However, no parameter was highly sensitive and specific to separate the groups. Conclusion Near-occlusions frequently have high PSV across the stenosis, particularly those without full collapse. Carotid Doppler ultrasound does not seem able to distinguish conventional stenosis from high-velocity near-occlusion. These findings question the use of ultrasound alone for preoperative imaging evaluation.

The ability to slow or reverse biological ageing would have major implications for mitigating disease risk and maintaining vitality 1 . Although an increasing number of interventions show promise for rejuvenation 2 , their effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. Adipose mesenchymal stromal cells, haematopoietic stem cells and hepatocytes are among those cell types that are especially responsive. On the pathway level, young blood invokes new gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. We observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it in select cell types. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity. A transcriptomics study demonstrates cell-type-specific responses to differentially aged blood and shows young blood to have restorative and rejuvenating effects that may be invoked through enhanced mitochondrial function.

Ageing is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death 1 . Despite rapid advances over recent years, many of the molecular and cellular processes that underlie the progressive loss of healthy physiology are poorly understood 2 . To gain a better insight into these processes, here we generate a single-cell transcriptomic atlas across the lifespan of Mus musculus that includes data from 23 tissues and organs. We found cell-specific changes occurring across multiple cell types and organs, as well as age-related changes in the cellular composition of different organs. Using single-cell transcriptomic data, we assessed cell-type-specific manifestations of different hallmarks of ageing—such as senescence 3 , genomic instability 4 and changes in the immune system 2 . This transcriptomic atlas—which we denote Tabula Muris Senis , or ‘Mouse Ageing Cell Atlas’—provides molecular information about how the most important hallmarks of ageing are reflected in a broad range of tissues and cell types. A single-cell transcriptomic atlas across the lifespan of the mouse, denoted Tabula Muris Senis , provides molecular information about the hallmarks of ageing in a range of tissues and cell types.